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Page i

Remington

An Introduction to Pharmacy
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Remington
An Introduction to Pharmacy

Edited by Loyd V Allen Jr, PhD, RPh

Professor Emeritus, University of Oklahoma School of Pharmacy
Editor-in-Chief, International Journal of Pharmaceutical Compounding
Edmond, OK, USA
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Published by Pharmaceutical Press

1 Lambeth High Street, London SE1 7JN, UK
© 2013 Royal Pharmaceutical Society of Great Britain 2012

is a trade mark of Pharmaceutical Press

Pharmaceutical Press is the publishing division of the Royal Pharmaceutical Society
Typeset by Laserwords Private Limited, Chennai, India
Printed in Ann Arbor, Michigan, USA by Edwards Brothers Malloy
ISBN 978 0 85711 104 3
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form
or by any means, without the prior written permission of the copyright holder.
The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this
book and cannot accept any legal responsibility or liability for any errors or omissions that may be made.
A catalogue record for this book is available from the British Library
This book is adapted from contributions published in Remington: The Science and Practice of Pharmacy 22nd edition.
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Contents

Preface xi
Acknowledgments xiii
About the editor xv
Contributors xvii

1 Scope of pharmacy 1
Education 2
Licensure requirements 2
Careers 2
Postgraduate training 8
Graduate education 8
Organizations 8
References 9
2 Evolution of pharmacy 11
The drug-taking animal 11
Prehistoric pharmacy 12
Antiquity 12
The Middle Ages 14
The Renaissance and early modern Europe 15
American pharmacy 18
Antebellum America: pharmacy finds its niche 20
The search for professionalism 21
Legislation 21
Transition to a modern profession 22
The era of count and pour 24
The emergence of clinical pharmacy 25
The conflicting paradigms of pharmaceutical care and managed care 25
The promise of a new century 26
The future 26
History as a discipline 26
A chronology for pharmacists 27
References 30
3 The new drug approval process and clinical trial design 31
The Food and Drug Administration 31
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vi | Contents

Overview of the US drug approval process 32

Post-approval activities 39
Clinical trial planning and design 40
Summary 49
References 49
4 Information resources in pharmacy and the pharmaceutical sciences 51
Introduction 51
Locating appropriate types of information resources 51
Acknowledgments 61
References 61
5 Pharmaceutical Chemistry 65
Inorganic pharmaceutical chemistry 65
Organic pharmaceutical chemistry 79
Structural determinants of drug action 92
Natural products 96
Structure–activity relationships and drug design 106
Pharmaceutical profiling 115
Conclusions and perspectives 121
Prodrugs 122
Fundamentals of medical radionuclides 124
Drug nomenclature 131
History 133
References 138
6 Pharmaceutical analysis and quality control 143
Analysis of medicinals 143
Biological testing 146
Clinical analysis 148
Quality assurance and control 149
Stability of pharmaceutical products 151
Bioavailability and bioequivalence testing 166
Chromatographic methods of analysis 169
Spectroscopic methods of analysis 172
Mass spectroscopic methods of analysis 175
Dissolution 177
Appendix A: Example specifications 180
Appendix B: 21 CFR food and drugs 182
References 185
7 Pharmaceutics 189
Modern-Day drug discovery and development 189
Metrology and pharmaceutical calculations 190
Molecular structure, properties and states of matter 196
Thermodynamics 223
Solutions and phase equilibria 229
Separation methods 232
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Contents | vii

Ionic solutions and electrolytic equilibria 233

Tonicity, osmoticity, osmolality and osmolarity 237
Chemical kinetics 245
Drug stabilization 248
Complex formation 250
Interfacial phenomena 251
Colloidal dispersions 251
Coarse dispersions 252
Rheology 257
Appendix A: sodium chloride equivalents, freezing-point depressions, and hemolytic effects of certain
medicinals in aqueous solution 258
Appendix B: isotonic solution values 281
References 282
8 Pharmacokinetics and pharmacodynamics 285
Basic pharmacokinetics and pharmacodynamics 285
Drug action and effect 288
Drug absorption, distribution, metabolism, and excretion 291
Clinical pharmacokinetics and pharmacodynamics 296
Principles of immunology 296
Pharmacogenomics 296
Pharmacokinetics/Pharmacodynamics in drug development 301
References 302
9 Pharmaceutical dosage forms: manufacturing and compounding 305
Powders 305
Solutions, emulsions, suspensions, and extracts 307
Sterilization processes and sterility assurance 314
Parenteral preparations 315
Pharmaceutical compounding: USP <797> sterile preparations 316
Ophthalmic preparations 317
Medicated topicals 324
Oral solid dosage forms 324
Coating of pharmaceutical dosage forms 327
Oral modified-release drug delivery systems 329
Aerosols 330
Biotechnology and drugs 332
Pharmaceutical packaging 337
Pharmaceutical excipients 339
References 340
10 Fundamentals of pharmacy practice 345
Application of ethical principles to practice dilemmas 345
Applied ethics and healthcare 346
Technology and automation 347
Pharmacy informatics 349
Technology and HIPAA 350
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viii | Contents

Emerging technologies 351

Clinical drug literature 351
Roles, responsibilities, and drug information 352
The patient: behavioral determinants 354
Drug education 358
Professional communications 364
The prescription 385
Drug product safety reporting programs 411
Providing a framework for ensuring medication use safety 413
Adverse drug reactions 417
Drug interactions 418
Poison control 423
Medication disposal 424
Surgical supplies 431
Health accessories 431
The entrepreneurial and intrapreneurial pharmacist 433
References 435
11 The scope of pharmacy practice 441
The practice of community pharmacy 441
The practice of health systems pharmacy 446
Pharmacy technicians, medication preparation, and distribution systems 448
Clinical pharmacy services 452
Medication use policy 456
Leadership 460
Contracting and procurement 464
Human resources 467
Information technology and automation 469
Education and training 472
Pharmacy practice in industry: potential roles for pharmacists 474
Pharmacists in government 474
Pharmacists and public health 475
Consultant pharmacy practice 475
Nuclear pharmacy practice 475
Home infusion pharmacy practice 482
Specialty pharmacy 483
Pharmacists in academia 485
Nutrition in pharmacy practice 486
Veterinary pharmacy 487
Extemporaneous prescription compounding 489
References 517
12 Social, behavioral, economic and administrative sciences 523
Laws governing pharmacy 523
Pharmacoeconomics 525
Product recalls and withdrawals, and disposal of unused medicines 528
Marketing pharmacy care services 529
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Contents | ix

Clinical pharmacy services 529

Current billing methods for pharmacists 530
Documentation: The SOAP System 532
Pharmacist credentialing 533
Medical claims and basic billing terminology 534
Claims for pharmacist services 537
Future directions 538
Pharmaceutical risk management 540
Pharmacoepidemiology and pharmacovigilance 542
References 544
13 Patient care 547
Pharmacists and disease state management 547
Development of a pharmacy care plan and patient problem solving 558
Specialization in pharmacy practice 562
Ambulatory care pharmacy practice 575
Self care 576
Diagnostic self-care 579
Complementary and alternative medical healthcare 579
Preventive care 579
Substance abuse care 582
Emergency medicine pharmacy practice 582
Pediatric pharmacy practice 583
Transplant pharmacy practice 585
Pharmacogenomics in pharmacy practice 585
Critical care pharmacy practice 586
Infectious diseases pharmacy practice 586
Pain and palliative care 588
Assessing pharmacy-related quality of care 590
Long-term care 591
Chronic wound care 591
References 592

Index 599
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Preface

There has been a long-time need for a book that divisions in the book; starting in Volume 1 and pro-
introduces the first year pharmacy student to all the gressing through Volume 2. The sections include the
different aspects of pharmacy and one that would (1) Introduction, (2) Pharmaceutical Chemistry, (3)
serve as an introduction to the content of the courses Pharmaceutical Analysis and Quality Control, (4)
involved in the making of a pharmacist. When this Pharmaceutics, (5) Pharmaceutical Dosage Forms;
Editor entered pharmacy school, the purchase of a full Manufacturing and Compounding, and (6) Pharma-
size Remington’s Practice of Pharmacy was manda- cokinetics and Pharmacodynamics. Next, comes (7)
tory. It was not used much the first year of pharmacy Fundamentals of Pharmacy Practice, (8) The Scope of
school but was extensively used later in the cur- Pharmacy Practice, (9) Social, Behavioral, Economic,
riculum. A volume such as this would have been a and Administrative Sciences, and (10) Patient Care.
great addition to the first-year experience in pharmacy This new book contains the information of interest
school. to early pharmacy students; it is extracted from the
Today, Remington: An Introduction to Pharmacy two-volume set. It contains the new chapters along
for the first time provides the student with an easy- with the long-standing parts of Remington.
to-use volume that gives a preliminary view into the What is the advantage of this book? It introduces
course content to which they will be exposed over the early pharmacy students to the scope of pharmacy
next few years along with a thorough discussion of practice and the course content that is required to
the various types of pharmacy practice that will be practice as a pharmacist. With this very valuable
available to them upon graduation. resource used as an early-on introduction, pharmacy
The book is organized in such a way that a team students should be able to confirm their career choice
of faculty members can cover the various sections early in their curriculum.
and emphasize their areas of expertise with the phar-
macy students. The content parallels both Volumes Loyd V Allen Jr, PhD, RPh
I and II in Remington: The Science and Practice of Edmond, OK, USA
Pharmacy. This book uses the Sections as the major February 2013
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Acknowledgments

The Editor-in-Chief wishes to express deep appreci- authors of all the chapters and the section-editors of
ation to the staff at Pharmaceutical Press, especially the 22nd edition of Remington: The Science and Prac-
Erasmis Kidd, Kristina Oberle, Christina DeBono and tice of Pharmacy, along with all those that worked on
Adrianne Brigido. Also, appreciation is extended to the this time-honored book in previous editions.
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About the editor

Dr Loyd V Allen Jr, PhD is Editor-in-Chief of the a consultant in pharmacy and pharmaceutics to the
International Journal of Pharmaceutical Compound- pharmaceutical industry in product development and
ing, CEO of the Midwest Institute of Research and patent infringement legal cases. He is currently Editor-
Technology and Professor Emeritus of the Univer- in-Chief of Remington: The Science and Practice of
sity of Oklahoma College of Pharmacy. He is also Pharmacy, 22nd edition.
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Contributors

Chapter 1 - Scope of Pharmacy Connecticut School of Pharmacy, Storrs, CT,

Philip J. Schneider, MS, FASP, FFIP, FASPEN USA
Professor and Associate Dean, University of Sharon Giovenale, MSLS
Arizona College of Pharmacy, Phoenix, AZ, USA
Pharmacy Librarian, University of Connecticut
Joseph L. Fink III, BSPharm, JD, FAPhA Pharmacy Library, Storrs, CT, USA
Professor, Kentucky Pharmacists Association
Professor of Leadership, Department of Chapter 5 - Pharmaceutical Chemistry
Pharmacy Practice and Science, College of Pardeep K. Gupta, PhD
Pharmacy, University of Kentucky, Lexington Associate Professor of Pharmaceutics,
KY, USA
Philadelphia College of Pharmacy, University of
Chapter 2 - Evolution of Pharmacy the Sciences in Philadelphia, Philadelphia, PA,
USA
Gregory J. Higby, PhD, RPh
Executive Director, American Institute of the Jason Wallach, BS
History of Pharmacy, University of Graduate Student, Department of Pharmaceutical
Wisconsin–Madison, Madison WI, USA Sciences, Philadelphia College of Pharmacy,
University of the Sciences in Philadelphia,
Chapter 3 - The New Drug Approval Process and
Philadelphia, PA, USA
Clinical Trial Design
Linda A. Felton, PhD Boyenoh Gaye
Chair, Department of Pharmaceutical Sciences, Scientist, GlaxoSmithKline, Philadelphia, PA,
Associate Professor of Pharmaceutics, College of USA
Pharmacy, University of New Mexico,
Adeboye Adejare, PhD
Albuquerque, NM, USA
Professor of Pharmaceutical Sciences,
Dennis W. Raisch, PhD, MS, RPh Philadelphia College of Pharmacy, University of
Professor and Chair, Graduate Program in the Sciences in Philadelphia, Philadelphia, PA,
Pharmacoeconomics, Epidemiology, USA
Pharmaceutical Policy, and Outcomes Research,
Ara H. DerMarderosian, PhD
College of Pharmacy, University of New Mexico,
Albuquerque NM, USA Research Professor of Pharmacognosy,
Department of Biological Sciences, University of
the Sciences in Philadelphia, Philadelphia, PA,
Chapter 4 - Information Resources in Pharmacy and
USA
the Pharmaceutical Sciences
Robin H. Bogner, PhD Vidhan Jaiswal, PhD
Associate Professor, Department of Director, Research and Development,
Pharmaceutical Sciences, University of Futurebiotics, Hauppauge, NY, USA
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xviii | Contributors

Randy J. Zauhar, PhD Nicola R. Sarrazin, PharmD

Associate Professor of Biochemistry, Director Drug Information Pharmacist, Iowa Drug
Graduate Program in Bioinformatics, Information Service, College of Pharmacy,
Department of Chemistry and Biochemistry, University of Iowa, Iowa City, IA, USA
University of the Sciences in Philadelphia,
Philadelphia, PA, USA Chapter 6 - Pharmaceutical Analysis and Quality
Eleonora Gianti, MS PhD Control
Candidate in Biochemistry, University of the Raymond D. Skwierczynski, PhD
Sciences in Philadelphia, Philadelphia, PA, USA Senior Director, Analytical Development
Millennium: The Takeda Oncology Company,
Bi-Botti C. Youan, PharmD, PhD Cambridge, MA, USA
Associate Professor of Pharmaceutical Sciences,
University of Missouri–Kansas, City School of Gail Goodman-Snitkoff, PhD
Pharmacy, Kansas City, MO, USA Associate Professor, Albany College of Pharmacy
and Health Sciences, Albany, NY, USA
Zeynep Ates-Alagoz, PhD
Professor, Department of Pharmaceutical Cathy Y. Poon, PharmD
Chemistry, Ankara University, Faculty of Professor and Vice Dean, Department of
Pharmacy, Tandogan, Ankara, Turkey Pharmacy Practice and Pharmacy
Adjunct Associate Professor, Department of Administration, Philadelphia College of
Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences,
Pharmacy, University of the Sciences in Philadelphia, PA, USA
Philadelphia, Philadelphia, PA, USA John H. Parker, PhD
Jeffrey P. Norenberg, MS, PharmD, BCNP, FASHP, President, Tech Manage Associates, Dalton, PA,
FAPhA USA
Professor and Director Radiopharmaceutical John E. Enders, PhD, MBA
Sciences Chief Operating Officer, Tech Manage
Associate Director, New Mexico Center for Associates, Dalton, PA, USA
Isotopes in Medicine College of Pharmacy,
University of New Mexico Allan D. Bokser, PhD
Director, Keck–UNM Small-Animal Imaging Independent Consultant, San Diego, CA, USA
Resource, University of New Mexico, Health Patrick B. O’Donnell, PhD
Sciences Center Senior Director, Pharmaceutical Development,
Executive Director, National Association of Ambit Biosciences Corporation, San Diego, CA,
Nuclear Pharmacies, Albuquerque, NM, USA USA
William B. Hladik III, MS, FASHP, FAPhA Steven B. Johnson, PhD
Associated Professor of Pharmacy, Practice Vice President Regulatory Affairs, Novo
College of Pharmacy, University of New Mexico, Nordisk, Princeton, NJ, USA
Albuquerque, NM, USA
Mandip Singh Sachdeva, PhD
Kevin G. Moores, PharmD Professor and Section Leader, Pharmaceutics,
Associate Professor (Clinical), Director, Division Florida A and M University College of Pharmacy,
of Drug Information Service, College of Tallahassee, FL, USA
Pharmacy, University of Iowa, Iowa City, IA, Editor-in-Chief, CRC Critical Reviews in
USA Therapeutic Drug Carrier Systems
Vicki R. Kee, PharmD, BCPS Chandraiah Godugu, PhD
Assistant Professor (Clinical), Iowa Drug Post-Doctoral Research Associate, Florida A and
Information Service, College of Pharmacy, M University College of Pharmacy, Tallahassee,
University of Iowa, Iowa City, IA, USA FL, USA
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Contributors | xix

Anthony C. Moffat, PhD Keith C. Gordon, PhD

Emeritus Professor of Pharmaceutical Analysis, Professor of Physical Chemistry, Department of
Department of Pharmaceutical and Biological Chemistry, University of Otago, Dunedin, Otago,
Chemistry, UCL School of Pharmacy, London, NZ
UK
Kirsten Graeser, PhD
David G. Watson, BSc, PhD, PGCE Formulation Research, F. Hoffmann-La Roche
Reader, University of Strathclyde, Strathycylde Ltd., Basel, Switzerland
Institute of Pharmacy and Biomedical Sciences, Timothy S. Wiedmann, PhD
Glasgow, UK Professor, Department of Pharmaceutics,
University of Minnesota, College of Pharmacy,
Vijai Kumar, MS, MBA
Minneapolis, MN, USA
General Manager and Vice President of
Technical Operations and Research and Pardeep K. Gupta, PhD
Development, Pharmaceutics International, Hunt Associate Professor of Pharmaceutics,
Valley, MD, USA Philadelphia College of Pharmacy, University of
the Sciences in Philadelphia, Philadelphia, PA,
Praveen Hiremath, PhD
USA
Principal Scientist – Pharmaceutical Formulation,
Bayer Healthcare, Overland Park, KS, USA Loyd V. Allen Jr., PhD, RPh
Professor Emeritus, University of Oklahoma
School of Pharmacy, Edmond, OK, USA
Chapter 7 - Pharmaceutics
Editor in Chief, International Journal of
Rick G. Schnatz, PharmD Pharmaceutical Compounding
Senior Scientific Liaison Compounding Expert,
Committee on Healthcare Quality and Barbara R. Conway, PhD
Compendia Affairs, United States Pharmacopeia, Professor of Pharmaceutics, Division of
Rockville, MD, USA Pharmacy and Pharmaceutical Sciences, School
of Applied Sciences, University of Huddersfield,
Roger L. Schnaare, PhD Queensgate, Huddersfield, UK
Professor Emeritus of Pharmacy, Philadelphia
College of Pharmacy, University of the Sciences Andrew Ingham, MRPharmS, PhD
in Philadelphia Lecturer in Pharmacy/Pharmaceutical Delivery,
Senior Pharmaceutics Fellow, Biosyn, School of Life and Health Sciences, Aston
Philadelphia, PA, USA University, Birmingham, UK

Cathy Y. Poon, PharmD (as above)

Shelly J. Prince, PhD
Associate Professor of Pharmaceutics, College of Rodney J. Wigent, PhD
Pharmacy, Southwestern Oklahoma State Professor of Chemistry; Research Professor of
University, Weatherford, OK, USA Pharmaceutics; Dean, College of Graduate
Studies; Director, Research Administration,
Sanford Bolton, PhD University of the Sciences in Philadelphia,
College of Pharmacy, University of Arizona, Philadelphia, PA, USA
Tucson, AZ, USA
Thorsteinn Loftsson, MSPharm, PhD
Richard Hirsch, PhD Professor of Physical Pharmacy, Department of
Faculty for Applied Sciences, Cologne University Pharmaceutical Sciences, University of Iceland,
of Applied Sciences, Cologne, Germany Hofsvallagata, Iceland
Thomas Rades, PhD Marcus E. Brewster, PhD
Faculty of Health and Medical Sciences, Distinguished Research Fellow, Johnson and
Department of Pharmacy, University of Johnson Pharmaceutical Research and
Copenhagen, Copenhagen, DK Development, Beerse, Belgium
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xx | Contributors

Paul M. Bummer, PhD Donald N. Franz, PhD

Associate Professor, Department of Professor Emeritus, Department of Pharmacology
Pharmaceutical Sciences, College of Pharmacy, and Toxicology, University of Utah School of
University of Kentucky, Lexington, KY, USA Medicine, Salt Lake City, UT, USA

Bill J. Bowman, RPh, PhD Michael R. Franklin, PhD

Assistant Professor of Pharmaceutical Sciences, Professor of Pharmacology and Toxicology,
Arizona College of Pharmacy-Glendale Department of Pharmacology and Toxicology,
Midwestern University, Glendale, AZ, USA College of Pharmacy, University of Utah, Salt
Lake City, UT, USA
Clyde M. Ofner III, PhD
Professor of Pharmaceutics, University of the Paul M. Beringer, PharmD
Sciences in Philadelphia, Philadelphia College of Associate Professor, Department of Clinical
Pharmacy, Philadelphia, PA, USA Pharmacy and Pharmaceutical Economics Policy
Hans Schott, PhD School of Pharmacy, University of Southern
Professor Emeritus of Pharmaceutics and California, Los Angeles, CA, USA
Colloidal Chemistry, Temple University, Michael E. Winter, PharmD
Philadelphia, PA, USA Professor Emeritus, University of California, San
Yvonne Perrie, PhD Francisco School of Pharmacy, San Francisco,
Head of Pharmacy, Professor in CA, USA
Pharmaceutics/Drug Delivery, Aston University, Susie H. Park, PharmD, BCCP
Birmingham, UK Assistant Professor of Clinical Pharmacy, School
James Swarbrick, DSc, PhD of Pharmacy, University of Southern California,
President, PharmaceuTech, Pinehurst, NC, USA Los Angeles, CA, USA

Joseph T. Rubino, PhD, RPh Stan G. Louie, PharmD

Pharmacist/Consultant, Towaco, NJ, USA Associate Professor of Clinical Pharmacy,
University of Southern California School of
Orapin P. Rubino, PhD
Pharmacy, Los Angeles, CA, USA
Director, Formulation and Product Development,
Glatt Air Techniques, Ramsey, NJ, USA Thomas C. Kupiec, PhD
President/Chief Executive Officer ARL
Lawrence H. Block, PhD
BioPharma, DNA Solutions, The Kupiec Group
Professor Emeritus, Mylan School of Pharmacy,
LLC, Oklahoma City, OK, USA
Duquesne University, Pittsburgh, PA, USA
Craig Shimasaki, PhD, MBA
Chapter 8 - Pharmacokinetics and President and CEO, BioSource Consulting
Pharmacodynamics Group, Oklahoma City, OK, USA
Raymond E. Galinsky, PharmD George L. Drusano, MD
Professor of Pharmaceutics, Department of Co-Director, Ordway Research Institute, Albany,
Industrial and Physical Pharmacy Purdue NY, USA
University College of Pharmacy, West Lafayette,
IN, USA Chapter 9 - Pharmaceutical Dosage Forms:
Craig K. Svensson, PharmD, PhD Manufacturing and Compounding
Dean, College of Pharmacy; Professor of Yi-Bo Wang
Medicinal Chemistry and Molecular Graduate Student in Pharmaceutics, The
Pharmacology, Purdue University, West University of Texas at Austin, College of
Lafayette, IN, USA Pharmacy, Austin, TX, USA
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Contributors | xxi

Robert O. Williams III, PhD Paul Missel, PhD

Johnson and Johnson Centennial Professor of Modeling and Simulation, Alcon Research, Fort
Pharmaceutics; Division Head, Pharmaceutics, Worth, TX, USA
The University of Texas at Austin, College of
Lawrence H. Block, PhD (as above)
Pharmacy, Austin, TX, USA
Editor-in-Chief, Drug Development and Ahmed Adel Sakr, PhD
Industrial Pharmacy Distinguished Chaired Professor of Industrial
Pharmacy and Pharmaceutics, Board of Trustees
Michael M. Crowley, PhD
Chair, Assistant Graduate Studies, Research and
President, Theridian Technologies LLL, Austin,
International Affairs, Future University in Egypt,
TX, USA
Cairo, Egypt
James Agalloco, BEChE, MSChE, MBA
Fars K. Alanazi, PhD
President, Agalloco and Associates, Belle Mead,
Professor of Pharmaceutics, Kayyali Chair for
NJ, USA
Pharmaceutical Industries, Department of
William G. Lindboe, Jr., PhD Pharmaceutics, King Saud University, Riyadh,
Independent Consultant, East Brunswick, NJ, Saudi Arabia
USA
Stuart C. Porter, PhD
Russell E. Madsen Senior Director, Global Pharmaceutical
President, The Williamsburg Group LLC, Applications, R and D International Specialty
Gaithersburg, MD, USA Products, Wayne, NJ, USA

Michael J. Akers Ali R. Rajabi-Siahboomi, PhD

Baxter Healthcare Corporation (Retired), Vice President and Chief Scientific Officer,
Bloomington, IN, USA Colorcon, Harleysville, PA, USA

Catherine Cone, PharmD, BCPS Manish S. Rane, PhD

Assistant Professor, Department of Pharmacy Formulation Technologies Manager, Colorcon,
Practice and Administrative Sciences, University West Point, PA, USA
of New Mexico Health Sciences Center,
Linda A. Felton, PhD (as above)
Albuquerque, NM, USA
Christopher J. Sciarra, BS, MS
Linda A. Felton, PhD
Industrial Pharmacy Vice President, Scientific,
Chair and Professor of Pharmaceutics,
Sciarra Laboratories, Hicksville, NY, USA
Department of Pharmaceutical Sciences, College
of Pharmacy, University of New Mexico, John J. Sciarra, PhD
Albuquerque, NM, USA Professor Emeritus and President, Sciarra
Laboratories, Hicksville, NY, USA
Amy Bachyrycz, PharmD
Assistant Professor, University of New Mexico, Ara H. DerMarderosian, PhD (as above)
Albuquerque, NM, USA
Zhiyu Li, PhD
Masood Chowhan, PhD Assistant Professor of Pharmaceutical Sciences,
Senior Director, Drug Formulation and Delivery, Philadelphia College of Pharmacy, University of
Alcon Laboratories, Fort Worth, TX, USA the Sciences in Philadelphia, Philadelphia, PA,
USA
John C. Lang, PhD
Senior Director, AZYP, and Senior Research C. Jeanne Taborsky, BSChem
Scientist/Adjunct Professor, University of Texas President and Chief Executive Officer, SciRegs
at Arlington, Arlington, TX, USA International, Columbia, MD, USA
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xxii | Contributors

Kathleen Deiss, RN Peggy Piascik, PhD

Quality Assurance Manager, SciRegs Professor of Pharmacy Practice and Science,
International, Columbia, MD, USA Associate Chair for Professional Education
Advancement, University of Kentucky College of
William J. Reilly, Jr. Pharmacy, Lexington, KY, USA
Director of Technical Services, Lannett
Pharmaceuticals, Philadelphia, PA, USA Heidi M. Anderson, PhD, FAPhA
Vice President and SACS Liaison Office of
Institutional Research, Planning and
Chapter 10 - Fundamentals of Pharmacy Practice
Effectiveness, University of Kentucky, Lexington,
E. J. Last, PharmD KY, USA
Drug Information Specialist, Indiana University
Health, Indianapolis, IN, USA Ashley H. Vincent, PharmD, BCACP BCPS
Clinical Assistant Professor of Pharmacy Practice,
Amy Marie Haddad, PhD Purdue University College of Pharmacy, Clinical
Director and Dr. C.C. and Mabel L. Criss Pharmacy Specialist Ambulatory Care, IU Health
Endowed Chair in Health Sciences, Creighton – Methodist Hospital Indianapolis, IN, USA
University Medical Center, Center for Health
Michael Montagne, PhD
Policy and Ethics, Omaha, NE, USA Professor of Social Pharmacy, Senior Associate
Bill G. Felkey, BA, MS Dean of Pharmacy, Department of Pharma-
Professor of Pharmacy Care Systems, Auburn ceutical Sciences, Massachusetts College of
University, Harrison School of Pharmacy, Pharmacy and Health Sciences, Boston, MA, USA
Auburn, AL, USA Amy Heck Sheehan, PharmD
Associate Professor of Pharmacy Practice, Purdue
Brent I. Fox, PharmD, PhD
University College of Pharmacy; Drug
Associate Professor, Pharmacy Care Systems,
Information Specialist, Indiana University
Auburn University, Harrison School of
Health, Indianapolis, IN, USA
Pharmacy, Auburn, AL, USA
Robert D. Beckett, PharmD, BCPS
Kenneth N. Barker, PhD Clinical Assistant Professor of Pharmacy
Professor Emeritus of Pharmacy Care Systems, Practice, Manchester University College of
Auburn University Harrison School of Pharmacy, Pharmacy, Fort Wayne, IN, USA
Auburn, AL, USA
Steven R. Abel, PharmD, FASHP
Marie A. Abate, BS, PharmD Associate Vice Provost for Faculty Affairs,
Professor of Clinical Pharmacy and Director, Associate Dean for Clinical Programs, Bucke
West Virginia Center for Drug and Health Professor of Pharmacy Practice, Purdue
Information, Director for Programmatic University College of Pharmacy, Indianapolis,
Assessment, West Virginia University School of IN, USA
Pharmacy, Morgantown, WV, USA Stephanie L. Enz, BSPharm, PharmD
Assistant Professor, Department of
Nathaniel M. Rickles, PharmD, PhD, BCPP
Pharmaceutical Sciences, Butler University
Associate Professor of Pharmacy Practice and
College of Pharmacy and Health Sciences,
Administration, School of Pharmacy,
Indianapolis, IN, USA
Northeastern University, Boston, MA, USA
Angela V. Ockerman, BSPharm, PharmD
Bonnie L. Svarstad, PhD Assistant Professor, Department of
Professor Emerita, University of Pharmaceutical Sciences, Butler University
Wisconsin–Madison School of Pharmacy, College of Pharmacy and Health Sciences,
Madison, WI, USA Indianapolis, IN, USA
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Contributors | xxiii

Matthew Grissinger, RPh, FISMP, FASCP Gerald W. Deom, RPh

Director, Error Reporting Program, Institute for Chief Executive Officer, Deom Health
Safe Medication Practices, Horsham, PA, USA Enterprises, Radcliff, KY, USA

Donna Horn, RPh, DPh Matthew C. Osterhaus, BSPharm, FASCP, FAPhA

Director, Patient Safety - Community Pharmacy Co-Owner, Osterhaus Pharmacy, Maquoketa,
Institute for Safe Medication Practices, Horsham, IA, USA
PA, USA
Steven T. Simenson, BPharm, FAPhA, FACA,
Robert K. Middleton, PharmD DPNAP
Director of Pharmacy Ministry, Saint Clare’s President and Managing Partner, Goodrich
Hospital, Weston, WI, USA Pharmacy, Anoka, MN, USA

Christopher A. Thomas, PharmD Ronald Hadsall, PhD

Clinical Pharmacy Specialist – Pediatric Professor, College of Pharmacy, University of
Cardiothoracic Surgery/Cardiology Department Minnesota, Minneapolis, MN, USA
of Pharmacy, Indiana University Health – Riley
Randall Seifert, PharmD
Hospital for Children, Indianapolis, IN, USA
Senior Associate Dean and Professor,
F Lee Cantrell, PharmD, DABAT Department of Pharmacy Practice and
Director, California Poison Control System, San Pharmaceutical Sciences, University of Minnesota
Diego Division Professor of Clinical Pharmacy, College of Pharmacy, Duluth, MN, USA
University of California, San Francisco; Clinical
Lowell J. Anderson, DSc, FAPhA
Professor of Pharmacy and Medicine, University
Professor, Department of Pharmaceutical Care
of California San Diego, San Diego, CA, USA
and Health Systems, Co-Director and Senior
Sean Patrick Nordt, MD, PharmD, DABAT Fellow, Center for Leading Healthcare, Change
Assistant Professor of Clinical Emergency College of Pharmacy, University of Minnesota,
Medicine, Attending Physiciam Director, Section Minneapolis, MN, USA
of Toxicology Department of Emergency
Medicine Chair, Medication Safety Committee, Chapter 11 - The Scope of Pharmacy Practice
Los Angeles County and USC Medical Center, Jay D. Currie, BSPharm, PharmD, RPh
Keck School of Medicine, University of Southern Professor (Clinical) and Vice Chair, Department
California, Los Angeles, CA, USA of Pharmacy Practice and Science Head, Division
Amy Sutton Peak, PharmD of Applied Clinical Sciences, University of Iowa
Director of Drug Information Services, Butler College of Pharmacy, Iowa City, IA, USA
University College of Pharmacy and Health Stevie R. Veach, PharmD, RPh, BCACP
Sciences, Indianapolis, IN, USA Clinical Pharmacist, CarePro Health Services,
Annette McFarland, PharmD Cedar Rapids, IA, USA
Assistant Professor of Pharmacy Practice, Drug Pamela K. Phelps, PharmD, FASHP
Information Specialist, Butler University College Director, Clinical Pharmacy Services, Fairview
of Pharmacy and Health Sciences, Indianapolis, Health Services, Minneapolis, MN, USA
IN, USA
Rowell Daniels, PharmD, MS
Thomas A. Barbolt, PhD, DABT Director of Pharmacy, UNC Hospitals and
Biocompatibility Consultant, TAB Consulting, Clinics, Chapel Hill, NC, USA
Cambridge, NY, USA
Mark Thomas, MS, RPh
Sylvia H. Liu, BVM, DACVP Executive Director – Safety and Reliability
Vice President Research and Development, Systems, CHRISTUS Spohn Health System,
ETHICON, Somerville, NJ, USA Corpus Christi, TX, USA
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xxiv | Contributors

Paul L. Pluta, PhD, RPh James A. Ponto, MS, BCNP

Adjunct Associate Professor, University of Illinois Chief Nuclear Pharmacist and Professor
at Chicago College of Pharmacy, Chicago, IL, (Clinical), University of Iowa Hospitals and
USA Clinics and College of Pharmacy, University of
Editor-in-Chief Journal of Validation Technology Iowa, Iowa City, IA, USA
and Journal of GXP Compliance, Advanstar
Stanley M. Shaw, PhD
Communications
Professor Emeritus, College of Pharmacy, Purdue
Richard Poska, RPh University, West Lafayette, IN, USA
Director of CMC Regulatory Affairs and
Strategic Initiatives, AbbVie Pharmaceutical Anna Nowobilski-Vasilios, PharmD, MBA,FASHP,
Products Group, Abbott Park, IL, USA CNSC, BCNSP
Principal, Anovation, Inc., Chicago, IL, USA
Aldona T. Matalonis, RPh Adjunct Assistant Professor, Midwestern
Principal Clinical Supplies Project Manager, University, Chicago College of Pharmacy,
Abbott Global Pharmaceutical Research and Downers Grove, IL, USA
Development, Abbott Park, IL, USA Adjunct Assistant Professor, Chicago State
Arthur J. Lawrence, RPh, MBA, PhD University College of Pharmacy, Chicago, IL,
Rear Admiral and Assistant Surgeon General USA
(retired), United States Public Health Service,
Hetty A. Lima, RPh, FASHP
Gaithersburg, MD, USA
Vice President, Specialty Infusion and Rare
William A. Hess, RPh, BSc Diseases Diplomat, Specialty Pharmacy, Flint,
Pharmacy Captain (retired), United States Public MI, USA
Health Service Pharmacist, US Food and Drug
Neal J. Benedict, PharmD
Administration, Silver Spring, MD, USA
Assistant Professor of Pharmacy and
Yiying Tsai, RPh, PharmD, MPH Therapeutics, University of Pittsburgh School of
Lieutenant, United States Public Health Service Pharmacy; Critical Care Pharmacist,
Commissioned Corps Pharmacist, United States UPMC-Presbyterian Hospital, Pittsburgh, PA,
Food and Drug Administration Special Assistant USA
to the Chief Pharmacy Officer, United States
David F. Kisor, BS, PharmD
Public Health Service. Silver Spring, MD, USA
Professor of Pharmacokinetics and Chair
Timothy J. Ives, PharmD, MPH, BCPS,FCCP, CPP Department of Pharmaceutical and Biomedical
Professor of Pharmacy and Adjunct Professor of Science, Ohio Northern University, Raabe
Medicine, UNC Eshelman School of Pharmacy, College of Pharmacy, Ada, OH, USA
University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA Kathleen M. Gura, PharmD, BCNSP, FASHP,
FPPAG
John M. Conry, BS, PharmD, BCPS, AAHIVP Clinical Pharmacy Specialist,
Associate Clinical Professor and Assistant Dean Gastroenterology/Nutrition, Children’s Hospital
for Service Programs, College of Pharmacy and
Boston, Boston, MA, USA
Allied Health Professions, St. John’s University,
Queens, NY, USA Ginger Langley, PharmD, BCNSP, BCPS, CPHQ
Nutrition Support Specialist Critical Care
Sean M. Jeffery, PharmD, CGP, FASCP
Systems, Houston, TX, USA
Clinical Professor, University of Connecticut
School of Pharmacy, Storrs, CT, USA Anne M. Tucker, PharmD, BCNSP
President-Elect, American Society of Consultant Clinical Associate Professor, Department of
Pharmacists, Alexandria, CT, USA Clinical Sciences and Administration, University
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Contributors | xxv

of Houston College of Pharmacy, Houston, TX, Science, Virginia Commonweath University

USA School of Pharmacy, Richmond, VA, USA

Joseph Boullata, PharmD, RPh, BCNSP Becky Armor, PharmD, CDE, BCACP
Professor of Pharmacology and Therapeutics, Clinical Associate Professor, University of
University of Pennsylvania, Clinical Pharmacy Oklahoma College of Pharmacy, Oklahoma City,
Specialist in Nutrition, Hospital of the University OK, USA
of Pennsylvania, Philadelphia, PA, USA
Kelly Epplen, PharmD, BCACP
Gigi Davidson, BSPh, RPh, FSVHP, DICVP Assistant Professor of Clinical Pharmacy,
Director of Clinical Pharmacy Services, College Practice, and Administrative Sciences, James L.
of Veterinary Medicine, North Carolina State Winkle College of Pharmacy, University of
University, Raleigh, NC, USA Cincinnati, Cincinnati, OH, USA

Dinah G. Jordan, BSPh, RPh, PharmD, FSVHP, Louis A. Morris, PhD

DICVP Louis A. Morris and Associates, Dix Hills, NY,
Clinical Professor and Chief of Pharmacy USA
Services, College of Veterinary Medicine, Eva Lydick, PhD
Mississippi State University, Starkville, MS, USA SmithKline Beecham Pharmaceuticals,
Loyd V. Allen Jr, PhD, RPh (as above) Collegeville, PA, USA

Marsha K. Millonig, MBA, BSPharm

Chapter 12 - Social, Behavioral, Economic and Associate Fellow, Center for Leading Healthcare
Administrative Sciences Change, University of Minnesota College of
Joseph L. Fink III, BSPharm, JD, FAPhA (as above) Pharmacy, Minneapolis, MN, USA
President and CEO, Catalyst Enterprises LLC,
William F. McGhan, PharmD, PhD
Eagan, MN, USA
Professor of Pharmacy and Health Policy,
Department of Pharmacy Practice and Pharmacy Michael D. Murray, PharmD, MPH
Administration, Philadelphia College of Executive Director, Regenstrief Center for
Pharmacy, University of the Sciences in Healthcare Effectiveness Research, Distinguished
Philadelphia, Philadelphia, PA, USA Professor of Pharmacy and Endowed Chair of
Medication Safety, Purdue University College of
Donna West-Strum, PhD, RPh
Pharmacy, Indianapolis, IN, USA
Chair and Associate Professor, Department of
Pharmacy Administration, Research Associate
Chapter 13 - Patient Care
Professor, Research Institute of Pharmaceutical
Sciences, University of Mississippi School of James Palmieri, PharmD
Chair, Clinical and Administrative Science and
Pharmacy, University, MS, USA
Associate Professor of Clinical Sciences,
Michael R. McConnell, RPh California Northstate University College of
Founder, National Notification Center, LLC, Pharmacy, Rancho, Cordova, CA, USA
Carmel, IN, USA
Yvette J. Crockell, MHA, RPh
Michael Rozembajgier, MBA Director of Clinical Pharmacy, American Health
Vice President of Recalls, ExpertRecall™ Care, Rocklin, CA, USA
Stericycle, Lake Forest, IL, USA
Bradley C. Cannon, PharmD
David A. Holdford, RPh, MS, PhD, FAPhA Clinical Assistant Professor, Department of
Professor and Vice Chair of Graduate Education, Pharmacy Practice, University of Illinois at
Department of Pharmacotherapy and Outcomes Chicago, College of Pharmacy, Chicago, IL, USA
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xxvi | Contributors

Sheila M. Allen, PharmD, BCPS Tara M. Jenkins, MS, MBA, MPH, PharmD
Clinical Assistant Professor and Director, Clinical Consultant Pharmacist, CVS Caremark,
Introductory Pharmacy Practice Experiences, Virginia Beach Territory, Hampton, VA, USA
College of Pharmacy, University of Illinois at Catherine Ulbricht, PharmD, MBAc
Chicago, Chicago, IL, USA Senior Attending Pharmacist, Massachusetts
Kristen L. Goliak, PharmD General Hospital Somerville MA USA
Assistant Head – Education Chief Editor, Natural Standard Research
Director, APPE Collaboration, Journal of Dietary Supplements
Clinical Assistant Professor, Department of Connie Grauds, RPh, MNPA
Pharmacy Practice, University of Illinois in President, Association of Natural Medicine
Chicago, College of Pharmacy, Chicago, IL, USA Pharmacists, Philadelphia, PA, USA

Robert L. Talbert, PharmD, FCCP, BCPS, FAHA Ara H. DerMarderosian, PhD (as above)
Professor, Pharmacotherapy Division, College of
Nancy L. Shapiro, PharmD, FCCP, BCPS
Pharmacy, University of Texas at Austin Operations Manager, Antithrombosis Clinic;
Professor, School of Medicine, Pharmacotherapy Clinical Associate Professor, Pharmacy Practice
Education, and Research Center, University of Director, Ambulatory Care Residency; University
Texas Health Science Center at San Antonio, San of Illinois at Chicago, College of Pharmacy,
Antonio, TX, USA Chicago, IL, USA
William M. Ellis, RPh, MS Adam J. Bursua, PharmD, BCPS
Executive Director, Board of Pharmacy Clinical Assistant Professor, College of
Specialties, Washington, DC, USA Pharmacy, University of Illinois at Chicago,
Chicago, IL, USA
Stuart T. Haines, PharmD, BCPS, BCACP, BC-ADM
Professor and Vice Chair for Clinical Services, Jeffrey N. Baldwin, BSPharm, PharmD, FAPhA,
University of Maryland School of Pharmacy, FASHP
Baltimore, MD, USA Professor and Vice-Chair of Pharmacy Practice,
College of Pharmacy, University of Nebraska
Seena L. Haines, PharmD, FASHP, FAPhA, BCACP, Medical Center, Omaha, NE, USA
BC-ADM, CDE
Professor and Associate Dean for Faculty and Melinda J. Ortmann, PharmD, BCPS
Clinical Pharmacy Specialist – Emergency
Residency Director PGY-1, Palm Beach Atlantic
Medicine, Department of Pharmacy, The Johns
University Gregory School of Pharmacy, West
Hopkins Hospital, Baltimore, MD, USA
Palm Beach, FL, USA
NMA Co-Editor Umbreen Idrees Murtaza, PharmD, BCPS
Clinical Pharmacy Specialist – Emergency
W. Steven Pray, BSPharm, MPH, PhD
Medicine Department of Pharmacy, The Johns
Bernhardt Professor Nonprescription Products
Hopkins Hospital, Baltimore, MD, USA
and Devices, College of Pharmacy, Southwestern
Oklahoma State University, Weatherford, OK, Carlton K. K. Lee, PharmD, MPH, FASHP
USA Clinical Pharmacy Specialist, Pediatrics; Program
Director, Pediatric Pharmacy Residency,
Marlon Honeywell, PharmD Department of Pharmacy, The Johns Hopkins
Associate Dean for Academic Affairs and Hospital; Associate Professor, Pediatrics, School
Professor College of Pharmacy and of Medicine, Johns Hopkins University; Clinical
Pharmaceutical Sciences, Florida A and M Professor, School of Pharmacy, University of
University, Tallahassee, FL, USA Maryland, Baltimore, MD, USA
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Contributors | xxvii

Cathy Y. Poon, PharmD (as above) Associate Professor, Tufts University School of
Medicine, Boston, MA, USA
Lindsey A. Pote, PharmD, BCPS
Clinical Pharmacist Specialist – Organ George P. Allen, PharmD
Transplantation, Department of Pharmaceutical Associate Professor, Department of Pharmacy
Services, University of Chicago Medicine, Practice, University of New England College of
Chicago, IL, USA Pharmacy, Portland, ME, USA

Lindsey Lombardi Thomas, PharmD, BCOP Andrea Deschambeault, PharmD, BCPS

Sidney Kimmel Comprehensive Cancer Center, Clinical Assistant Professor, Department of
The Johns Hopkins Hospital, Department of Pharmacy Practice, University of New England
Pharmacy, Baltimore, MD, USA College of Pharmacy, Portland, ME, USA

Grace M. Kuo PharmD, MPH, PhD, FCCP Julie Waldfogel, PharmD, CPE
Associate Professor of Clinical Pharmacy, Assistant Professor, Division of Pain Medicine,
Associate Dean for Academic Clinical Affairs, Department of Anesthesiology, University of
Associate Adjunct Professor of Family and Florida, Gainesville, FL, USA
Preventive Medicine, Director of SDPharmNet™
Suzanne Amato Nesbit, PharmD, CPE
and PharmGenEd™, Skaggs School of Pharmacy
Clinical Pharmacy Specialist, Pain Management
and Pharmaceutical Sciences, University of
Research Associate, Department of Oncology,
California, San Diego, La Jolla, CA, USA
Department of Pharmacy, The Johns Hopkins
Kelly C. Lee, PharmD, BCPP Hospital, Baltimore, MD, USA
Assistant Professor of Clinical Pharmacy, Skaggs
Ana Lucia Hincapie, MS
School of Pharmacy and Pharmaceutical
College of Pharmacy University of Arizona,
Sciences, University of California San Diego, San
Tucson, AZ, USA
Diego, CA, USA
Neil J. MacKinnon, PhD, FCSHP
Joseph D. Ma, PharmD
Professor and The Walter H. Pearce Endowed
Assistant Professor of Clinical Pharmacy, Skaggs
Chair Director, Center for Rural Health; Section
School of Pharmacy and Pharmaceutical
Chair, Public Health Policy and Management,
Sciences, University of California San Diego, San
Mel and Enid Zuckerman College of Public
Diego, CA, USA
Health, University of Arizona, Tucson, AZ, USA
John J. Lewin III, PharmD, MBA
David P. Nau, PhD, BPharm, CPHQ
Division Director, Critical Care and Surgery
Senior Director, Research and Performance
Pharmacies Adjunct; Assistant Professor,
Measurement Pharmacy Quality Alliance,
Anesthesiology and Critical Care Medicine,
Fairfax Station, VA, USA
Division of Neurosciences Critical Care, The
Johns Hopkins Hospital and Johns Hopkins Terri L. Warholak, PhD, RPh
University School of Medicine; Clinical Assistant Professor, Division of Health
Professor, University of Maryland School of Promotion Sciences, College of Public Heath,
Pharmacy, Baltimore, MD, USA Department of Pharmacy Practice, and Science
College of Pharmacy; Adjunct Clinical Instructor,
John W. Devlin, PharmD, FCCM, FCCP
College of Nursing, University of Arizona,
Associate Professor Department of Pharmacy
Tucson, AZ, USA
Practice Northeastern University; Clinical
Pharmacist, Medical ICU Special and Scientific Carol A. Ott, PharmD, BCPP
Staff, Division of Pulmonary, Critical Care, and Clinical Associate Professor of Pharmacy
Sleep Medicine, Tufts Medical Center; Adjunct Practice, Purdue University College of Pharmacy;
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xxviii | Contributors

Clinical Pharmacy Specialist Psychiatry, Wishard Mathew Thambi, PharmD, MPH, BCPS
Health Services/Midtown Community Mental Clinical Assistant Professor and Clinical
Health, Indianapolis, IN, USA Pharmacist, University of Illinois at Chicago
College of Pharmacy, Chicago, IL, USA
Elayne D. Ansara, PharmD, BCPS, BCPP
Clinical Pharmacy Specialist Psychiatry, Wishard
Health Services/Midtown Community Mental
Health, Indianapolis, IN, USA
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1
Scope of pharmacy

Education 2 Graduate education 8

Licensure requirements 2 Organizations 8

Careers 2 References 9
Postgraduate training 8

Pharmacy has historic roots as the art and science therapy. Pharmacy practice therefore involves the
of preparing and dispensing medications. While this review and interpretation of prescription orders; the
traditional role is still a viable role for pharmacists, compounding, labeling, and dispensing of drugs and
the preparation of medicines has transitioned in large devices; drug product selection and medication-use
part to the pharmaceutical industry. Dispensing of evaluation (MUE); patient monitoring and interven-
medicines has increasingly become more centralized tion; and the provision of information related to
and automated, with many of the tasks formerly per- use of medications and non-pharmacological modal-
formed by pharmacists being done using technology ities. The American Pharmacists Association (APhA)
or delegated to pharmacy technicians. The provi- describes the mission of pharmacy as serving society as
sion of drug-related information to other healthcare ‘‘the profession responsible for the appropriate use of
professionals and the public and disease-state manage- medications, devices, and services to achieve optimal
ment programs to assure the proper use of medicines therapeutic outcomes.’’ The Report of the Commis-
has become a more important role for pharmacists. It sion of Pharmacy, Pharmacists for the Future (often
is now recognized that medication-use is a complex referred to as the Millis Report), states that ‘‘phar-
and problem-prone process, in which errors that result macy should be conceived basically as a knowledge
in injury to patients can occur at each step. This pro- system that renders a health service by concerning
cess includes prescribing, transcribing, interpretation itself with understanding drugs and their effects.’’
of the order, preparation and dispensing, and admin- Pharmaceutical care holds that the important role
istration and monitoring. It has been estimated that of the pharmacist is ‘‘the responsible provision of
more than 2 million hospitalized patients per year drug therapy for the purpose of achieving definite
experience an adverse drug reaction, two thirds of outcomes that improve a patient’s quality of life.’’
which were the cause of hospital admission and more Pharmacists are experts on medications. They are
than 100 000 of which are fatal.1 For pharmacists to also the most accessible member of today’s healthcare
contribute to improving the value of medicines, they team, and often they are the first source of assistance
must have a role in every aspect of medication use, and advice on many common ailments and healthcare
from preparation to monitoring the outcome of drug matters.
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2 | An Introduction to Pharmacy

Education increasingly popular. Most prominent are hospital/

institutional pharmacy, nuclear pharmacy, manage-
The Doctor of Pharmacy (PharmD) is the entry level ment, and various research specialties.
degree in pharmacy. This is a graduate professional
degree at the doctoral level with a clinical focus,
much like medicine (MD), dentistry (DDS), optometry Licensure requirements
(OD), and veterinary medicine (DVM). The PharmD
curriculum requires at least six academic years to The practice of pharmacy is regulated by each individ-
complete and in some cases, where a BS degree is ual state through the Board of Pharmacy within that
required for entry into a PharmD program, eight aca- state. The law in all states, including the District of
demic years. For the six-year program, coursework Columbia, Puerto Rico, and US Territories, requires
often commences in the third academic year that is applicants for licensure to be of good moral character,
considered the first professional year (PY 1). For all have graduated from an ACPE accredited first profes-
programs, the final professional year (PY 4) consists sional degree program, have passed an examination
entirely of experiential education. There are 122 col- given by the Board of Pharmacy, and be 21 years
leges and schools of pharmacy in the United States of age.
(see Table 1.1; http://www.aacp.org2 ). Colleges of All states require that candidates for licensure have
Pharmacy are accredited by the Accreditation Coun- a record of practical experience or internship training
cil for Pharmacy Education (ACPE). Accreditation is acquired under the supervision and instruction of a
the public recognition accorded a professional pro- licensed practitioner. Some jurisdictions grant licen-
gram that is judged to meet established qualifications sure by licensure transfer. Requirements vary from
and educational standards through initial and sub- state to state. Information about licensure transfer is
sequent periodic evaluations (see: https://www.acpe- available from the National Association of Pharmacy
accredit.org/3 ). (http://www.nabp.net/programs/licensure/licensure-
transfer/index.php4 ).
The vast majority of the states have established
Pre-professional courses continuing education requirements for re-licensure.
Mathematics and the physical and biological sciences This requirement has been adopted as a way to reas-
teach the principles, the application of which find their sure the public that licensed pharmacists are keeping
way into many of the upper-level professional phar- up-to-date to maintain their professional competence.
macy courses. Courses in chemistry, including general The types of programs that are recognized and the pre-
and organic chemistry, are of particular importance scribed range of acceptable content matter are fairly
in preparing for the pharmacy curriculum. Courses uniform. The ACPE also has responsibility for accred-
in mathematics, including calculus, are also impor- iting providers of professional continuing education
tant. Courses in the social sciences, humanities, arts, programming.
history, and literature provide the broad general edu- A list of the governmental agencies that license
cation required of a professional in today’s society. pharmacists in the various states is available from
the National Association of Boards of Pharmacy, 700
Busse Highway, Park Ridge, IL 60068–2402 (see
Professional Courses http://www.nabp.org5 ).
Basic to most pharmacy curricula are courses
in pharmacology, medicinal chemistry, pharma-
ceutics, biopharmaceutics, therapeutics, and the Careers
clinical-pharmacy externships. Courses in social and
administrative pharmacy, as well as pharmacy law, Job opportunities for pharmacists are expected to con-
also are found in this sequence. tinue to be strong because of the increased use of med-
Opportunities for students to specialize in certain ications by a growing and aging population6 . There
professional areas have become more available and are other factors that may increase the demand for
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Scope of pharmacy | 3

Table 1.1 Pharmacy professional degree programs

The following colleges and schools offering professional degree programs in pharmacy hold membership in the AACP.

Alabama Auburn University, Harrison School of Pharmacy, Auburn University, AL 36849

Samford University, McWhorter School of Pharmacy, Birmingham, AL 35229

Arizona Midwestern University, College of Pharmacy-Glendale, Glendale, AZ 85308

University of Arizona, College of Pharmacy, Tucson, AZ 85721

Arkansas Harding University, College of Pharmacy, Searcy, AR 72149

University of Arkansas for Medical Sciences, College of Pharmacy, Little Rock, AR 72205

California California Northstate College of Pharmacy, Rancho Cordova, CA 95670

Loma Linda University, School of Pharmacy, Loma Linda, CA 92350
University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093
University of California, San Francisco, School of Pharmacy, San Francisco, CA 94143
University of the Pacific, Thomas J. Long School of Pharmacy and Health Sciences, Stockton, CA 95211
University of Southern California, School of Pharmacy, Los Angeles, CA 90089
Touro University, College of Pharmacy California, Vallejo, CA 94592
Western University of the Health Sciences, College of Pharmacy, Pomona, CA 91766

Colorado Regla University, School of Pharmacy, Denver, CO 80221

University of Colorado, Skaggs School of Pharmacy, Denver, CO 80262

Connecticut St. Joseph College School of Pharmacy, Hartford, CT 06103

University of Connecticut, School of Pharmacy, Storrs, CT 06269

District of Columbia Howard University, College of Pharmacy, Washington, DC 20059

Florida Florida Agricultural and Mechanical University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL
32307
Nova Southeastern University, College of Pharmacy, Fort Lauderdale, FL 33328
Palm Beach Atlantic University, Lloyd L. Gregory School of Pharmacy, West Palm Beach, FL 33416
University of Florida, College of Pharmacy, Gainesville, FL 32610
University of South Florida, College of Pharmacy, Tampa, FL 33612

Georgia Mercer University, College of Pharmacy and Health Sciences, Atlanta, GA 30341
Philadelphia College of Osteopathic Medicine School of Pharmacy, Suwanee, GA 30024
South University, School of Pharmacy, Savannah, GA 31406
University of Georgia, College of Pharmacy, Athens, GA 30602

Hawaii University of Hawaii at Hilo, College of Pharmacy, Hilo, HI 96720

Idaho Idaho State University, College of Pharmacy, Pocatello, ID 83209

Illinois Chicago State University, College of Pharmacy, Chicago, IL 60628

Midwestern University, Chicago College of Pharmacy, Downers Grove, IL 60515
Roosevelt University, College of Pharmacy, Shaumburg, IL 60173
Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
Southern Illinois University Edwardsville, School of Pharmacy, Edwardsville, IL 62026
University of Illinois at Chicago, College of Pharmacy, Chicago, IL 60612

(continued overleaf)
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4 | An Introduction to Pharmacy

Table 1.1 (continued)

Indiana Butler University, College of Pharmacy and Health Sciences, Indianapolis, IN 46208
Purdue University School of Pharmacy and Pharmacal Sciences, West Lafayette, IN 47907

Iowa Drake University, College of Pharmacy and Health Sciences, Des Moines, IA 50311
University of Iowa, College of Pharmacy, Iowa City, IA 52242

Kansas University of Kansas, School of Pharmacy, Lawrence, KS 66045

Kentucky Sullivan University, College of Pharmacy, Louisville, KY 40205

University of Kentucky, College of Pharmacy, Lexington, KY 40536

Louisiana University of Louisiana at Monroe, School of Pharmacy, Monroe, LA 71209

Xavier University of Louisiana, College of Pharmacy, New Orleans, LA 70125

Maine Husson University, School of Pharmacy, Bangor, ME 04401

University of New England, College of Pharmacy, Portland, ME 04103

Maryland Notre Dame of Maryland University, School of Pharmacy, Baltimore, MD 21210

University of Maryland, School of Pharmacy, Baltimore, MD 21201
University of Maryland Eastern Shore, School of Pharmacy, Princess Anne, MD 21853

Massachusetts Massachusetts College of Pharmacy and Health Sciences - School of Pharmacy - Boston, Boston, MA 02115
Massachusetts College of Pharmacy and Health Sciences - School of Pharmacy - Worcester, Worcester, MA 01610
Northeastern University, School of Pharmacy, Boston, MA 02115
Western New England University, College of Pharmacy, Springfield, MA 01119

Michigan Ferris State University, College of Pharmacy, Big Rapids, MI 49307

University of Michigan, College of Pharmacy, Ann Arbor, MI 48109
Wayne State University, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48202

Minnesota University of Minnesota, College of Pharmacy, Minneapolis, MN 55455

Mississippi University of Mississippi, School of Pharmacy, University, MS 38655

Missouri St Louis College of Pharmacy, St Louis, MO 63110

University of Missouri-Kansas City, School of Pharmacy, Kansas City, MO 64110

Montana University of Montana, School of Pharmacy and Allied Health Sciences, Missoula, MT 59812

Nebraska Creighton University, School of Pharmacy and Health Professions, Omaha, NE 68178
University of Nebraska Medical Center, College of Pharmacy, Omaha, NE 68198

Nevada Roseman University of Health Sciences, College of Pharmacy, Henderson, NV 89014

New Jersey Rutgers, The State University of New Jersey, Ernest Mario College of Pharmacy, Piscataway, NJ 08854

New Mexico University of New Mexico, College of Pharmacy, Albuquerque, NM 87131

(continued overleaf)
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Scope of pharmacy | 5

Table 1.1 (continued)

New York Albany College of Pharmacy and Health Sciences, Albany, NY 12208
D’Youville College, School of Pharmacy, Buffalo, NY 14201
Long Island University, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Brooklyn, NY 11201
St. John Fisher College, Wegmans School of Pharmacy, Rochester, NY 14618
St John’s University, College of Pharmacy and Allied Health Professions, Jamaica, NY 11439
Touro College of Pharmacy - New York, New York, NY 10027
University of Buffalo, The State University of New York, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260

North Carolina Campbell University, School of Pharmacy, Buies Creek, NC 27506

University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, NC 27599
Wingate University, School of Pharmacy, Wingate, NC 28174

North Dakota North Dakota State University, College of Pharmacy, Fargo, ND 58105

Ohio Northeast Ohio Medical University, College of Pharmacy, Rootstown, OH 44272

Ohio Northern University, R.H. Raabe College of Pharmacy, Ada, OH 45810
The Ohio State University, College of Pharmacy, Columbus, OH 43210
University of Cincinnati, College of Pharmacy, Cincinnati, OH 45267
The University of Findlay, College of Pharmacy, Findlay, OH 45840
University of Toledo, College of Pharmacy, Toledo, OH 43606

Oklahoma Southwestern Oklahoma State University, School of Pharmacy, Weatherford, OK 73096

University of Oklahoma, College of Pharmacy, Oklahoma City, OK 73190

Oregon Oregon State University, College of Pharmacy, Corvallis, OR 97331

Pacific University Oregon, Hillsboro, OR 97123

Pennsylvania Duquesne University, Mylan School of Pharmacy, Pittsburgh, PA 15282

Lake Erie College of Osteopathic Medicine, School of Pharmacy, Erie, PA 16509
Temple University, School of Pharmacy, Philadelphia, PA 19140
Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, PA 19107
University of Pittsburgh, School of Pharmacy, Pittsburgh, PA 15261
University of the Sciences, Philadelphia College of Pharmacy, Philadelphia, PA 19104
Wilkes University, Nesbitt School of Pharmacy, Wilkes-Barre, PA 18766

Puerto Rico University of Puerto Rico, School of Pharmacy, San Juan, PR 00936

Rhode Island University of Rhode Island, College of Pharmacy, Kingston, RI 02881

South Carolina Presbyterian College, School of Pharmacy, Clinton, SC. 29325

South Carolina, College of Pharmacy – MUSC Campus, Charleston, SC 29425
South Carolina, College of Pharmacy – USC Campus, Columbia, SC 29208

South Dakota South Dakota State University, College of Pharmacy, Brookings, SD 57007

Tennessee Belmont University, School of Pharmacy, Nashville, TN 37212

East Tennessee State University, Bill Gatton College of Pharmacy, Johnson City, TN 37614
Lipscomb University, College of Pharmacy, Nashville, TN 37204
Union University, School of Pharmacy, Jackson, TN 38305
University of Tennessee, College of Pharmacy, Memphis, TN 38163

(continued overleaf)
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6 | An Introduction to Pharmacy

Table 1.1 (continued)

Texas Texas AandM Health Sciences Center, Kinsville, TX 78363

Texas Southern University, College of Pharmacy and Health Sciences, Houston, TX 77004
Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, TX 79106
University of Houston, College of Pharmacy, Houston, TX 77204
University of the Incarnate Word, Feik School of Pharmacy, San Antonio, TX 78209
The University of Texas at Austin, College of Pharmacy, Austin, TX 78712

Utah University of Utah, College of Pharmacy, Salt Lake City, UT 84112

Virginia Appalachian College of Pharmacy, Oakwood, VA 24631

Hampton University, School of Pharmacy, Hampton, VA 23668
Shenandoah University, Bernard J Dunn School of Pharmacy, Winchester, VA 22601
Virginia Commonwealth University, School of Pharmacy, Richmond, VA 23298
University of Washington, School of Pharmacy, Seattle, WA 98195
Washington State University, College of Pharmacy, Pullman, WA 99164

West Virginia University of Charleston, School of Pharmacy, Charleston, WV 25304

West Virginia University, School of Pharmacy, Morgantown, WV 26506

Wisconsin Concordia University Wisconsin, School of Pharmacy, Mequon, WI 53097

University of Wisconsin-Madison, School of Pharmacy, Madison, WI 53705

Wyoming University of Wyoming, School of Pharmacy, Laramie, WY 82071

pharmacists. Scientific advances, including genomics, pharmacy. In addition to dispensing pharmaceuticals,

will result in the discovery of more drugs for the pharmacists in community pharmacies answer ques-
prevention, diagnosis, and treatment of disease. A tions about prescription and over-the-counter (OTC)
better understanding of how drugs work will result drugs and give advice about home healthcare sup-
in personalized medicine. There will be new devel- plies and durable medical equipment. Of an estimated
opments in how medications are administered. The 200 000 pharmacists now in practice, the majority
increased availability of information about medicines are in community pharmacy practice. Pharmacy tech-
by well-informed consumers, who are sophisticated nicians and pharmacy interns are also important
about healthcare, will create a need to help them members of the community pharmacy workforce.
understand how to make use of this information. While there are still independent community phar-
macies in smaller communities and those that provide
specialty services such as compounding, an increas-
Community pharmacy
ing number of community pharmacies are chain drug
Community pharmacy is a hybrid practice requiring stores or located in larger retail settings, including
well-developed professional skills and, in many cases, grocery stores.
management abilities. Success in community phar-
macy practice depends on business management skills
Health-systems pharmacy
because a pharmacy is a business, and on clinical and
therapeutic knowledge because a pharmacist is also a Health-systems pharmacy is the practice of pharmacy
healthcare provider. People skills are also important in private and government-owned hospitals, health
because of the direct patient contact in a community maintenance organizations (HMOs), clinics, walk-in
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Scope of pharmacy | 7

health centers, and nursing homes. This has become Government service
a significant setting for pharmacy practice over the
Government service offers opportunities to phar-
past 50 years. In these settings pharmacists, with
macists in various capacities. They may serve as
the assistance of pharmacy technicians, pharmacy
noncommissioned or commissioned officers in the
interns, and automated technologies, prepare and dis-
Army, Navy, Air Force, and Coast Guard. They also
pense medications, compound nonsterile and sterile
serve as commissioned officers in the United States
preparations, advise other professionals and patients
Public Health Service, which furnishes pharmacists
on the use of drugs, monitor drug regimens, and eval-
for the Food and Drug Administration, Bureau of
uate drug use. They advise other professionals on the
Prisons, and the Indian Health Service. Appointments
selection and effects of drugs and, in some cases, make
are available for pharmacists in the Drug Enforcement
patient rounds with them or provide direct patient
Administration of the Department of Justice, and in
care. Hospital pharmacy practice involves working
the National Institutes of Health, the Center for Medi-
extensively with other members of the healthcare
team, including physicians, nurses, and other health care and Medicaid Services, the Health Resources and
professionals and workers. Services Administration, and various other agencies.

Nuclear pharmacy Pharmaceutical education

Nuclear pharmacy applies the principles and prac- Pharmaceutical education offers opportunities to
tices of pharmacy and nuclear chemistry to produce pharmacists with advanced degrees in any of the
radioactive drugs used for diagnosis and therapy. professional specialties. Expanding enrollments and
Some of these pharmacists work in hospitals and oth- changes in the curricula at colleges to meet the
ers work for private nuclear pharmacies that provide employment needs of the future result in an increased
radioactive drugs to hospitals. need for college-level instructors. Potentially higher
salaries, more freedom for research and writing, inde-
Industrial pharmacy pendence of action, and the cultural surroundings in
pharmaceutical education make teaching attractive.
Industrial pharmacy offers opportunities to pharma-
cists of all educational levels. The largest number
of pharmacists is involved in marketing, sales, and
Pharmaceutical journalism
administration. Some pharmaceutical manufacturers This offers rewarding experiences for a limited num-
employ pharmacists as their professional service rep- ber of pharmacists with writing and editing skills.
resentatives, to educate physicians and pharmacists
about the manufacturer’s products. This can be a
Organizational management
rewarding career for persons with the right person-
ality and motivation, and it is often a stepping-stone Organizational management careers are available for
to supervisory positions in sales and a path toward those with pharmacy education who wish to serve in
integration into the administrative and sales structure national and state associations and on state boards
of a pharmaceutical firm. Pharmacists with master’s of pharmacy. The increasing number of pharmacists
degrees in business or additional degrees in law find and the interface of pharmacy with insurance carriers
additional opportunities in the pharmaceutical indus- and health and welfare agencies mean the respon-
try in the marketing, sales, and legal departments. sibilities of associations and boards must expand
Pharmacists can also serve the industry as professional accordingly and be complicated by the greater involve-
communications managers and clinical research scien- ment of state and federal governments in healthcare.
tists; research and development personnel often have Thus, pharmacists who have organizational interests
advanced degrees, although this is not always the case. and talents will be in great demand and will play
Production and quality-control (or quality-assurance) important roles in the future of pharmacy in the
supervisory positions often are held by pharmacists. United States.
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8 | An Introduction to Pharmacy

Postgraduate training and pharmaceutical scientists and students. Since its

founding in 1852, the APhA has been a leader in
More than 20% of graduating pharmacists enter the professional and scientific advancement of phar-
pharmacy residency programs.2 An increasing num- macy. Membership in one of the three academies of
ber of hospitals require the completion of a pharmacy the APhA – the Academy of Pharmacy Practice and
residency as a requirement for employment. Phar- Management (APPM), the Academy of Pharmaceuti-
macists interested in advanced clinical roles almost cal Research and Science (APRS), and the Academy
always need to have completed a pharmacy practice of Student Pharmacists (ASP) – offers members spe-
residency and often a second specialty residency. Phar- cialized benefits and the opportunity to influence their
macy practice residencies (post-graduate year (PGY) practice areas.
1 residencies) are 12-month programs with a general
focus on all aspects of practice in a defined area, such
American Society of Health-System
as a health-system, community pharmacy or managed
Pharmacists (ASHP)
care. Specialty residencies (PGY 2 residencies) are 12 The ASHP is the professional association of pharma-
months or longer, require a PGY 1 residency as a pre- cists who practice in organized healthcare settings.
requisite, and focus on a particular area of practice, The ASHP endeavors to create an environment in
such as pediatrics, psychiatry, hematology-oncology, which pharmacists can focus the full potential of their
transplant, critical care, nutrition support, or knowledge and expertise on patient care. The mission
infectious diseases. The American Society of Health- of the ASHP is to represent its more than 30 000
System Pharmacists (ASHP) accredits pharmacy members, providing leadership that will enable phar-
residency programs. The increase in the knowledge macists in organized healthcare settings to provide
about medicines and the advanced roles that pharma- high-quality pharmaceutical services that foster the
cists play in medication-use management increasingly efficacy, safety, and cost-effectiveness of drug use;
requires formal postgraduate training beyond an contribute to programs and services that emphasize
entry level degree and licensure in pharmacy. the health needs of the public and the prevention
Fellowship programs in similar specialty practice of disease; and promote pharmacy as an essential
areas focus on research and are usually 24 months or component of the healthcare team. Members can par-
longer. Pharmacists interested in an academic career ticipate in seven Sections and Forums, including the
often have a graduate degree and/or fellowship train- Pharmacy Student Forum, New Practitioner Forum,
ing, in addition to an entry level degree in pharmacy. Section of Ambulatory Care Practitioners, Section of
Clinical Specialists and Scientists, Section of Inpa-
Graduate education tient Practitioners, Section of Pharmacy Informatics
and Technology, and Section of Pharmacy Practice
Areas of graduate study include pharmaceutics, Managers.
industrial pharmacy, pharmacology, pharmaceuti-
cal/medicinal chemistry, pharmacognosy, and social American Society of Consultant
and administrative pharmacy. A master’s or PhD Pharmacists (ASCP)
degree in the pharmaceutical sciences or a related The ASCP promotes the development and advance-
field usually is required for research positions, and ment of pharmaceutical care activities directed at
a PharmD, MS, or PhD degree is necessary for elderly patients, particularly those in long-term care
administrative or faculty positions. institutions. The ASCP has more than 7000 mem-
bers and 4500 student members. There are 23 ASCP
Organizations chapters that are defined by geographic region.

American Pharmacists Association National Community Pharmacists

(APhA) Association (NCPA)
The APhA is the national professional organization Membership in the NCPA, formerly known as the
of pharmacists representing pharmacy practitioners, National Association of Retail Druggists (NARD), is
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Scope of pharmacy | 9

open to independent community pharmacy owners, ACCP’s membership is composed of practitioners,

managers, and employees, as well as pharmacy stu- scientists, educators, administrators, students, resi-
dents and corporations. The NCPA is dedicated to dents, fellows, and others committed to excellence in
the continuing growth and prosperity of the 23 000 clinical pharmacy and patient pharmacotherapy.
independent community pharmacies in the United
States. American Association of Colleges of
Pharmacy (AACP)
American Association of Pharmaceutical Founded in 1900, the AACP is the national organiza-
Scientists (AAPS) tion representing pharmacy education in the United
The AAPS serves an advocacy role for the pharma- States. The mission of the Association is to both rep-
ceutical sciences, promotes the economic viability of resent and be an advocate for all segments of the
the pharmaceutical sciences and its scientists, and rep- academic community in the profession of pharmacy.
resents scientific interests within academia, industry, The AACP comprises all colleges and schools with
government, and other research institutions. AAPS pharmacy degree programs accredited by the Accred-
members are eligible for membership in one of sev- itation Council for Pharmacy Education, including
eral sections: Analysis and Pharmaceutical Quality; approximately 57 000 professional degree students,
Biotechnology; Clinical Pharmacology and Transla- 5700 students enrolled in graduate studies, and more
tional Research; Drug Design and Discovery; For- than 5600 full-time faculty.
mulation Design and Development; Manufacturing
Science and Engineering; Physical Pharmacy and Bio-
pharmaceutics; Pharmacokinetics, Pharmacodynam-
References
ics, and Drug Metabolism; and Regulatory Sciences. 1. Lazarou J et al. Incidence of adverse drug reactions in
There are 12 000 members of the AAPS. hospitalized patients. JAMA 1998; 279: 1200–1205.
2. American Association of Colleges of Pharmacy.
http://www.aacp.org.
American College of Clinical Pharmacists 3. Accreditation Council for Pharmacy Education.
(ACCP) https://www.acpe_accredit.org/.
4. http://www.nabp.net/programs/licensure/licensure-
The ACCP is a professional and scientific society transfer/index.php
5. National Association of Boards of Pharmacy.
that provides leadership, education, advocacy, and
http://www.nabp.org
resources, enabling clinical pharmacists to achieve 6. Murphy JE. Predicting the supply of pharmacists. Phar-
excellence in practice and research. macotherapy 2009; 29: 1014–1016.
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 Remington_Pharmacy c02.tex V1 - 04/08/2013 6:24 P.M. Page 11

2
Evolution of pharmacy

The drug-taking animal 11 Transition to a modern profession 22

Prehistoric pharmacy 12 The era of count and pour 24

Antiquity 12 The emergence of clinical pharmacy 25

The Middle Ages 14 The conflicting paradigms of pharmaceutical

care and managed care 25
The Renaissance and early modern Europe 15
The promise of a new century 26
American pharmacy 18
The future 26
Antebellum America: pharmacy finds its niche 20
History as a discipline 26
The search for professionalism 21
A chronology for pharmacists 27
Legislation 21
References 30

The drug-taking animal understood. As with other tools, drugs have been used
to gain increased control over our lives, to make them
Among the several characteristics unique to Homo better and longer. Over the millennia the understand-
sapiens is our propensity to treat ailments, physical ing of how drugs work has changed dramatically, in
and mental, with medicines. From archeological evi- part influencing how they are used (and abused). As
dence, this urge to soothe the burdens of disease is as is often the case with knowledge, however, common
old as humanity’s search for other tools. Like the nod- wisdom about medicines is a mixture of myth and
ules of flint used to make knives and axes, medicines science, folklore, and demonstrated fact. Old ideas
rarely occur in nature in their most useful (or palat- meld with new concepts to produce a faulty jumble
able) form. First, the active ingredients or drugs must that can lead patients into trouble.
be collected, processed, and prepared for incorpora- A basic introduction to the development of ideas
tion into medicaments. This activity, done since the concerning drugs, as well as the evolution of the
dawn of humanity, is still the central focus of the profession, increases the ability of pharmacists to
practice of pharmacy. Put another way, pharmacy is, adjust to the challenges presented as professional
and has been, the art (and later science) of fashioning roles expand. Pharmacists have much to gain from a
one of our most important tools – medicines. basic appreciation of the complex role that drugs and
For today’s pharmacists it is imperative that this medicines have played in the past and of pharmacy’s
deep-seated role of medicines in human history is part in this development.
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12 | An Introduction to Pharmacy

A complete world history of how drug knowledge, evil spirits. Early peoples explained illness in super-
medical progress, commerce, technology, and profes- natural terms, as they did the other changes and
sional development came together to produce modern disasters surrounding them. Treatments followed suit,
pharmacy would fill an entire volume. Instead, this in that beneficial medicines worked through super-
short chapter will tell two parallel stories: how the natural means. The spells of sorcerers, sometimes cast
concept of drug evolved over time and how a separate with the aid of magical substances, could be combated
profession arose to prepare drugs into medicines in with the same remedies.
the West. The magical potions for curing were part of the
Throughout history, drugs have held a special duty of the shaman. Usually in charge of all or most
fascination. Beyond sensational stories of the part things supernatural in a tribe, the shaman diagnosed
drugs have played in exploration, commerce, political and treated most serious or chronic illness. He or
intrigue, scientific discovery, and the arts, they have she compounded the remedies needed to stave off
directly influenced the lives of millions. Drugs such as the influences of evil spells or spirits. This basic pat-
insulin have kept thousands alive, and antibiotics and tern, common among ancient peoples, held sway over
chemotherapeutic agents have saved thousands more. nearly the full span of human existence. The sub-
The simple fact that all drugs become useful through stances of healing potions, connected for thousands
pharmacy bears repeating, and the safe and effective of years with the supernatural world, continue to hold
use of such medicines has developed recently into a a special place, a fascination for all. Thus, out of these
primary concern for this relatively young profession. origins a dual heritage has been derived: drugs as both
Although pharmacy as a skill is perhaps as old as simple tools and substances with nearly supernatural
the making of stone implements, the practice of this powers.
singular art by a recognized specialist is only about The discovery that certain natural substances such
1000 years old. For this specialization to occur a as opium or myrrh could ease the suffering of human
need had to arise – but that is getting a bit ahead of existence, however, should not be trivialized. Even
the story. though early peoples discovered only a small num-
ber of effective drugs, the very concept of influencing
bodily functions via an outside force must be consid-
Prehistoric pharmacy ered one of humanity’s greatest advances. The further
development of this concept required the environment
Since humanity’s earliest past, pharmacy has been of civilization. To flourish, rational medical therapy
a part of everyday life. Excavations of some of needed the tools provided by settled cultures – writing,
mankind’s oldest settlements, such as Shanidar (ca systems of exchange, and weights and measures.
30,000 BC), support the contention that prehistoric
peoples gathered plants for medicinal purposes. By
trial and error, the folk knowledge of the healing prop- Antiquity
erties of certain natural substances grew. Although
tribal healers or shamans often guarded this heal- When organized settlements arose in the great fertile
ing knowledge closely, the recognition of medicinal valleys of the Nile, the Tigris and Euphrates, the
plants, which were sometimes used as food, spices, Yellow and Yangtze, and the Indus Rivers, changes
or charms, apparently was so widespread that it hin- occurred that gradually influenced the concepts of
dered any necessity for a special class of drug gatherers disease and healing. As men and women learned
and keepers. The arts of primitive pharmacy proba- how to control aspects of nature through farming,
bly were mastered by all who practiced the domestic permanent shelter, and large-scale building projects,
medicine of the household. the powers of the gods in day-to-day life started to
When healers at Shanidar or other prehistoric set- decline. These changes are evident among the remains
tlements approached disease, they placed it within of the great civilizations of Mesopotamia and Egypt
the context of their general understanding of the of the second millennium BC, whose clay tablets and
world around them, which was alive with good and papyri document the beginnings of rational drug use.
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Evolution of pharmacy | 13

An examination of these ancient records reveals the god Asklepios, where they would sleep with the
a gradual separation of empirical healing (based on hope of being visited during the night by the god or
experience) from the purely spiritual. For the Baby- his daughter Hygeia, who carried a magical serpent
lonians, medical care was provided by two classes and a bowl of healing medicine.
of practitioners: the asipu (magical healer) and the The rational tradition within Greek medicine that
asu (empirical healer). The asipu relied more heav- was evident in Homer’s work was refined and cod-
ily on spells and used magical stones far more than ified in the body of literature connected with the
plant materials; the asu drew upon a large collection name of Hippocrates of Cos (ca 425 BC). Building on
of drugs and manipulated them into several dosage the foundations laid by previous natural philosophers
forms that are still basic today, such as suppositories, such as Thales (ca 590 BC), Anaximander (ca 550
pills, washes, enemas, and ointments. The asipu and BC), Parmenides (ca 470 BC), and Empedocles (ca
the asu were not in direct competition and sometimes 450 BC), the Hippocratic writers constructed a ratio-
cooperated on difficult cases. Apparently the ill often nal explanation of illness. They accomplished this by
went back and forth between the two types of healers forging a conceptual link between the environment
looking for a cure. and humanity by connecting the four elements of
The extensive records that survive of Egyptian earth, air, fire, and water to four governing humors
medical practices demonstrate a high level of pharma- of the body: black bile, blood, yellow bile, and
ceutical sophistication with a wider range of dosage phlegm. The Greek physician (iatros) who followed
forms compounded from detailed recipes. The Egyp- the Hippocratic method favored dietary and life-style
tian medical texts, like those from Babylon, show a adjustments over drug use. If these conservative meth-
close connection between supernatural and empiri- ods failed, the physician prepared his own medicines
cal healing. Suggested recipes usually began with a or left prescriptions behind for family members to
prayer or incantation. Plant drugs, of which laxa- compound and administer.
tives and enemas were the most prominent, were the Most Greek medicines were prepared from plants,
main vehicle of healing power. As was the case with and the first great study of plants in the West was
healing practices in Mesopotamia, certain individuals accomplished by Theophrastus (ca 370–285 BC), a
specialized in the preparation and sale of drugs. Were student of Aristotle. His example of combining infor-
these early medicine makers the forebears of today’s mation from scholars, midwives, root diggers, and
pharmacists? No, because physicians and other heal- traveling physicians was emulated 300 years later by
ers again took on the duties of medicine preparation Dioscorides (ca 65 AD). The latter Greek physician’s
as these two great river civilizations declined. A fully summary of the drug lore of his times, the Mate-
separate pharmaceutical calling would be centuries ria Medica, became, in its various forms, the standard
away. encyclopedia of drugs for hundreds of years to follow.
During the millennium that followed, the roots Through the teachings and writings of Galen, a
of the modern medical profession in the West arose Greek physician who practiced in Rome in the sec-
out of the flowering of Greek civilization in the basin ond century AD, the humoral system of medicine
of the Aegean Sea. In the earliest records of ancient gained ascendancy for the next 1500 years. Setting
Greece, one finds a similar mixed concept of drug or aside the conservative drug use of the orthodox Hip-
pharmakon, a word that meant magic spell, remedy, pocratists, Galen devised an elaborate system that
or poison. In the Odyssey, Homer (ca 800 BC) refers attempted to balance the humors of an ill individual
to the esteemed medical wisdom of Egypt, thus illus- by using drugs of a supposedly contrary nature. For
trating the ebb and flow of ancient knowledge long example, to treat an external inflammation, a fol-
before the printed word. The early Greek physicians lower of Galen might apply cucumber, a cool and
described by Homer, the demiourgoi, had advanced to wet drug. The same Galenist also might have tried
where they diagnosed natural causes for illness, while bleeding, a favorite treatment to remove the apparent
still not rejecting the use of supernatural healing in excess of blood that caused the illness. In addition
conjunction with empirical remedies. Some people to the practice of bleeding, Galen advocated the use
beset with persistent afflictions traveled to a temple of of polypharmaceutical preparations (what would be
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14 | An Introduction to Pharmacy

termed ‘‘shotgun prescriptions’’ today). He argued sin and disease were related intimately. The stories of
that a patient’s body pulls out the substances that miracles connected with Saints Cosmas and Damian,
it needs to restore humoral balance from a complex twin brothers who healed the sick in ca AD 300,
prescription. exemplifies this attitude. Monasteries became centers
Medicine in classic antiquity reached its pinnacle for healing, both spiritual and corporal, because the
with Galen, and the writers who followed tended two were not viewed as essentially separate. Cast
to be compilers and commentators on his work, not to their own devices, monks put together their own
original thinkers. Galen’s influence was so pervasive short versions of classical medical texts (epitomes)
among medical practitioners that the basics of his and planted gardens to grow the medicinal herbs that
healing approach – the balance of the body’s four were no longer available after the collapse of trade
humors through contrary drugs – mixed with folklore and commerce. Strong in their faith, these amateur
and superstition to guide common people in their healers tended to ascribe their cures to the will of
own treatment of ailments. In the Western half of God, rather than to their meager medical resources.
the Roman Empire, such medical knowledge became As western Europe struggled, a new civilization
especially valuable as civilization crumbled in the arose among those who followed the teachings of
years following 400 AD. Mohammed (570–632). The formerly nomadic peo-
ples who united into the nations of Islam conquered
huge areas of the Middle East and Africa, eventu-
The Middle Ages ally expanding into Spain, Sicily, and eastern Europe.
Because their faith taught them to respect the written
Traditionally, the Middle Ages are defined as the word and those who studied it, they tolerated the
period from the first fall of Rome (ca 400 AD) to the scholarship of the Christian sectarians who had fled
fall of Constantinople (1453). The first half of this persecution in the eastern Roman Empire; the Nesto-
millennium was once referred to as the ‘‘Dark Ages’’ rians, for example, established a famous school in
by historians because of the political and social chaos Gondeshapur in the sixth century.
that existed in the lands that had once been part of the At first the Arabs accepted the authority of Greek
western half of the Roman Empire. Modern historians medical writings totally, especially those of Galen and
have revealed, however, that many advances were Dioscorides. But as their sophistication grew, Islamic
made during the centuries between 400 and 900, medical men like Rhazes (860–932) and Avicenna
including a new, independent calling that emerged (980–1063) added to the writings of the Greeks. The
out of the flourishing Islamic civilization – pharmacy. far-flung trading outposts of the conquering Arabs
The story of how Greco-Roman philosophy, sci- also brought new drugs and spices to the centers of
ence, and art returned to western Europe and sparked learning. Moreover, Arab physicians rejected the old
the creative period known as the Renaissance is one idea that foul-tasting medicines worked best. Instead,
of the most fascinating of human history. It began they devoted a great deal of effort to making their
with the crumbling of civil authority in the west- dosage forms elegant and palatable through the cover-
ern half of the Roman Empire during the fourth ing of pills with gold or silver leaf (gilding or silvering)
and fifth centuries. Greco-Roman culture survived in and the use of sweetened vehicles.
the Eastern (Byzantine) half of the empire, but with The new, more sophisticated medicines required
less creative energy. With Roman authority gone in elaborate preparation. In the cosmopolitan city of
the West, the Church became the stabilizing cultural Baghdad of the ninth century, this work was taken
force, and local feudalism arose to replace centralized over by specialists, the occupational ancestors of
government. today’s pharmacists. In places such as Spain and
The use of drugs to treat illness underwent another southern Italy where the Islamic world interacted most
shift, as pagan temples, some of which had operated with recovering western Europe, several of the institu-
in conjunction with Greco-Roman healing methods, tions and developments of the more highly developed
were closed. Rational drug therapy declined in the Arabic culture – such as the separation of pharmacy
West, to be replaced by the Church’s teaching that and medicine – passed over to the West.
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Evolution of pharmacy | 15

By the mid-thirteenth century, when Frederick time, Johann Gutenberg began printing with movable
II, the ruler of the Kingdom of the Two Sicilies, type, starting an information revolution. Within a half
codified the separate practice of pharmacy for the century, Columbus discovered the New World, Vasco
first time in Europe, public pharmacies had become da Gama found the sea route to India that Columbus
relatively common in southern Europe. Practition- had sought, commerce based on money and banking
ers of pharmacy had joined together within guilds, was established, and syphilis raged through Europe.
which sometimes included dealers in similar goods, It was a time for new ideas through reinterpretation
such as spicers or grocers or physicians. These proto- of the old classical themes, and through exploration
pharmacists usually called themselves ‘‘apothecaries’’ on the high seas and in the laboratory.
after the Latinized Greek term ‘‘apotheca,’’ which The time was ripe for casting off the old concepts
meant storehouse or repository. Like bakers (bakeries) of diseases and drugs of Galen. The new drugs that
and grocers (groceries), apothecaries were identified were arriving from far-off lands were unknown to the
closely with their shops. ancients. Printers, after fulfilling the demand for reli-
Arabic culture had returned classical scientific and gious books such as bibles and hymnals, turned to pro-
medical knowledge to Europe. At centers such as ducing medical and pharmaceutical works, especially
Toledo and Salerno, the writings of the Greeks, which those that could benefit from profuse and detailed
had been translated into Arabic centuries before on illustrations. On the medical side, for example, this
the fringes of the old eastern half of the Roman trend is exemplified in the anatomical masterworks of
Empire, were translated into Latin for the use of Andres Vesalius (1514–1564).
European scholars. Thus, at the emerging universi- For pharmacy, printing had a profound effect on
ties of Europe such as Paris (1150), Oxford (1167), the study of plant drugs, because illustrations of the
and Salerno (1180), scholars discussed the works of plants could be reproduced easily. Medical botanists
medical authorities such as Dioscorides, Galen, and such as Otto Brunfels (1500–1534), Leonhart Fuchs
Avicenna. (1501–1566), and John Gerard (1545–1612) illus-
However, the debates on medicine among Euro- trated their works with realistic renditions of plants,
pean academics were based on speculation, not obser- allowing readers to do serious field work or to find
vation. Theirs was a philosophical pursuit, with no the drugs needed for their practices. Among the most
great impact on medical practice. For significant gifted of these investigators was Valerius Cordus
change to occur in the use of drugs, the scholastic (1515–1544), who also wrote a work in another
approach had to be set aside and a more skepti- popular genre – formula books. His Dispensatorium
cal, observational methodology adopted. This new, (1546) became the official standard for the prepa-
experimental age we now call the Renaissance. ration of medicines in the city of Nuremberg and
generally is considered the first pharmacopeia.
Although they were critical to the advancement
The Renaissance and early of medical science, the nearly modern, precise works
modern Europe of Fuchs and Vesalius did not influence the treat-
ment of disease as much as the speculative, mystically
The Renaissance, simply put, was the beginning of the tinged writings of an itinerant Swiss surgeon who
modern period. Changes that had begun during the dubbed himself ‘‘Paracelsus.’’ Born Philippus Aureo-
European Middle Ages, and were stimulated further lus Theophrastus Bombastus von Hohenheim in 1493,
by contacts with other cultures, gained momentum. the year Columbus went on his second trip, this medi-
The burst of creative energy that would result in our cal rebel represents well the combined attitudes of the
present shared culture of the West stemmed not from common man, the scholarly physician, the practical
a single episode but from a series of events. surgeon, and the alchemist. The battles of Paracel-
In 1453 Constantinople (current Istanbul) fell to sus against the static ideas of Galen, Avicenna, and
the conquering Turks, and the remnants of the Greek other traditional authorities opened a window into
scholarly community there fled west, carrying their the complicated mind of the Renaissance. As Erwin
books and knowledge with them. About that same Ackerknecht observed in A Short History of Medicine,
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16 | An Introduction to Pharmacy

Paracelsus is one of the most contradictory significant investigations into the chemistry of drugs,
figures of a contradictory age. He was more and along the way isolated many drugs that are still
modern than most of his contemporaries in his used today and contributed much to general chemical
relentless and uncompromising drive for the knowledge. During that same period, when men and
new and in his opposition to blind obedience their ships sailed the seas looking for new lands, and
to authoritarianism and books. On the other returned with new drugs, practitioners of pharmacy
hand, he was more medieval than most of explored a much smaller, but equally exciting, world
his contemporaries in his all-pervading mystic in their laboratories.
religiosity. His writings are a strange mix- Much of the stimulation for the early research
ture of intelligent observation and mystical came out of the discovery of drugs in recently explored
nonsense, of humble sincerity and boasting lands. Just as Galen did not know all the diseases
megalomania. in the world, Dioscorides and his Arab elaborators
did not know all the drugs in the world. Tobacco,
Paracelsus was the most important advocate of guaiac, cascara sagrada, ipecac, and cinchona bark
chemically prepared drugs from crude plant and were among the scores of new plant drugs from the
mineral substances, yet he believed firmly that the New World.
collection of those substances should be determined
Cinchona bark, from which quinine was extracted
by astrology. He stated, again and again, his total
in 1820, first came to Europe around 1640, at which
faith in observation while at the same time preaching
point it created a crisis within scholastic medicine.
the ‘‘doctrine of signatures,’’ a belief that God had
Galen’s elaborate system of balancing humors by
placed a sign on healing substances indicating their
using drugs of opposite qualities could not explain cin-
use against disease (e.g., liverwort resembles a liver,
chona bark’s efficacy against malaria. Not only did the
thus it must be good for liver ailments).
bark cure malarial fevers, but also it had little effect
An outspoken enemy of university-educated
on other fevers. Here was something Galen said could
physicians, Paracelsus denigrated their scholasticism
not exist, but Paracelsus insisted must exist – a specific
and wrote his own works in his native language rather
remedy for a disease. This conceptual crisis, plus the
than in the traditional Latin. He harshly criticized
efforts of those advocating chemical medicines, dis-
pharmacy practitioners as well, even though his
placed the therapeutic agreement of Galenism, which
advocacy of chemically prepared medicines was to
had lasted nearly 1500 years. The following period,
spark the growth of the modern pharmaceutical
about 250 years, was a time of therapeutic chaos that
sciences. Chemical processes, especially distillation,
empowered disciples of Paracelsus to isolate the heal- lasted until the present era of modern pharmacology.
ing principles of a drug, its quintessence. Eventually, During the time of turmoil for therapeutics while
as the efficacy of some of these drugs became known, the followers of Paracelsus and Galen argued, the
they entered professional medical practice and calling of pharmacy established the legal and scientific
appeared in books on medicines. Largely by this path, foundations of the modern profession. Out of the
chemistry became an important part of pharmacy’s medieval complex of guilds on the European continent
pursuit of more effective and palatable medicines. grew organizations that represented pharmacy.
Paracelsus and his followers, who chastised prac- As the occupational division from medicine
titioners of pharmacy, soon took a position on the spread north, pharmacy practitioners joined together
forefront of chemistry during the sixteenth century. or aligned themselves with similar groups, such as
The apothecary Johann Hartmann (1568–1631), for the sellers of spices or physicians and surgeons. The
example, was the first professor of chemistry at a guilds of the late Middle Ages and early Renaissance
European university. This trend continued through wielded considerable power, setting up training
the seventeenth, eighteenth, and into the beginning requirements, examinations, and restrictions on the
of the nineteenth century as chemistry emerged as number and locations of shops. Conflicts within
a separate profession. For a period of about 300 guilds of pharmacists and near competitors often
years, a small minority of practicing pharmacists made led to government intervention and new laws that
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Evolution of pharmacy | 17

clarified the professional role of pharmacy. Even- Freidrich Mohr (1806–1879) (improved burette),
tually, however, inter-professional friction would and Henri Moissan (1852–1907). Moissan, a French
lead to the separation of pharmacists into their own pharmacist, received the Nobel Prize in Chemistry in
organizations, often under governmental authority 1906 for his isolation of fluorine.
(e.g., the French Collége de Pharmacie in 1777). Because most drugs before 1900 were derived
The cooperation between pharmaceutical guilds from the plant kingdom, it is not surprising that
and governmental bodies also led to the standardiza- pharmacists dominated the investigation of botanical
tion of medicines through the publication of books drugs during the 1700s and 1800s. In collaboration
called pharmacopeias. Because of greater pharmaceu- with interested physicians, pharmacists documented
tical sophistication, the increased number of herbals the sources of plant drugs around the globe, making
and distillation books, and the availability of new significant contributions to the nascent science of
drugs, physicians wanted assurance that their pre- botany. Combining this proficiency with their skills
scriptions would be prepared uniformly within their in manipulative chemistry, pharmacists continued the
city or state. To this end, in 1499 the guild of physi- search begun by the Paracelsians to find pure healing
cians and pharmacists of Florence sanctioned the principles within medicinal plants.
Nuovo receptario as their book of standards. Histori- Approaching pharmacy with a more modern view-
ans, however, generally credit the Dispensatorium of point, these men sought to isolate pure, crystalline
Valerius Cordus as the first pharmacopeia, which was chemicals that could be measured accurately and
adopted by the government of Nuremberg, Germany, identified chemically. Medicinal preparations of crude
in 1546. drugs, no matter how carefully made, fluctuated con-
It is a bit ironic that from the mid-1600s to the siderably in potency because of the natural variation
mid-1800s, when controversy raged within medicine of active constituents in botanicals. Thus, the pursuit
regarding the proper use of drugs, pharmacy made its of active principles was no easy task, and it fascinated
greatest contribution to science as well as becoming pharmaceutical investigators for nearly 300 years. To
firmly established as a profession on the European con- search, separate, characterize, and identify the scores
tinent. As chemical medicines became more prevalent of chemicals contained in the simplest plant drug was
in medical practice, pharmacists were forced to learn a challenge as great as any exploration.
the new methods of preparation and manipulation. Discoveries came gradually through hit-and-miss
To do so they turned to the most popular textbooks research until the late 1700s, when Scheele, for
on chemistry, which were composed by pharmacists example, extracted several plant acids including
such as Nicaise LeFebvre (Traité de chymie, 1660) and citric acid (1784). The single, most important
Nicolas Lemery (Cours de chymie, 1675). breakthrough occurred during the first decade of the
The volume of chemical discoveries made by nineteenth century when the pharmacist Friedrich
pharmacists would fill a chapter twice this size. Sertürner extracted morphine from crude opium.
Carl Wilhelm Scheele (1742–1786), for example, The announcement of his method opened up the
discovered oxygen in 1773, a year before Priestley, as era of alkaloidal chemistry, which resulted in the
well as chlorine, glycerin, and several inorganic acids. isolation of several pure drugs from crude prepara-
Martin Klaproth (1743–1817) was a pharmacist tions. The French pharmacists Joseph Pelletier and
who pioneered the field of analytical chemistry. Joseph Caventou isolated several alkaloids, notably
Like Scheele, he made his discoveries using the quinine in 1820. Not only were these new, pure
equipment of the pharmacy in which he worked. drugs rapidly adopted by physicians because their
Other pharmacists, such as Andreas Marggraf potency was assured, but their existence allowed
(1709–1782), became such proficient chemists that physiologists to administer drugs accurately during
they pursued chemical work full-time. Along the their research, which became the wellspring for
way pharmacists contributed much to the develop- modern pharmacology.
ment of chemical apparatus, especially analytical Much later, after 1850 or so, the scientific disci-
chemists such as Klaproth, Marggraf, Antoine plines of pharmacy began to become more profession-
Baumé (1728–1804) (modern hydrometer), Carl alized in colleges and manufacturing concerns with a
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18 | An Introduction to Pharmacy

subsequent decline in drug shop science. Pharmacists settlers came to the shores of North America, there
interested in research left the shop behind for the was little to attract trained or established medical per-
institutional laboratory. sonnel. Unlike the lands of Central and South Amer-
Despite the impressive achievements of a few phar- ica, there were no treasures to confiscate or spices
macy practitioners, most pharmacists of the early to export. This was a land for toil, not spoils. As the
modern period viewed science as secondary to pro- frontier was pushed back slowly, most of the populace
fessional and financial success. European pharmacists relied on domestic or ‘‘kitchen’’ medicine guided by
achieved these goals through strict internal controls home medical books (if the settler could read). When
on the profession and relatively cordial relations with this failed, the colonist often turned to a nearby figure
physicians. In some states on the European continent, of authority such as a clergyman or government official
laws limited the number and location of pharmacies, to provide medical advice or guidance.
and dictated the requirements for education and licen- As the colonies grew more prosperous during
sure. Lists of standard prices softened competition. the early eighteenth century, they attracted ambitious
By the nineteenth century, the combination of the businessmen from England, including apothecaries.
fame generated by scientific contributions and solid In the New World, British apothecaries continued to
upper-middle-class credentials had elevated pharma- combine pharmaceutical and medical practice, serving
cists throughout much of Europe to a social position the large segment of the public who could not afford
similar to that of physicians. university-trained physicians. In North America, the
Such conditions did not hold for England, how- boundaries between medicine and pharmacy were
ever, where the position of the pharmaceutical profes- even cloudier, with most physicians having some sort
sion within the hierarchy of healing did not become of shop practice. Most apothecary shops were run
established firmly until the mid-nineteenth century. either by an attending physician or his apprentice, or
The original class of pharmacy practitioners, the by an apothecary hired by the owner-physician. In
apothecaries, had evolved during the 1600s and 1700s other words, most men who practiced medicine for
into a second group of medical practitioners, servicing their livelihood also had their own pharmacy, either
those who could not afford the high fees demanded out of their homes or in doctor shops.
by the small cadre of university-educated physicians. A few eighteenth-century chemists and druggists –
As apothecaries became more and more like gen- practitioners who limited themselves to drug-selling
eral practitioners of medicine, chemists and druggists and medicinal preparation – did practice in the larger
(i.e., those who manufactured and sold drugs and cities on the Atlantic coast. These forerunners of
medicines for the apothecaries) rose up to take over today’s pharmacists had two main areas of sales.
the open pharmaceutical niche. Conflicts and court As druggists they served as wholesalers of the drugs
cases erupted during these years, and the boundaries and medicines used by apothecaries, surgeons,
between the physicians, apothecaries, chemists, and midwives, and physicians. They also undersold the
druggists shifted accordingly. It was during this period apothecaries in the marketing of so-called patent
of confusion within their health community that the medicines (trademarked secret remedies originally
British settled what would become the United States of protected from competition by ‘‘letters patent’’),
America, a situation that contributed to the develop- which became increasingly popular up through
ment of the unique American profession of pharmacy. the Revolutionary War. There were few laws that
directly involved Anglo-American pharmacy during
the colonial period, and no effective laws restricted
American pharmacy the practice of American pharmacy until the 1870s.
Anyone with luck, pluck, and sufficient capital could
The exceptional character of American pharmacy (The open up an apothecary or druggist shop.
discussion on American pharmacy is based in part The hardships imposed by the Revolutionary War
on data from ‘‘Professionalism and the Nineteenth- proved to be critical in the development of a sepa-
Century American Pharmacist,’’ Pharm Hist 1986; rate pharmaceutical occupation in America. Britain
28: 115.) arises out of its remarkable history. When had been the source of almost all drugs dispensed
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Evolution of pharmacy | 19

by physicians and apothecaries. In order to meet New York Hospital (1804), a ‘‘house Surgeon and
demand, American druggists, the wholesale distrib- Apothecary constantly reside in the Hospital – these
utors of drugs, had to learn how to manufacture offices are filled by the students of the Physicians and
their own chemically based drugs and how to make Surgeons belonging to the Hospital, which affords
common preparations of the crude drugs previously an excellent school for the young men appointed to
obtained from Britain. In addition, these druggists those places.’’ The staff apothecary practiced both
had to learn how to imitate the popular British patent pharmacy and medicine in a manner analogous to the
medicines that were so much in demand by the pub- British apothecary of the eighteenth century, going on
lic. To meet war needs wholesale drug firms, such as rounds and treating patients.
that of the respected Marshall family in Philadelphia, By 1811, however, the position of apothecary at
expanded their production capabilities. Out of the the New York Hospital had changed. The person
war came a network for the production, packaging, chosen was a full-time pharmaceutical practitioner
and distribution of drugs and medicines. who was tested, before hiring, on his prowess as a
But a profession of pharmacy, at least as we compounder of medicines. Instead of being obligated
know it, was not spawned during the period of to go on rounds, he was required to stay in the
the Revolutionary War. Pharmacy – the compound- pharmacy at all times. By 1819 the services of the
ing of medicines – still was done almost completely New York Hospital apothecary were so critical that
by physicians in their own shops or offices (con- he was required to put up a $250 bond to guarantee
tinuing to practice according to the model of the that he would not leave his position with less than a
British apothecary) or by their apprentices. Aside from two-month notice.
those wholesale druggists who also had an out front The war with England cut off trade with the
business – that is, a retail store that sold their prod- largest suppliers of drugs and medicines to the United
ucts and filled occasional prescriptions – nonmedical States. In contrast with the stopgap measures used
practitioners of pharmacy were rare and without any during the Revolutionary War, the American drug
sort of group identity. Many of those who did prac- trade during the War of 1812 developed its own
tice pharmacy solely were either immigrants from the resources for the production of basic pharmaceuticals,
European continent or former employees in doctor including patent medicines. When peace returned,
shops who bought businesses from their old physician- some American firms faltered under English pressure,
employers. but others continued and formed the basis for the
To succeed, these chemists needed prescriptions future American drug industry.
to dispense. Back in the 1760s, in his famous Dis- The years following the War of 1812 were transi-
course on medical education, Dr John Morgan, a tional. More and more physicians gained their clinical
pioneer in American medical education, had advo- experience in hospitals and dispensaries instead of
cated the separation of medicine and pharmacy with with preceptors, learning to write prescriptions, rather
physicians writing prescriptions. A few physicians did than compound them. After graduation some of these
follow Morgan’s lead, but the practice did not become young physicians continued to write out prescrip-
common until well into the nineteenth century. Mor- tions, thereby stimulating the growth of pharmacy.
gan himself returned to operating a shop to make As physicians began writing prescriptions for apothe-
ends meet. caries to dispense, concern arose over the consistency
The years surrounding the War of 1812 brought with which these medicines were being compounded.
significant changes in American business and health- In 1808 the Massachusetts Medical Society published
care that strongly influenced pharmacy’s professional a state guide to drug standards, with a national
development. It was not until the early years of the convention of physicians approving a Pharmacopoeia
nineteenth century that American physicians began to of the United States of America (USP) in 1820.
view the special service of an apothecary as distinct Although the USP was not recognized as official by
and essential. The first hospitals of the young repub- the federal government for years to come, it rapidly
lic, for instance, employed medical apprentices as staff became accepted nationally as the primary guide
apothecaries. As described in the Brief Account of the to drugs.
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20 | An Introduction to Pharmacy

The appearance of these books reflected both the from Europe declined, physicians began to rely on the
growing amount of prescription writing and the med- expertise of pharmacy practitioners to detect adulter-
ical profession’s increasing reliance on pharmacists. ated or low-potency drugs.
The number of pharmacy practitioners in urban areas The relationship between the physician and
reached the critical mass necessary for the establish- the druggist began to sour in the 1840s. Feeling
ment of local pharmaceutical societies such as the more confident of their social standing, apothecaries
Philadelphia College of Pharmacy (1821) and the began shifting their efforts from pleasing physicians
Massachusetts College of Pharmacy (1823). These to attending the ills of customers. Consequently,
colleges (the term being used in the sense of asso- American apothecaries took to refilling prescriptions
ciated colleagues) established night schools for the without physician authorization or directly treating
instruction of apprentices and discussion groups on customers, a practice called counter-prescribing. In
scientific pharmacy. The small class of retail apothe- the large cities, doctor’s shops were back on the
caries and wholesale druggists presented no particular rise after a decline of two decades. Medical schools
threat to urban physicians in the first decades of the continued to turn out graduates by the hundreds,
nineteenth century, and the situation provided them most of whom sought their fortunes in urban areas,
with several conveniences. where they would open shop.
As the 1850s progressed, the growth of Ameri-
can pharmacy accelerated. The US Census figures for
Antebellum America: pharmacy druggists and apothecaries in 1850 and 1860 illustrate
finds its niche the dramatic growth in the profession, especially when
compared with physicians. In 1850 and 1860, respec-
The years prior to the American Civil War were to tively, the per capita number of physicians did not
be the most critical for American practitioners of change significantly (1 : 572 to 1 : 576), while the num-
pharmacy; the boundaries of practice between physi- ber of druggists grew by nearly 25% (from 1 : 3778 to
cians and pharmacists that were drawn during this 1 : 2850). This trend continued, at a slightly lower rate,
period still exist relatively unchanged today. Dur- through the rest of the nineteenth century.
ing the 1820s and 1830s, East Coast apothecary American pharmacy was caught up both in devel-
shops became more standardized in their appearance opments within the healthcare sector and in the larger
and in the stock they carried. Pharmacy followed the changes occurring in American commerce. As mass-
trend of specialty retailing and concentrated on drugs, manufacturers began producing drug preparations in
medicines, surgical supplies, artificial teeth and limbs, the late 1850s, less-skilled men entered the ranks of
dyestuffs, essences, and chemicals. Grocers took over pharmacy. With large firms doing much of the com-
the selling of exotic dietary items such as figs, raisins, plicated work, these mere shopkeepers flooded the
and citrus fruits. Drugstores in small cities and towns, marketplace. Physicians had supported the growth
however, tended to keep in stock more general arti- of the pharmaceutical profession largely because it
cles such as glass, paints, varnishes, and oils. Above served their own interests, releasing them from the
all, apothecary shops became the main distributors of drudgery of compounding medicines and stocking a
patent medicines, one of the most profitable lines of shop. Moreover, physicians came to depend upon
merchandise in the history of American business. the expertise of the best druggists and apothecaries.
The educated elite of Atlantic coast physicians With the development of the pharmaceutical industry,
fostered the development of a well-trained, yet sub- however, this relationship changed. As one physician
servient, pharmaceutical profession. They welcomed put it in 1860, ‘‘It is an admitted and lamentable
the early pharmaceutical associations and served as fact that many of those now practicing pharmacy are
faculty for the first American pharmacy schools. totally incompetent to fulfill the responsibilities of the
Physicians voiced support for the growth of an inde- true apothecary. They know nothing of the science of
pendent profession of pharmacy as a ‘‘necessity for a preparing medicines.’’
division of labor’’ to meet the ‘‘growing demands’’ of By the late 1850s, while the general economy was
their communities. As the quality of drugs imported in crisis and secession strife was imminent, physicians
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Evolution of pharmacy | 21

and pharmacists indulged in a great deal of finger- Most American pharmacists, undereducated and
pointing in both the professional and popular arenas. under-skilled, took advantage of the growing number
Both groups blamed each other for the continued of ready-made preparations offered by large firms.
popularity of patent medicines. Moreover, competi- This was in spite of the arguments put forth by the
tion had reached such a high level that it threatened leaders of pharmacy since the 1830s that the special
the integrity of the boundaries that had developed to ability to produce official preparations successfully
separate the two professions. Pharmacists were con- in-house was what made the individual pharmacist
vinced that dispensing physicians and doctor’s shops more than a mere merchant. Moreover, this expertise
were the cause of much of their difficulties, whereas only could be learned through experience, under the
physicians complained about counter-prescribing. watchful eye of a preceptor. As fewer basic ingredients
With no legal restrictions on medical or pharma- for compounding were made in the shop, however,
ceutical practice, the lines of separation between apprentices would become preceptors and pass along
medicine and pharmacy were growing hazy. The their ignorance.
onset of the Civil War ended much of the bickering Pharmacists, at the conclusion of the Civil War,
between apothecaries and physicians. After the War, initially rejected the notion that formal educational
the boundaries between the professions were drawn requirements would solve the problem. They had no
more clearly, aided in part by new approaches to interest in any measures that interfered with their free-
professionalization. dom to practice. Moreover, some immigrants from the
Continent, where states often restricted pharmaceuti-
cal practice, expressed opposition to the legal control
The search for professionalism of pharmacies. Many had come to North America to
open their own shops, rather than wait years in their
In part to raise the stature of their rapidly grow-
native lands for permission.
ing calling, a small group of elite druggists and
In the late 1860s the academic model of profes-
apothecaries met in Philadelphia in 1852 to found
sionalism being worked out by other so-called ‘‘new
the American Pharmaceutical Association (APhA).
professions’’ such as engineering attracted the atten-
They saw the gains made by pharmacy in the 1830s
tion of some pharmaceutical leaders. Using university
and 1840s being swept away by a rising tide of
degrees, plus state licensing or institutional certifi-
destructive competition. For American pharmacists
cation, these new professions set themselves apart
of the mid-nineteenth century, organizations like the
from other occupations as ‘‘communities of the com-
Philadelphia College of Pharmacy or the APhA held
petent.’’ They sought to avoid the ordeals of the
the promise of increasing their professional stature by
marketplace by putting a cognitive gap between their
fostering individual improvement, not by winning the
work and the public’s understanding. Theoretically,
favor of physicians or government bureaucrats.
by controlling admissions to professional schools and
The crux of this independent achievement was the
raising examination standards, destructive competi-
mastery of prescription compounding. The growth of
tion could be reduced or even eliminated.
large-scale pharmaceutical manufacturing during the
Civil War years struck fear in the hearts of pharmacy
leaders. As William Procter Jr stated (1869),
Legislation
Pharmacy may be defined to be the art of
preparing and dispensing medicines, and The APhA responded to the movement of the late
embodies the knowledge and skill requisite to 1860s toward increased public protection and occu-
carry them out in practice. But if the prepara- pational security through law by publishing a model
tion of medicines is taken from the apothecary pharmacy act. Physicians and others concerned with
and he becomes merely the dispenser of them the safe use of poisons and potent drugs had peti-
his business is shorn of half its dignity and tioned state legislatures for laws governing pharmacy.
importance, and he relapses into a simple Initially, pharmacists took a negative view, reacting
shopkeeper. to the idea that physicians or bureaucrats would gain
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22 | An Introduction to Pharmacy

authority over pharmacy practice via state inspectors century, the prestige attached to the sheep-skin at-
or licensing boards. To ensure that the profession’s tracted students to the burgeoning number of schools,
best interests would be protected, the APhA empow- as public expectations increased and ‘‘professional’’
ered a committee to draw up a model law. Reflecting became a coveted title.
the ambivalent attitude of many pharmacists toward Pharmaceutical education around the turn of the
legal regulation, the APhA published and distributed century was related closely to practice as pharmacist-
their model law without endorsement. As small busi- educators such as Joseph Remington replaced the
nessmen, pharmacists did not want outside restriction physicians and other non-pharmacy practitioners who
on their trade. had dominated the earlier schools. Students also had a
During the 1870s state legislatures began con- wide range of possible educational experiences: Many
sidering in earnest pharmacy bills sponsored by if not most taught themselves by reading textbooks
non-pharmacists. Reacting to this trend, pharmacists while working as apprentices. Others attended short-
organized statewide associations to coordinate term cram schools that focused only on passing state
support for their own bills, which were often versions board examinations. Perhaps one-in-five future phar-
of the APhA model. Although not enthusiastic at macists attended one or two years of serious pharmacy
first about regulation of their businesses, pharmacists school. Most of these were small, local schools of
wanted a voice in the process. The eventual success pharmacy that sprang up in medium-sized cities offer-
of their efforts in the 1870s, 1880s, and 1890s ing basic instruction and large diplomas for display.
evinced a changing attitude toward the pursuit of A handful of old-line schools, affiliated with local
professionalism from the 1860s. pharmaceutical organizations in larger cities, pro-
The boundary between masters of the pharma- vided students with excellent practical education, plus
ceutical art and mere store clerks, which had always an opportunity to explore specialty areas of research,
been flimsy, was disintegrating. Pharmacists sought depending on the college’s faculty. And lastly, start-
new ways to demonstrate their competence and to ing with the University of Michigan in 1868, schools
separate themselves from ignorant drug sellers and of pharmacy affiliated themselves with state colleges
quacks. The evidence for this expertise, however, and universities, a trend that altered eventually the
shifted away from individual achievement in the mar- direction of American pharmaceutical education.
ketplace toward group identification and institutional As part of larger university communities, these
certification. pharmacy schools aspired to the high standards of
scholarship exhibited by established disciplines and
other professions. The leaders of the university facul-
Transition to a modern profession ties helped transform pharmaceutical education from
a vocational to a scientific orientation through phar-
The period between 1870 and 1920 was transitional macy programs that emphasized full-time coursework
for both pharmacy and pharmaceutical education. and laboratory study.
Before the Civil War perhaps only 1 in 20 Amer- During this period pharmacy’s part in healthcare
ican pharmacists had finished formal schooling in solidified, as the dispensing of medicines by physicians
pharmacy, which had consisted of night courses to declined. However, the rise of the cut-rate drug-
supplement apprenticeship training. With the passage store and, more importantly, the chain drugstore,
of state laws requiring the examination and regis- also occurred during these 50 years, which further
tration of pharmacists from the 1870s on, pharmacy increased economic pressure on the profession.
became part of the wave of professionalization sweep- Still, most pharmacists worked in their own cor-
ing across American society. The new professionals ner drugstore, which became a fixture in American
based their claims of status on their diplomas and life with its shelves of patent medicines for all ills and
licenses, not their products. a soda fountain for delightful beverages; the propri-
Pharmacy got caught up in this trend, and etor, often called doc, attended to the minor aches
even though state laws did not require a pharmacy and pains of customers or made chocolate sodas
school diploma for licensure until the early twentieth with equal skill. Although the pharmacist relied on
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Evolution of pharmacy | 23

prescription compounding for his professional iden- suffering associated with illness. Even though phar-
tity, this provided only a small fraction of his income. macies served as important outlets for sera, antitoxins,
Most drugstore owners received more income from and vaccines, most of the medicines compounded or
sales at the tobacco counter or the soda fountain. sold by pharmacists around the turn of the century
Beginning in the early 1800s, soda water was sold at eased symptoms, rather than treated root illnesses.
first in pharmacies for its supposed medicinal value. As scientific pharmacology explained how drugs
Masters of natural flavorings, pharmacists added new worked on a cellular and organ system level, the con-
specialties that became the basis of the American soft- cept of drugs and their actions held by professionals
drink industry. (Coca-Cola, Dr. Pepper, and Pepsi- and laypeople diverged. The public clung to outdated
Cola all originated at drugstore fountains.) After the ideas of humoralism augmented by a modicum of
Civil War, soda water concoction sales grew rapidly germ theory. Such beliefs made consumers suscep-
and stores added elaborate beverage counters of mar- tible to patent medicine advertising, which misled
ble, chrome, and glass that became identified with the them into equating the effects of strong laxatives
institution of the American drugstore. and analgesics with the cure of disease. With far
To protect this independent and uniquely Amer- greater understanding of the nature of disease, health
ican style of practice from the incursion of larger professionals joined together with muckraking jour-
retailers, the National Association of Retail Druggists nalists and politicians of the Progressive Era to attack
patent medicine cure-alls. The 1906 Pure Food and
(NARD) was founded in 1898. At first the APhA
Drug Act, passed mainly in response to poor food-
welcomed and cooperated with the new national
production methods, also addressed problems in the
organization, but the split that eventually developed
drug trade. Even though it proved ineffectual against
between the APhA, which was oriented to scientific
patent medicine fakery, the 1906 act did establish the
and professional advancement, and NARD, which
United States Pharmacopeia as well as the National
concentrated on the individual commercial success of
Formulary of the APhA as official compendia, pro-
owners, weakened the profession’s voice in national
viding the United States with truly national drug
affairs in the years to come.
standards for the first time.
It was an exciting time in medicine, with thera-
It was during these years that pharmacists finally
peutics undergoing a transformation. The germ theory
abandoned the in-shop manufacturing of the ingredi-
of disease, championed by laboratory scientists such
ents of their prescriptions. The pharmaceutical indus-
as Louis Pasteur and Robert Koch, resulted in signifi-
try had progressed to the point where they could
cant immunological advances in the 1880s and 1890s.
produce basic preparations of crude drugs more
Pasteur’s rabies vaccine and Emil von Behring’s diph- cheaply and reliably than could the individual practi-
theria antitoxin demonstrated that cures for infectious tioner. Moreover, industry was the source for the new
diseases could arise from the laboratory. Paul Ehrlich synthetic drugs such as antipyrine and aspirin that
transcended the biological efforts of his predeces- resulted from developments in organic chemistry. As
sors when he introduced Salvarsan in 1910, the compounding, not the making of stock preparations,
first chemotherapeutic agent. Although it fell short always had been the crux of pharmacy practice, this
of Ehrlich’s ideal of a magic bullet, which could change was lamented only by a few of the profession’s
destroy microorganisms selectively without damaging old guard. The hands of pharmacists still fashioned
the patient, Salvarsan did inspire others to search for the essential tools of medicine.
drugs with chemotherapeutic potential. Aside from Pharmacy education adapted gradually to the
the biologicals, however, few of the drugs discovered change. Course-work shifted away from the iden-
during the late nineteenth and early twentieth cen- tification of crude plant drugs and their various
turies had a significant impact on the prevention or preparations to a greater emphasis on the chemical
cure of disease. compatibility of the ingredients within each pre-
Industrial research on drugs produced several new scription. The professional credentials of American
agents, such as the analgesic and antipyretic aspirin or pharmacists were strengthened in 1932 when a four-
the sedative chloral hydrate, that reduced the pain and year BSc degree became standard for licensure. For the
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24 | An Introduction to Pharmacy

next three decades pharmacy schools graduated phar- Pharmacists, however, were not at a loss for work.
macists who could claim to be chemists on the corner. The number of prescriptions grew even faster as
Yet at the same time that the profession achieved the new, effective drugs came onto the market in the
goal of a scientifically trained workforce fully capable 1950s, 1960s, and 1970s. In community pharma-
of carrying out all the steps involved in the making cies the income from the sale of prescription drugs
of medicines, the technology of the pharmaceutical increased faster than out-front sales of over-the-
industry assumed that responsibility. counter medicines, cosmetics, and other traditional
drugstore goods. Chain stores and other large retail-
ers rushed into the drug business in the post-war era,
The era of count and pour displacing the independent corner drugstore as the
typical purveyor of pharmaceutical services, especially
The middle third of the twentieth century was a time in urban areas by the 1980s.
of dramatic change for all of medical care including Modifications in pharmaceutical legislation and
pharmacy. In therapeutics, many of the great scourges education reflected these dramatic changes in thera-
of humanity were conquered through the introduction peutics and practice, to varying degrees. Federal laws
of antibiotics. Although the phenomenon of antibio- regulating the production of drugs and pharmacy
sis had been observed by Pasteur in the 1870s, the practice were modernized in 1938, 1952, and 1962,
first significant antibiotic substance was not discov- the last set of amendments requiring that medicines
ered until Alexander Fleming noticed the effects of a be judged both safe and effective to be on the mar-
colony of penicillium mold on a misplaced petri dish ket. Laws regulating drugs of high abuse potential
in 1928. Development of penicillin did not occur, were updated through the Drug Abuse Act of 1970,
however, until a decade later when the threat of war which was subsequently enforced through the Drug
in Europe inspired a British team to pursue the scaled- Enforcement Agency. In contrast to the law, educa-
up production of the drug. Other antibiotics followed tional reform came more slowly.
shortly, as did new classes of therapeutic agents, such Proposals for six-year Doctor of Pharmacy degrees
as the corticosteroids, tranquilizers, antidepressants, to elevate the professional standing of pharmacy
antihypertensives, radioactive isotopes, and oral con- gained interest in a few places, with the first such
traceptives. The pharmacy, which had served as an program initiated at the University of Southern Cal-
outpost for the relief of suffering and the treatment of ifornia in 1950. But, as a whole, pharmaceutical
minor ailments, came to hold preventives and cures educators compromised and selected a five-year bach-
for serious disease. elor of science in pharmacy as the standard degree
Following World War II American pharmaceuti- beginning in 1960. The pharmacy curriculum contin-
cal firms applied high technology to the production ued to emphasize the physical sciences that underlie
of medicines and rapidly became one of the most the making of medicines, however, ignoring the fact
advanced industries in the world. New drugs, new that compounding was disappearing from American
dosage forms, and new marketing methods rein- pharmacy practice.
forced a trend evident from the early 1900s of Because of the large growth of prescribing, com-
physicians shifting away from prescribing complex munity pharmacists of the 1950s and 1960s stepped
mixtures of ingredients toward ready-made, single- back from soda fountains and cigar counters to prac-
entity medicines mass-manufactured by large compa- tice pharmacy nearly full time. Yet, for all of their
nies. In the 1930s about 75% of prescriptions required education, they did little more than routinely fill
some compounding by a pharmacist; by 1950 that prescriptions – placing a small number of dosage units
figure had dropped to about 25%. The movement from a large bottle into a smaller, properly labeled
away from prescriptions ‘‘tailor-made’’ for each indi- one. Despite the added responsibility of distributing
vidual patient accelerated so that by 1960 only about the hundreds of new and potent medicines coming on
1 in 25 prescriptions needed the compounding skills the market, pharmacists had little opportunity to use
of a pharmacist, with the trend leveling out around their four, five, or six years of higher education. The
1970 at about 1 in 100. restricted role of the pharmacist is exemplified by the
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Evolution of pharmacy | 25

following statement from the Code of Ethics of the declined. Pharmacists, by sharing insights into the
APhA, which was in effect from its adoption in 1952 workings of medicines with their patients, became
until its revision in 1969: trusted professionals in American society.
Aside from recent innovations in the relationship
The pharmacist does not discuss the thera-
between pharmacist and patient, several other notable
peutic effects or composition of a prescription
changes have occurred within American pharmacy
with a patient. When such questions are asked,
that have gone relatively unnoticed by the public. Out-
he suggests that the qualified practitioner (i.e.,
wardly, the practice of pharmacy today differs little in
physician or dentist) is the proper person with
appearance from that of 60 years ago. An individual
whom such matters should be discussed.
hands over a small slip of paper received from a physi-
In 1969 the APhA revamped its Code of Ethics in cian to a pharmacist who then retreats into a work area
the face of the large changes occurring in pharmacy. and appears later with a container of medicine. But on
Instead of deferring to physicians, the APhA advanced closer examination, the changes seem revolutionary.
this statement as the first section of its Code: ‘‘A phar- For example, women, who made up only 4% of the
macist should hold the health and safety of patients profession in 1950, entered the field rapidly starting
to be of first consideration; he should render to each in the 1970s. By the year 2007 they were approx-
patient the full measure of his ability as an essential imately 50% of the pharmaceutical workforce and
health practitioner.’’ This dramatic reversal resulted should remain the majority into the foreseeable future.
from a new idea that swept through pharmacy during Pharmacists, traditionally conservative in the
the mid- to late-1960s called clinical pharmacy. face of technological innovation, adapted computer
technology to their work as quickly as any other
profession of the late twentieth century. Institutional
The emergence of clinical pharmacy
practice, once viewed as the lowest rung on the
profession’s ladder, became the work area of choice
The concept of clinical pharmacy sprang from a
for graduates during the 1970s and 1980s, a period
combination of factors, including the development
of unprecedented hospital growth. Just as the division
of the subdiscipline of hospital pharmacy since the
of labor opened up a niche for pharmacists in the
1920s, the growth of clinical pharmacology since the
early 1800s, pharmaceutical specialties such as radio-
1940s, innovative teaching programs connected with
pharmacy, clinical pharmacotherapy, and nutritional
the new PharmD degree, the decline of pharmacology
support practice have demonstrated the maturity of
instruction in medical schools, and the appearance
the American pharmaceutical profession. Once rele-
of office-style community pharmacies exemplified by
gated to counting and pouring, pharmacists headed
Eugene V. White’s practice in Berryville, Virginia.
institutional reviews of drug utilization and served as
To some extent, pharmacy took over an aspect of
consultants to all types of healthcare facilities.
medical care that had been partially abandoned by
physicians. Overburdened by patient loads and the
explosion of new drugs, physicians turned to pharma-
The conflicting paradigms of
cists more and more for drug information, especially
within institutional settings. pharmaceutical care and managed
Viewed historically, however, the expansion of care
pharmacy’s role to include patient instruction on
proper drug use seems a logical extension of the The 1990s in American pharmacy begin with a clar-
pharmacist’s role as toolmaker. Moreover, clinical ion call for a paradigm shift to Pharmaceutical Care,
pharmacy practice bridged the gap between profes- a practice model described by Charles D. Hepler and
sional and lay understanding of drug action. During Linda Strand as ‘‘the responsible provision of drug
the past century medical science far surpassed the therapy for the purpose of achieving definite outcomes
public’s comprehension of physiology and disease. that improve a patient’s quality of life.’’ The diverse
The concept of how the tool of medicine works, once organizations of American pharmacy rallied to this
shared by both doctor and patient, had been lost. The expanded vision of practice. Established schools of
public’s trust in medical practitioners subsequently pharmacy shifted in earnest to all-PharmD programs
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26 | An Introduction to Pharmacy

to better prepare graduates for the expected chal- were included along with the new outpatient drug
lenges. Governmental regulations, such as those con- benefit under Medicare Part D. As defined by the lead-
nected with the Omnibus Budget Reconciliation Act ing pharmaceutical associations, MTM ‘‘is a distinct
of 1990 (OBRA 90), pushed pharmacy in the direction service or group of services that optimize therapeutic
of greater responsibility. OBRA 90 requires pharma- outcomes for individual patients.’’ In contrast with the
cists to provide counseling to Medicaid patients and older, more generalized Pharmaceutical Care model,
to participate in prospective and retrospective drug MTM services are geared toward individualized con-
use review (DUR) programs. Eventually, states added crete plans that often focus on one or more disease
rules calling for more pharmacy services. This new states. In 2005, the Joint Commission of Pharmacy
path to a greater professional role for pharmacists Practitioners (JCCP) adopted a vision statement for
seemed assured. 2015: ‘‘Pharmacists will be the health professionals
As the 1990s moved ahead, it soon became clear responsible for providing patient care that ensures
that the supposed decade of pharmaceutical care optimal medication therapy outcomes.’’ Convinced
was turning into a decade of confusion, conflict, of the importance of obtaining optimal clinical phar-
and controversy. The Clinton Administration tackled macy skills, pharmacy graduates in recent years have
the difficult task of reforming the complex Ameri- flocked to residency programs, a trend that reflects
can healthcare system. This effort failed, but it did their desire to accept further professional responsibil-
inspire a raft of consolidations throughout the phar- ities. The implications for pharmacy of The Patient
maceutical enterprise, which resulted in a leaner and Protection and Affordable Care Act signed by Pres-
meaner industry. Third parties turned to the prin- ident Barack Obama in March 2010 are uncertain,
ciples of managed care to cut costs. Important new however, because of unresolved legal and legislative
classes of drugs appeared, which when combined challenges.
with an aging population, led to a rapid rise in pre-
scription volume. Prescribing further increased under
the pressure of direct-to-consumer advertising, which The future
was given relatively free rein by the late 1990s.
The emergence of Internet pharmacies, building on It is too soon for historians to judge the long-term
the established mail-order business of earlier years, influence of the emerging practice paradigm of MTM.
added to the turmoil of the pharmaceutical market- Two full generations of pharmacists have been edu-
place. Independently owned drugstores closed across cated and trained after the general adoption of the
the nation, replaced in many localities by pharmacies aims of clinical pharmacy. Present day-to-day practice
tucked inside mass merchandisers or grocery stores. reflects this important shift from the product orienta-
As the decade ended with the distractions of the Y2K tion of previous decades to a practice concerned with
non-event, far more pharmacists found themselves patients receiving necessary drug information and pro-
acting as arbiters of managed care squabbles than as fessional guidance. In the midst of a harsh economic
advanced care providers. and political climate, only time will tell if the often
divided and divisive pharmaceutical profession will
unite and continue its progress toward greater societal
The promise of a new century responsibility for the ancient tool we call medicines.

The American people met the twenty-first century

with enthusiasm that turned to wariness and dis- History as a discipline
couragement after the events of September 11, 2001.
Pharmacy entered the new century with hope built Like the other fields of pharmacy described in this
upon the unifying nature of the single PharmD degree textbook, the history of pharmacy is a distinct disci-
for new pharmacists. Various efforts to expand drug pline that produces a body of research. The follow-
coverage for seniors under Medicare came to fruition ing bibliography and chronology, updated from the
in late 2003 when President George W. Bush signed article by Glenn Sonnedecker,1 is provided for those
the Medicare Modernization Act. For the first time interested in pursuing some specific aspect of pharma-
Medication Therapy Management (MTM) services ceutical history. Readers interested in learning more
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Evolution of pharmacy | 27

about important figures in the history of American

1345 Apothecary shops have been established in London.
pharmacy should consult Osol & Hoover2 . Additional
guidance can be obtained from the American Institute 1348 The Black Death (bubonic plague) strikes Europe.
of the History of Pharmacy, University of Wiscon-
sin at Madison, 777 Highland Avenue, Madison, WI 1480 Poison law is enacted by James I of Scotland.
53705. Links to useful websites pertinent to the field
1499 Guild pharmacopoeia is published in Florence, Italy.
are found at http://www.aihp.org.
1529 Paracelsus (1493–1541) publishes his first treatise.

A chronology for pharmacists

1546 The Nuremberg Pharmacopoeia (Dispensatory of
Valerius Cordus) is perhaps the first to become ‘‘official.’’
The dating of events often involves uncertainties,
approximations, and questions of meaning that are 1589 Galileo Galilei demonstrates the law of falling bodies.
not apparent in a concise table such as that below.
Particularly, dates before the eighteenth century often 1604 Louis Hébert becomes first pharmacist to settle in North
America.
are unverifiable or estimated.
1617 Society of Apothecaries in London is organized.
BC
1618 First London pharmacopoeia is published.
2000? Earliest formulary known in history (Sumerian).
1620 Pilgrims settle at Plymouth, Massachusetts.
1500 Ebers Papyrus, Egyptian manuscript pertaining to phar-
macy and therapy. 1628 William Harvey publishes his book on the circulation of
the blood.
460 Hippocrates, famous Greek physician, is born.
1646 William Davis operates an apothecary shop, possibly one
350 Diocles writes an important treatise on materia medica. of the first in America (Boston).

372 Theophrastus (372–285), the ‘‘father of botany,’’ is born. 1665 Sir Isaac Newton describes the law of gravitation.

AD 1680 Antonie van Leeuwenhoek discovers yeast plants.

50 Dioscorides writes an important book on materia medica. 1703 English apothecaries are authorized to prescribe as
well as dispense.
130 Galen, a Roman physician who experimented with com-
pounded drugs, is born. 1715 Bartram’s Botanical Gardens established at Philadelphia.

303 Cosmas and Damian, patron saints of pharmacy and 1718 Geoffroy Étienne/Saint-Hilaire, French pharmacist,
medicine, are martyred. establishes the first tabulation of relationships between
chemical substances.
857 Johann Mesue Senior (777–857), Arabian physician, dies.
1736 First law related to pharmacy in America is enacted in
925 Rhazes (865–925), Persian physician, dies. Virginia.

1035 Avicenna (980–1035), physician and philosopher, dies. 1752 First hospital pharmacy in America is established at
Pennsylvania Hospital in Philadelphia; Jonathan Roberts is
1178 Pharmacists are mentioned in French records. the apothecary.

1180 Guild of Pepperers is already active in London. 1762 Antoine Baumé publishes his Élémens de pharmacie in
France.
1225 Apothecary shop is established at Cologne.
1765 John Morgan, American medical education pioneer, advo-
1297 Guild of Pharmacists is organized in Bruges (Flanders). cates prescription writing in US.
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28 | An Introduction to Pharmacy

1773 Karl Wilhelm Scheele isolates oxygen about 1773. 1823 Massachusetts College of Pharmacy founded.

Joseph Priestley independently isolates oxygen by 1774. 1825 First American professional journal of pharmacy pub-
lished, the American Journal of Pharmacy.
1774 Scheele discovers chlorine.
1826 Antoine Balard, French pharmacist, discovers bromine.
National Association of Retail Druggists is founded in
the US. Hennel synthesizes ethyl alcohol.

1776 Declaration of Independence is written, and the position 1828 Friedrich Wöhler synthesizes urea, thus bridging gulf
of Apothecary General is created for the Continental Army. between organic and inorganic chemistry.

Christopher Marshall, famous American pharmacist, 1829 New York College of Pharmacy is founded.
makes medicines for wounded soldiers.
1831 Chloroform is prepared independently by Justus von
1777 Collége de Pharmacie is established in Paris. Liebig and by Eugene Soubeiran.

1783 Pilâtre de Rozier, a pharmacist, makes first human flight 1832 Pierre Robiquet, French pharmacist, isolates codeine.
in a balloon accompanied by the Marquis d’Arlandes.
1834 Friedlieb Ferdinand Runge, German pharmacist, pre-
1785 William Withering publishes his treatise on digitalis. pares carbolic acid and aniline.

Thomas Fowler introduces Fowler’s Solution (potassium 1842 Crawford Long performs the first operation using ether
arsenite solution). anesthesia.

1787 Ergot introduced in obstetrics by Paullitzsky. 1843 Oliver Wendell Holmes points out that puerperal fever is
contagious.
1790 First US patent law passed. Elisha Perkins takes out first
medical patent in 1796. 1848 First American code of pharmaceutical ethics prepared
by Philadelphia College of Pharmacy.
1793 Yellow fever epidemic strikes Philadelphia.
First drug import law enacted by Congress to curb adul-
Trommsdorff’s Journal der pharmacie is founded, terations.
the first professional-scientific journal devoted to
pharmacy. 1852 American Pharmaceutical Association is founded as the
first national organization.
1798 Edward Jenner publishes his work on vaccination.
1859 Charles Darwin publishes his Origin of Species.
1805 German pharmacist Friedrich Sertürner reports isolation
of morphine. 1865 First international pharmaceutical conference is held in
Brunswick, Germany.
1809 Journal de pharmacie et de chimie founded; first pub-
lished as Bulletin de pharmacie. 1868 University of Michigan opens pharmacy course that will
have far-reaching influence in modernizing American phar-
1811 Bernard Courtois, a French pharmacist, discovers iodine. maceutical education.

1818 French pharmacist-chemists Joseph Caventou and Pierre 1883 First National Retail Druggists Association founded.
Pelletier isolate strychnine.
1888 First National Formulary issued by American Pharma-
1820 Pelletier and Caventou isolate quinine. ceutical Association.

First edition of United States Pharmacopoeia is pub- 1890 Emil von Behring and Shibasaburo Kitasato introduce
lished. serum therapy.

1821 Philadelphia College of Pharmacy is founded as the first 1893 Felix Hoffmann and Arthur Eichengrün discover aspirin.
local association and school of pharmacy in the United
States. 1895 Wilhelm Roentgen discovers x-rays.
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Evolution of pharmacy | 29

1898 Marie and Pierre Curie discover radium. 1948 First Pan-American Congress of Pharmacy and Bio-
chemistry.
1899 Walter Reed proves mosquitoes carry yellow fever.
1949 Cortisone and ACTH are introduced for rheumatic arthritis.
1900 American Association of Colleges of Pharmacy is
founded. Influence for change initiated by analysis and suggested
reforms from Pharmaceutical Survey (US).
1902 First International Pharmacopeial Conference held at
Brussels, Belgium. 1951 First International Pharmacopoeia of the World Health
Organization.
First American PhD supervised in pharmacy granted at
University of Wisconsin. 1952 Chlorpromazine is introduced into psychiatry, thus open-
ing the field of psychopharmacology.
1906 Federal Food and Drugs Act passed in the US.
1955 Salk poliomyelitis vaccine is released for general use.
1910 Paul Ehrlich and Sahachiro Hata introduce ar
sphenamine (also known as Salvarsan or ‘‘606’’) in 1959 Synthetic modifications of natural penicillin introduced.
widespread clinical trial for the treatment of syphilis.
American Society of Pharmacognosy founded.
1912 First Assembly of International Pharmaceutical Federa-
tion at The Hague, Netherlands. 1962 Important amendments of the US Food, Drug, and Cos-
metic Act.
1922 Sir Frederick Banting and Charles Best isolate insulin.
1969 American Society of Consultant Pharmacists (ASCP)
1928 Sir Alexander Fleming discovers penicillin, the first established.
antibiotic.
1973 US Supreme Court decision (No 72–1176) holds that states
1935 Gerhard Domagk introduces prontosil, the first sulfa may require that licensed pharmacists have ownership-
drug. control of pharmacies.

1937 American Journal of Pharmaceutical Education is Congress enacts Health Maintenance Organization Act.
founded, the first periodical devoted to pharmaceutical
education. 1975 Official drug standardization program is unified by US
Pharmacopeia absorbing National Formulary. Report by
1938 League of Nations Commission on International Phar- Study Commission on Pharmacy (AACP) gives impetus to
macopeial Standards holds conferences. trend toward drug information and counseling role of
pharmacists.
1938 Important revision of Federal Pure Food and Drugs Act
(US). 1977 Clinical trials of adenine arabinoside against herpes raise
prospect of controlling viral diseases.
1940 Howard Florey and Ernst Chain hold the first clinical
trials of penicillin. 1979 American College of Clinical Pharmacy is founded.

1942 American Society of Hospital Pharmacists is founded. 1982 Specialty certification begins in American pharmacy with
the board certification of 63 pharmacists in the field of
1944 Antibiotic activity of streptomycin is announced. nuclear pharmacy.

1945 Atomic energy released for use in warfare and medicine. 1984 Drug Price Competition and Patent Term Restoration Act
growth of generics.
1947 Medical Service Corps created in US Army, with phar-
macy represented by special group of commissioned 1986 American Association of Pharmaceutical Scientists is
officers. founded.
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30 | An Introduction to Pharmacy

1989 American Council on Pharmaceutical Education (ACPE)

References
announces intent to develop accreditation standards for
Doctor of Pharmacy programs only. 1. Sonnedecker G. Evolution of pharmacy. In: Osol A &
Hoover JE eds, Remington’s Pharmaceutical Sciences,
14th edn. Easton, PA: Mack, 1970, pp. 16–19.
1990 Omnibus Budget Reconcilation Act (OBRA) requires that
2. Osol A & Hoover JE eds, Remington’s Pharmaceutical
pharmacists counsel Medicaid patients (effective 1993).
Sciences, 14th edn. Easton, PA: Mack, 1970, p. 20.

1995 Pharmacy Technician Certification Board formed.

1996 National Association of Retail Druggists (f. 1898) changes

name to National Community Pharmacists Association.

2003 After 150 years, the APhA changes its name to the Ameri-
can Pharmacists Association.

2006 Outpatient prescription drug coverage becomes part of

Medicare.
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3
The new drug approval process and
clinical trial design

The Food and Drug Administration 31 Clinical trial planning and design 40

Overview of the US drug approval process 32 Summary 49

Post-approval activities 39 References 49

The research and development efforts needed to The initial legislation, the Pure Food and Drug Act
ensure the safety and efficacy of new drugs are of 1906, was passed in response to Upton Sinclair’s
complex, time consuming, and financially risky. exposé of the meat packing industry, The Jungle,
Thousands of compounds undergo extensive testing which described deplorable practices resulting in con-
for every one new chemical that receives marketing tamination. Over time, the authority of the agency
approval.1 Research and development costs for each expanded, but it remained relatively powerless to
new drug product are estimated at approximately effectively assure the safety and efficacy of medicines.
$1 billion.2 It has been reported that only 30% of In 1937, a sulfanilamide product containing diethy-
drugs that reach the marketplace generate sufficient lene glycol as a solvent to enhance the aqueous
revenue to recover the average cost of development.3 solubility of the drug was developed. Diethylene gly-
This chapter discusses the stages of new drug col, however, is a highly toxic agent used in antifreeze
development and approval in the United States solutions, and numerous deaths resulted from its
with a focus on clinical trial design and method- ingestion. Based on these tragic events, Congress
ology. Readers are encouraged to refer to specific passed the Food, Drug, and Cosmetic Act of 1938,
Food and Drug Administration (FDA) guidance which increased the regulatory authority of the FDA
documents for more detailed information (http:// to oversee the development of new drug products.4
www.fda.gov/Drugs/GuidanceComplianceRegulatory The Act required disclosure of the ingredients and for-
Information/Guidances/default.htm). Note that other mulation, assay methods, manufacturing processes,
countries have similar regulatory authorities that and all animal and human testing to the FDA prior to
oversee drug approvals. the distribution of drug products.
Although the Act of 1938 required new drug
products to be safe, efficacy standards were not estab-
The Food and Drug Administration lished until another tragedy occurred in the early
1960s. Thalidomide, a synthetic sedative/tranquilizer,
The Food and Drug Administration (FDA) oversees had been sold in Europe without a prescription and
the new drug approval process in the United States. was viewed as a possible alternative to the more
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32 | An Introduction to Pharmacy

toxic barbiturates.5 Prior to FDA approval of thalido- Other countries have similar regulatory authori-
mide, several incidences of toxicity in Europe were ties that oversee the approval of new drug products.
reported. Severe birth defects were noted when the For example, the European Medicines Agency (EMA)
drug was administered to pregnant women, the most regulates most European markets. The pharmaceu-
common being phocomelia or arrested limb devel- tical industry and regulatory authorities, including
opment. These events brought about the Kefauver- the FDA, have been working closely with the
Harris Amendments of 1962, which strengthened International Conference on Harmonization (ICH)
existing laws and emphasized the need for the safety of to develop standardized regulatory processes for the
approved drugs.6 These Amendments required man- major markets and allow results of international
ufacturers to establish both safety and efficacy of new clinical trials to be used to support approvals across
drug products prior to approval and required investi- countries.
gators to file Investigational New Drug Applications
(INDs) prior to testing drugs in humans. As a side Overview of the US drug
note, thalidomide is currently approved in the United
approval process
States for the treatment and prevention of painful
skin lesions associated with erythema nodosum lep-
As mentioned previously, drug discovery and develop-
rosum and multiple myeloma. Other potential uses of
ment is a complex and expensive endeavor. The next
this drug under investigation include several types of
several sections of this chapter discuss the new drug
cancer, Crohn’s disease, and autoimmune deficiency- development and approval processes in the United
associated diseases.5,7 States. Although focused specifically on the CDER
The role of the FDA is to promote and protect the and new drugs/drug products, similar requirements
health of Americans. A multidisciplinary staff, con- exist for biologics. Medical devices are approved in
sisting of pharmacists, physicians, pharmacologists, a different manner, depending on how they are used
chemists, statisticians, attorneys, and other scientists, and their invasiveness on human functions. Devices
as well as administrative personnel, is employed at the require an approved Investigational Device Exemp-
FDA to achieve this goal. The FDA consists of several tion (IDE) prior to beginning clinical studies. The
Centers, each designated with specific responsibilities. drug approval process is divided into two sections:
The Center for Food Safety and Applied Nutrition (1) preclinical testing (lead compound selection and
oversees food and cosmetic products. The Center for animal testing of new chemicals) and (2) clinical test-
Veterinary Medicine is responsible for animal feed ing (administration of new chemicals to humans).
and drugs. The Center for Devices and Radiologi- Figure 3.1 shows a schematic of these steps.
cal Health covers the safety and efficacy of medical
devices. This Center also oversees radiation-emitting
Drug discovery and lead
devices, such as lasers, x-ray systems, microwave
compound selection
ovens, and cellular telephones. The Center for Bio-
logics Evaluation and Research (CBER) supervises Pharmaceutical companies begin the discovery
biologics. Finally, the Center for Drug Evaluation process by targeting a broad disease category (for
and Research (CDER) is responsible for drugs and example, cancer or cardiovascular disease) or a
drug products. In addition to reviewing the safety and specific disease state (for example, breast cancer or
efficacy of all prescription and over-the-counter drug hypertension). A chemical with potential therapeutic
products prior to marketing, the CDER is respon- benefit(s), known as a lead compound, must first
sible for monitoring drug safety after initial market be identified, and researchers use various high-
approval and has the authority to withdraw drugs throughput assay techniques to rapidly screen large
posing significant health risks from the market. The numbers of chemicals for biological activity.
CDER provides healthcare professionals and con- Random screening, as the name implies, requires
sumers with drug-related information and screens biological testing of a large variety of diverse com-
television, radio, and print ads for truthfulness and pounds from existing chemical libraries. Although less
balance. up-front financial investment is needed, thousands of
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The new drug approval process and clinical trial design | 33

Preclinical Revision Clinical

testing Chemical hold
(4+ years) synthesis and
scale-up testing

Biologic
Drug discovery Formulation
activity IND IND
and development
testing application filing
lead compound
(in vivo) and stability
selection

Safety testing in
animals

IND
approval

Phase i Phase ii Phase iii

clinical trials clinical trials clinical trials
(20–80 healthy (100–300 patient (1000–3000 patient
volunteers*) volunteers) volunteers)

Clinical
testing
(6+ years)

Revision NDA
filing

FDA FDA conditional FDA

disapproval approval approval

Market

Post-approval safety
reports to FDA

Figure 3.1 Schematic of the new drug approval process in the United States. For life-threatening illnesses such as cancer,
patients enrolled in Phase I studies may suffer from the disease.

compounds may be screened and tested before one are randomly added to enhance biological activity.
agent with significant biochemical activity is identi- This technique is a more expensive, more complex
fied. A more mechanism-based drug design is targeted method of identifying potential lead agents. Another
synthesis, where researchers focus on one step in a method to enhance biological activity is drug model-
disease process as the target for drug intervention. ing, where computers are used to manipulate virtual
Although an extensive knowledge of the disease state structures and calculate protein binding capabilities.
is required, this more directed approach increases Although initial costs are significant, drug modeling
the likelihood of successfully identifying a lead com- techniques show a great deal of promise for future
pound. In combinatorial chemistry, one compound is drug discovery as more research is conducted to iden-
used as a base chemical and various functional groups tify biochemical pathways. Generally, these discovery
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34 | An Introduction to Pharmacy

techniques are used in combination to identify lead the most appropriate animal model to predict human
compounds.8 – 10 response is not known, thus toxicity studies are con-
ducted in at least two animal species, one rodent and
one nonrodent, to obtain a comprehensive view of
Preclinical testing
the potential toxicity. Early ADME or toxicity prob-
A multidisciplinary team of researchers works to lems may be corrected by slight modifications in the
determine many of the lead compound’s critical prop- chemical structure of the new entity.
erties. This team might continue to work with the Animals should be given the new drug product by
compound throughout the entire development pro- the same route intended for humans. Certain dosage
cess or the development responsibilities might be forms, such as aerosol, nasal, or buccal delivery sys-
transferred to another group of scientists during the tems, might be difficult to administer to animals. In
clinical testing phase. Preclinical testing includes: these circumstances, alternative drug delivery routes
may be used, and the selected route of administration
• discovery testing to ensure biological activity
should ensure sufficient exposure to the new chemical
in vivo
entity. During animal safety testing, dosing studies
• chemical synthesis and scale-up to ensure adequate
are conducted, and the highest no-effect dose is deter-
quantities of high purity can be made
mined. In addition to dose, plasma concentrations
• formulation development and stability testing to
of the drug are followed, and noted toxicities are
characterize various chemical properties, develop
correlated to dose and/or plasma concentration.
the initial drug delivery system, and determine the
Generally, once discovery testing shows thera-
stability of the compound
peutic promise, the chemical synthesis, formulation
• animal safety testing to ensure limited toxicities of
development, and animal safety testing occur con-
the lead agent.
currently (see Figure 3.1). Although resources may
At this stage of the development process, good labora- be wasted on earlier failures, successful candidates
tory practices (GLPs) are followed. These regulations, will be ready for human testing more quickly. The
in the Code of Federal Regulations (CFR) 21 Part administration of drugs in humans at the earliest time
58, provide standards for the design and conduct of possible ultimately saves valuable resources, as highly
preclinical studies. Qualifications of personnel and toxic compounds can be eliminated and alternative
requirements for standard operating procedures are lead compounds can be developed.
specified. Additional preclinical studies may be conducted
During discovery testing, the specifics of the com- during clinical testing to support larger trials and,
pound’s properties, such as the mechanism of action eventually, the marketing of the drug product. Formu-
in animal models, compound specificity, duration lation development continues throughout the process,
of action, and structure–activity relationships, are and the data gained from both animal and human test-
determined. Adequate quantities of the new chemi- ing allow for optimization of the drug delivery system.
cal compound must be produced at a high level of It is imperative to identify and resolve formulation
purity. Impurities present at concentrations greater problems early in the development process, as unre-
than 0.1% must be characterized and tested for tox- solved problems will surely re-emerge later, costing
icity. The physicochemical properties of the active the company both time and money as clinical testing is
compound are determined, and development of the delayed. More chronic animal exposure experiments
drug delivery system to be used in human testing are conducted to support further clinical testing.
begins. Animal testing provides initial data regarding
the absorption, distribution, metabolism, and excre- Pre-IND meetings
tion (ADME) in a living system. Possible side effects Pre-IND meetings may be held prior to submission of
and toxicities are noted. Toxicity studies of at least an Investigational New Drug application (IND) and
the same duration as the proposed human testing and at the request of the sponsor, during these early stages
a minimum of two weeks must be completed. Active of development to discuss testing plans and data
and inactive metabolites must be characterized. Often, requirements. These meetings are especially useful
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The new drug approval process and clinical trial design | 35

when a drug has been developed overseas and a under the IND. A subsequent section of this chapter
great deal of preclinical and clinical data is readily describes this process more fully.
available. During pre-IND meetings, the sponsor and Although the trial may proceed, reviewers at the
FDA should agree on the acceptable phase of the FDA may place a ‘‘clinical hold’’ on the trial at any
initial clinical investigation. Clinical data from other time. A ‘‘clinical hold’’ prevents human testing under
countries, if obtained following ICH requirements, the IND until FDA concerns have been adequately
may eliminate the need for Phase I human safety addressed. Reasons for placing an IND under a clin-
testing in the United States. FDA guidance documents ical hold include unreasonable or significant risk of
provide an overview of procedures for requesting illness or injury to trial subjects, insufficient infor-
formal meetings. These meetings are not intended to mation or procedures to assess and minimize patient
replace informal discussions with the FDA. risks, inadequate qualifications of the clinical inves-
tigators, or a misleading, erroneous, or incomplete
Investigational New Drug Investigator’s Brochure (a document containing all
Application (IND) relevant information about the drug). Revisions to
clinical protocols, as well as new protocols or substud-
An IND must be filed with the FDA and approved
ies, are submitted to the FDA as amendments to the
prior to administering new drug products to humans.
IND. Progress reports regarding the trial must also be
The guidelines for preapproval of all clinical testing
provided annually. The contents of the annual report
are specified in 21 CFR Part 312. FDA guidances for
are specified in the regulations. Furthermore, the spon-
INDs can be found on its website. The name and
sor must report any unexpected, serious adverse drug
chemical description of the active components, a list
events that occur during the trial to the FDA and the
of active and inactive components, and the manufac-
IRB within specified time periods.
turers of these components must be provided. The
Not all clinical trials require INDs. A sponsor
method of preparation and the dosage form to be
proposing a trial with a commercially available, FDA-
administered are required. The IND includes all pre-
approved drug product is exempt, if the trial (1) is not
clinical animal data and the names and locations of the
intended to be submitted to the FDA to support label-
investigators performing the planned clinical trials.
ing changes or a new indication; (2) is not intended to
Data from clinical trials conducted in other countries
support a major change in advertising; and (3) does
should also be included. A major component of the
not involve a route of administration, dose, or patient
IND is the study protocol(s) implemented to evaluate
population that significantly increases the risk of the
the drug. The protocol must address all aspects of the
drug. An IND is not required, if the trial is exempt
trial, including study procedures, informed consent,
according to the above criteria, regardless whether a
data collection, and analysis, as well as mechanisms
placebo (inert or inactive treatment) is employed as a
for subject selection, follow-up, and safety monitoring
to protect the patient. Upon receipt, an IND number control group. Independent investigators, rather than
is assigned by the FDA, which is used to track all sub- pharmaceutical companies, often conduct these types
sequent communication between the study sponsor of clinical trials.
and the FDA. The IND is assigned to the appropri-
ate division of the Center for Drug Evaluation and Clinical investigations
Research, and the contents are thoroughly reviewed.
The FDA has 30 days from receipt of the IND to Clinical investigations involve the administration of
decide if the proposed clinical trial should proceed. a drug product to humans. This segment of the
Rather than ‘‘approving’’ an IND, the FDA must pro- drug development process requires substantial finan-
vide notification if the trial is placed on ‘‘clinical hold’’ cial and time commitments.11 Figure 3.2 shows the
pending clarifications or changes to the study proto- considerable increase in development costs associated
col. If no further communication is received from the with the initiation of clinical trials. Human testing is
FDA, the sponsor is allowed to begin the study by divided into four phases, each phase having specific
enrolling patients. Each facility’s Institutional Review objectives. The following sections discuss the various
Board (IRB) must approve the protocol(s) conducted phases of clinical testing.
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36 | An Introduction to Pharmacy

during Phase II testing is common, as the human body

NDA
submission
is more complex than a test tube or animal testing.
As with any study conducted in humans, clinical
Begin protocols for Phase II trials must be sent to the FDA
phase III
Cumulative cost

Preclinical testing
prior to beginning the trial. They may be included as
testing amendments to the IND approved for a Phase I study.
initiated
Begin
Lead phase I
compound testing Phase III clinical trials
selection
At the end of Phase II testing, sponsors are encouraged
to meet with the FDA personnel who are assigned
to the review division for the therapeutic area (for
0 2 4 6 8 10+
example, Division of Psychiatry Products, Division of
Development time (years)
Neurology Products, Cardiovascular Renal Products,
Figure 3.2 Relationship between the time devoted to new etc.). These meetings involve review of the accept-
drug development and dollars invested.6 ability of past trials, the design of future trials, and
the general drug development plan. Scientists at the
FDA carefully review preclinical and clinical data in
Phase I clinical trials evaluating proposed Phase III protocols. Specific areas
The first series of experiments performed in humans of the proposed Phase III trials that are scrutinized
occurs during Phase I clinical testing. A small number include the study objectives, informed consent, inclu-
of healthy volunteers (approximately 20–80 people) sion/exclusion criteria, dosing regimens, methods and
are exposed to the new drug product in closely moni- timing of data collection, duration of treatment and
tored trials primarily to assess the compound’s safety. follow-up assessment, blinding of the drug products
For the investigation of drugs to treat life-threatening and plans for maintaining the blind, plans to assess
diseases, such as cancer or Acquired Immune Defi- compliance with the protocol, identification of pri-
ciency Syndrome (AIDS), patients afflicted with the mary outcome variables, and methods to account for
disease may be enrolled.12 In Phase I trials, the dropouts. Addressing these key areas of proposed
starting dose is low, often one-tenth of the highest Phase III protocols is expected to limit the bias of trial
no-effect dose in the animal models. After the ini- results. An overall goal of the meeting is a good-faith
tial treatment is completed, additional subjects may agreement between the sponsor and the FDA regard-
be recruited, and higher doses may be administered ing data required for submission of a New Drug
to determine the maximum dose tolerated without Application (NDA), the final regulatory hurdle before
significant side effects. During this phase of testing, the drug product can be marketed.
preliminary absorption, distribution, metabolism, and Phase III clinical trials are the longest and most
excretion data of the parent drug and all metabolites comprehensive evaluation of new compounds. Signif-
should be evaluated. Data regarding pharmacokinetic icantly larger numbers of patients (1000–3000) who
and pharmacological effects are used in the design of are afflicted with the target illness are tested. Patients
future Phase II trials. are often recruited, tested, and monitored by several
major hospitals and clinics throughout the country.
Phase II clinical trials Phase III trials may also be conducted internationally.
Phase II clinical testing shifts the focus of the trials In addition to determining efficacy, these trials moni-
from safety to efficacy. In comparison to Phase I tor adverse reactions. The new drug may be compared
trials, a larger number of people (100–300 patients) to existing therapeutic regimens (that is, comparator
are enrolled, and the majority of these participants products) or a placebo. The final market formulation
suffer from the target illness. Side effects from the for the drug product should be optimized prior to the
new drug product are also investigated. These clinical start of Phase III trials. Compounds that successfully
trials are closely monitored and well-controlled (see complete Phase III testing have a 95% chance of being
Clinical Trial Planning and Design section). Failure approved by the FDA.1
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The new drug approval process and clinical trial design | 37

Prior to the completion of Phase III testing and approximately 13 months in 2008 (6 months for pri-
NDA submission, sponsors are encouraged to meet ority review).13 The faster review times have been
with the appropriate review division of the FDA again. attributed to the Prescription Drug User Fee Act
These meetings help establish the format of the sub- (PDUFA) of 1992.14
mission, so that the review proceeds smoothly and to When an NDA is submitted, relevant sections
determine whether additional animal or human trials of the document are distributed to the appropri-
are necessary. The meeting should be held sufficiently ate reviewers and evaluated first for completeness.
in advance of the tentative NDA filing date to allow If the document is sufficiently complete, the NDA
ample time to incorporate recommended changes or is accepted for review and assigned a priority sta-
perform additional trials. tus. NDAs for new chemical entities are classified
as either ‘‘P’’ for priority review or ‘‘S’’ for stan-
Phase IV clinical testing
dard review. A ‘‘P’’ rating is given to new drug
Phase IV trials are post-approval clinical trials products with improved therapeutic effects, safety,
designed for one of several reasons. The FDA and/or side effects in comparison to currently mar-
may mandate Phase IV testing in a specific patient keted drugs. NDAs assigned a ‘‘P’’ rating are expected
population to further assess efficacy and side effects. to be reviewed in a more timely manner than those
Companies may also choose to conduct additional
assigned an ‘‘S’’ rating. If the NDA is deemed too
clinical tests to more fully understand how their
incomplete to review, it is not filed. The decision to
product compares to other commercially available
accept the NDA is made within 60 days of the date of
therapeutic regimens. Since duration of exposure and
submission.
number of patients treated are often limited during
Once the NDA is accepted, detailed evaluation
Phase III testing, Phase IV trials may be required to
continues, and the FDA has 180 days from submis-
assess long-term safety of the drug.
sion to complete the review. Each reviewer submits
written comments of his or her assigned section and
The New Drug Application (NDA) makes a recommendation. The NDA may also be
presented to an Advisory Committee for comment.
Once the Phase III trials have been completed, all
All documents are then compiled and ultimately
preclinical and clinical data are compiled into an
submitted to the Director of the Office of Drug
NDA, which is submitted to the FDA for review.
Evaluation. The FDA may approve the product for
The FDA also reviews the product’s labeling and
package insert. The NDA approval process is the market, approve with specific conditions attached
last hurdle prior to marketing. An NDA document (Conditional Approval), or disapprove the drug prod-
typically consists of hundreds of thousands of pages uct. Primary reasons for disapproval include lack of
and contains highly detailed information. Regulation demonstrated safety and efficacy, issues with the man-
guidelines, including the information required for an ufacturing/processing procedures, or false/misleading
NDA, are provided in 21 CFR Part 314 Subpart B. labeling. If not approved, a letter is sent to the sponsor
Primary items include: detailing deficiencies in the application. If the NDA
is approved, an approval letter, along with a draft of
1. safety and efficacy of the drug treatment(s) the product labeling, is sent to the sponsor. The label
2. components of drug product(s) is a combination of the draft submitted by the spon-
3. description of methods and controls used in man- sor and revisions provided by the reviewing section
ufacturing the active ingredient and drug delivery of the FDA. Standardized labeling requirements are
system and its packaging provided in 21 CFR Part 201.57.
4. proposed labeling. Prior to NDA approval, the FDA conducts an
inspection of the sponsor’s facilities to ensure com-
According to the Center for Drug Evaluation and pliance with current Good Manufacturing Practices
Research, the time for a standard NDA review has (cGMPs) as set forth in 21 CRF Parts 210 and 211.
been reduced from a median of 22 months in 1992 to These are industry standards to ensure consistent
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38 | An Introduction to Pharmacy

quality of manufactured drug products. Preapproval testing is required for most dosage forms. Applicants
inspections are conducted within 45 days of the NDA may request a waiver from performing in vivo bioe-
acceptance. If deficiencies are noted, a letter (FDA quivalence studies for certain drug products where
Form 483) is sent to the sponsor delineating the prob- bioavailability may be established by submitting
lems. Once the deficiencies are resolved, the company (1) a formulation comparison for products whose
must provide written certification, and the FDA will bioavailability is evident (that is, oral solutions,
then clear the application within 45 days, if the cor- injectables) or (2) comparative dissolution. The FDA
rections are adequate. As this step is critical in the provides guidance on establishing bioequivalence. If
approval process, companies often hold mock preap- any portion of the application is not acceptable, a
proval audits. letter of deficiency that details the insufficiencies and
The NDA approval process is complicated and requests additional information and data to resolve
challenging, and may involve several revisions. these concerns is issued. A tentative approval letter
In 2012, 75 to 80% of reviews were approved. delaying the marketing of the generic product may
(http://www.pharmalot.com/2012/06/fda-approvals- be issued, if approval of the generic occurs prior to
are-back-on-track/). the expiration date of patents or exclusivities of the
In response to the FDA Modernization Act of reference drug product.
November 1997, the National Institutes of Health
(NIH), in collaboration with the FDA, established
the Clinical Trials Website (http://www.clinical-
Rapid access to new drug products
trials.gov). This website is a searchable database that As a result of the demand for more rapid access to new
provides information on clinical trials, including the drug products, the FDA has written several regulations
purpose of the study, recruiting status, criteria for and policies specifically designed for drugs intended to
participation, study drug(s), and the location of the treat severely debilitating or life-threatening illnesses.
trials. Investigators are required by law to provide Subpart E (21 CFR 312.80-88) regulations expedite
results on the website once the trial is completed. This the development and approval process. For example,
process was established to ensure that the results of treatment INDs (21 CFR 312.34) are intended to make
nonsignificant or negative studies were made public. drugs relatively far along in the development process
Most medical journals require proof of registry at available to seriously ill patients and are typically made
http://www.clinicaltrials.gov prior to publication of available during Phase III clinical trials.
clinical trial results. Accelerated approval is a mechanism whereby
products are approved for marketing based on limited
data and exposure of small numbers of patients to the
The Abbreviated New Drug
product. Approvals may be granted when studies
Application (ANDA)
have been performed using surrogate endpoints, such
In addition to approving new drug products for the as laboratory finding or physical signs that may not
United States, the FDA is charged with the approval of directly measure patient response yet are considered
generic drug products (21 CFR Part 314). This work is likely to predict therapeutic benefit or delays in disease
accomplished through the Center for Drug Evaluation progression rather than ultimate endpoints, such as
and Research’s Office of Generic Drugs. A generic mortality. The process is limited to life-threatening
drug product must be bioequivalent in comparison indications, such as HIV and cancer. When a drug is
to an approved proprietary drug product. The review approved via accelerated approval, the FDA requires
process for generic drugs is specifically focused on specific post-approval studies be performed within a
bioequivalence testing rather than safety and efficacy. predetermined amount of time. However, often, these
Thus, conventional clinical testing is not required. studies are difficult to perform, because patients may
To be considered bioequivalent, both the rate and not be willing to participate in trials in which the
extent of drug absorption must be within established new treatment may not be given. Thus, completion of
parameters in comparison to the reference drug. these post-approval commitments is often delayed.15
In vivo (within a biological system) bioequivalence For example, from December 1992 to July 2010, the
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The new drug approval process and clinical trial design | 39

FDA approved 47 new oncology indications for 35 all statements and publishes a tentative final mono-
drugs, but only 26 were converted to regular approval, graph. The FDA also publishes the nature of the
within a median of 3.9 years. Delays in completing comments received and provides further opportunity
post-marketing studies have been as much as 10.5 for feedback. Then, the final monograph is published
years.15 Lack of completion of confirmatory trials was in the Federal Register and goes into effect one year
cited as the reason for not moving to regular approval after publication. The monographs establish condi-
among 14 of the 21 indications. Furthermore, as with tions under which OTC drugs are recognized as safe
other FDA approved products, the use of accelerated and effective and are not misbranded. By following a
approval products often extends beyond the approved monograph, a company can then market an OTC drug
indications, because prescribers are allowed to utilize without additional FDA approval. For any unsubstan-
them in off-label settings. tiated claims that a company wishes to make (that is,
claims not approved in the monograph), data must
Orphan drug approval be presented to the FDA to justify revision of the
monograph or the sponsor may submit a NDA.
Orphan drugs are drugs used to treat rare diseases
or conditions that affect less than 200,000 people in
the United States. Orphan drugs go through the same Post-approval activities
FDA review process previously described. However,
the review is expedited, as the majority of orphan Safety monitoring
drugs are used in the treatment of serious or life-
After an NDA has been granted and marketing is
threatening disease. The process by which a company
initiated, drug safety is still monitored. Sponsors of
can file an application for orphan drug designation is
the NDA must periodically submit reports of adverse
described in 21 CFR Section 316.20. Due to substan-
events. For newly approved drugs, these reports are
tial drug development costs, orphan drugs provide
filed quarterly for the first three years, then annually
limited opportunities for companies to recoup their
thereafter. For adverse events that are considered seri-
investments. The United States federal government,
ous and unexpected (that is, fatal or life-threatening,
through the Orphan Drug Act of 1983, established
permanently disabling, or requiring or prolonging
tax incentives, reduced user fees, and created exclu-
hospitalization), the sponsor must provide a report
sivity agreements to encourage research in the orphan
to the FDA as soon as possible (a written report
diseases.16 Grants are also available through the FDA
within 15 days of receipt of the information and
to support clinical research, and annual requests for
a telephone or facsimile report within 7 calendar
applications may be found in the Federal Register.
days). The FDA’s MedWatch program (see http://
Thirty nine new products (new chemical entities and
www.fda.gov/Safety/MedWatch/default.htm) encour-
new biologic license applications) for orphan diseases
ages healthcare providers and patients to directly
were approved in 2012.17
report serious adverse reactions to drugs to the FDA.
The program also provides alerts to practitioners
Over-the-counter drug approval
regarding actions and recommendations by the FDA.
The approval process for over-the-counter (OTC) Serious adverse events may require minor labeling
drugs is considerably different from prescription med- changes or the addition of warning or precaution
ications, and their review is not held to the same statements. If serious safety concerns arise, the FDA
standards as an NDA. The first phase of the approval may withdraw approval of the NDA. Another alter-
process involves an advisory panel consisting of a native is the addition of a ‘‘Boxed Warning’’ in the
multidisciplinary group of scientists that review data product label. Boxed warnings are usually accompa-
provided by manufacturers and other previously pub- nied by a ‘‘Dear Health Professional’’ letter that is sent
lished research. The findings are submitted to the directly to licensed health providers to increase aware-
FDA, and these reports are subsequently summarized ness of the potential problem. The boxed warnings
in the Federal Register. Interested parties are given may specify a newly identified risk or provide addi-
an opportunity to comment. Next, the FDA reviews tional guidelines for use of the products in certain
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40 | An Introduction to Pharmacy

patient groups. Often, an FDA Advisory Committee development are assessed. Potential risk is impacted
reviews the NDA in light of the new data prior to an by the pharmacological profile, specifically the effi-
official NDA withdrawal. In some instances, manu- cacy and toxicity of the drug. The potential expenses
facturers have withdrawn drug products prior to FDA associated with activities required to continue devel-
action.18 opment of the drug are considered, and success in the
For certain medications that pose a serious and marketplace is estimated. Success is determined by the
significant public health concern, the FDA requires the number of competitors, regardless whether the drug
distribution of approved patient medication informa- is the first in its class, and the potential for patients
tion. This Medication Guide is intended to ensure to change from other competing products. Once the
patients’ safe and effective use of the drug products. pharmaceutical company determines the product has
The FDA Amendments Act of 2007 further requires a good potential for success, clinical trials are planned
risk evaluation and mitigation strategy (REMS) from and conducted to move the product forward. The
manufacturers to ensure that the benefits of a drug remaining sections of this chapter discuss the clinical
or biological product outweigh its risks. A draft guid- trial design and planning process for pharmaceutical
ance on the subject of REMS and Medication Guides development and subsequent therapeutic research of
was recently issued by the FDA and can be found on marketed products.
its website, along with a list of products subject to a
risk evaluation and mitigation strategy. Selecting trial objectives
Trial objectives vary depending upon the phase of
Changes to an approved product the trial. Objectives for Phase I trials are limited to
Any change made to an FDA-approved drug product, determining toxicity at a range of dosages. Phase
including component or composition, chemical syn- I trials of treatments for terminal illnesses, such as
thesis, analytical methods, manufacturing site, man- cancer chemotherapy or human immunodeficiency
ufacturing process, batch size, or labeling, must be virus (HIV), may also involve efficacy assessment.
submitted to the FDA. Some of the so-called scale- Objectives of Phase II and III trials are usually based
up and post-approval changes (SUPAC) require FDA upon clinical efficacy of the product in increasingly
approval prior to the implementation of the change. large samples of patients, respectively. Phase IV tri-
Depending on the type of change made and the impact als assess efficacy and side effects in specific patient
the change may have on the quality of the drug prod- populations.
uct, notification to the FDA may be provided through A statement of trial objectives should include, at
annual reports or supplemental new drug applications minimum, the approach of the trial (for example,
(SNDA). to compare, assess, evaluate), the specific disease,
the types of patients, drug therapy(ies) and dosages
being studied, the purpose (for example, safety, effi-
Clinical trial planning and design cacy, pharmacokinetic properties), and the clinical
endpoints to be measured (for example, biologic mea-
Once preclinical testing has been completed, the sure, rate of cure, cost effectiveness).20 Clinical trial
company will determine whether to pursue further objectives drive the entire project, from determina-
development of the drug, often based on the attrac- tion of sample size, to recruitment, to measurement
tiveness and competitiveness of the pharmaceutical.19 of effects of the drug. They also determine feasibil-
The pharmacological profile must be such that the ity of the trial, because trial duration and costs are
product be equal to or better than existing competi- directly impacted by the objective under considera-
tors regarding therapeutic effect. The drug should tion. Objectives involving ultimate outcomes, such
address an unmet medical need or improve therapy in as mortality or hospitalizations, can require dura-
a population of individuals. The incidence of morbid- tions of several years, as well as large sample sizes
ity and mortality associated with the illness impacts and multiple trial sites. Trial objectives limited to
medical need. The market potential must be suffi- pharmacokinetic or clinical measurements may be
cient to sustain profitability, and risk factors for drug conducted over a shorter time period, at a single site,
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The new drug approval process and clinical trial design | 41

and with a small number of patients. Broader objec- of terazosin, an alpha blocker, and finasteride, an anti-
tives have more generalizability and, thus, greater androgen, for benign prostatic hypertrophy.22 The
clinical implications. research question included comparisons between each
Often, several trial objectives are of interest. When drug and each drug versus placebo, plus the combi-
this is the case, the most crucial clinical question nation of both drugs versus the other three therapies.
becomes the primary objective, and the others become Another type of trial is the crossover design.
secondary objectives. Selecting the primary objective Crossover designs allow patients to receive more than
is important, because sample size and data analyses one drug treatment or dosage level during the course
techniques are dependent upon it. Although secondary of the trial. The assumption with a crossover design is
objectives should be assessed in regards to sample size, that the drug therapy does not have a carryover effect
it is understood that sample size may be inadequate between the different treatment periods. Usually, there
to address all of them. Data collection procedures is a ‘‘washout’’ period between drug treatment periods
and statistical analyses are established from the trial in which patients receive a placebo or no medication.
objectives during planning. The length of time of the ‘‘washout’’ period is depen-
Occasionally, results indicate no significant dif- dent on the duration of action and rate of elimination
ference in the primary objective, yet the secondary of the trial drug(s). A key issue addressed in crossover
objectives are significant. An example is the DIG designs is whether the washout period is sufficient to
trial,21 where no significant differences in the primary eliminate potential carryover effects of the drug(s).
objective of all-cause mortality were found between If a drug may have long-term effects after discon-
the digoxin versus placebo treatments, but there were tinuation, the crossover design is inappropriate. In
significant differences in rates and days of hospital- crossover studies, the type or dosage of therapy may
ization and quality of life. Thus, secondary objectives be randomly assigned to allow detection of crossover
can be very important and should be well-described effects (see Table 3.1). During the washout period,
prior to the trial being conducted. trial data and clinical measures are collected to assess
the impact of the previous treatments. These mea-
Trial designs sures are considered baseline data for subsequent
treatments. Crossover designs are efficient in regards
Various designs are used in clinical trials, and the to numbers of patients required to collect a great
most suitable may be related to the testing phase of deal of scientific data. Repeated measures statistical
the research trial. During Phase I trials, all patients analyses are used to account for the potential impact
receive the drug, thus an unblinded, open label trial of collecting data in the same patients over time and
is suitable. In Phase II through III trials, clinical effi- different treatments.
cacy trial objectives usually dictate that the drug be In post-marketing surveillance (Phase IV) tri-
compared to placebo or an alternative therapy. Usu- als, nonexperimental (observational) designs are
ally, patients receive one of the treatments during the used. These include epidemiologic designs, such as
entire course of the trial. This is referred to as a par- case–control or cohort studies, in which drug therapy
allel design. Depending on the objectives of the trial, is not assigned by the researcher.23
the treatments may vary by drug, combinations of
drug therapy, or dosage levels. In some parallel trials,
Controlling for bias
the same patients may receive various dosages of a
drug therapy over time. A factorial design is a type A critical component to minimize bias in a clinical trial
of parallel design used to compare different types and is control of the intervention studied. Control occurs
combinations of drug therapy. It allows comparisons primarily at three levels: assignment of patients to
between single drug therapies and the combination of the interventions, application of the intervention, and
the two drugs. Factorial designs answer several clini- measurement of the trial outcomes.
cal questions with one trial but are complex and must
include sufficient sample sizes to detect differences Assignment of intervention (randomization)
between all treatment options. An example is the Vet- The ability to control assignment is important,
erans Affairs Cooperative Studies Program (CSP) trial because cause and effect relationships between drug
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42 | An Introduction to Pharmacy

Table 3.1 Patient treatment regimens in a crossover design with three treatments and washout periods

Patient First Treatment Washout Period Second Treatment Washout Period Third Treatment

1 A Placebo or no treatment B Placebo or no treatment C

2 A C B

3 B C A

4 B A C

5 C B A

6 C A B

therapy and clinical outcomes can then be established. to each treatment group. This procedure avoids
Unless the assignment is controlled, confounding an imbalance in enrollment between the treatment
variables may affect the outcomes measured in the groups as the trial progresses. Often, the sizes of
trial. Control of assignment of interventions is accom- the blocks of trial patients are randomly varied (for
plished through randomization, whereby patients are example, 8, 4, 16, 12) to help prevent site personnel
assigned to treatment groups by chance. A random- from guessing patient treatment assignment.
ization scheme generated by a computer program or
from random numbers lists is often used to ensure Application of interventions
assignment to treatment intervention is unbiased. The protocol is used to control the application of
In most trials, patients have an equal chance of the intervention during a clinical trial. Unless the
receiving each treatment. However, some trials are interventions are provided similarly to all patients
designed to have imbalance in treatment assignment. between and within each treatment group, variations
For example, if previous clinical research indicates one in outcomes may be due to differences in how the
treatment is likely to be superior, more patients may intervention was administered. Protocols are designed
be randomly assigned to that treatment (for example, to address most potential contingencies that occur
2 : 1 or 3 : 1). Specific statistical analysis techniques during the trial, including requirements for dosage
are used to adjust for the differences in sample size. adjustments associated with varying patient condi-
Stratified randomization is used to adjust for tions. Protocol adherence is monitored throughout
potential differences in response between specific the trial. Deviations from the protocol are docu-
patient groups or trial sites. The characteristic of mented and discussed by individuals administering the
concern (for example, type or severity of disease, trial. Clinical site personnel may need to be retrained
gender, age, race, or site) is determined, and then regarding the protocol or, if deviations are common,
patients are randomized within their stratification the protocol may need revision. In multicenter trials,
group. This assures that equal numbers of patients repeated deviations by a particular site may result in
with these characteristics are assigned to each trial disciplinary action, such as removal from the trial.
treatment. For example, after stratified randomiza-
tion, equal proportions of patients in each treatment Measurement of trial outcomes
group would be male, over age 65, etc. Control of the measurement of trial outcomes is also
Block randomization is also used in clinical trials. critical to decrease bias and is accomplished in sev-
The sample size for a specific number of patients is eral manners. If a special type of measurement tool
established, so that, as randomization occurs, at reg- or instrument is used to measure outcomes, training
ular intervals, equal numbers of patients are assigned of all trial personnel in the use of the instrument is
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The new drug approval process and clinical trial design | 43

performed prior to trial start-up. Training includes an from standard (or placebo) therapy to the new treat-
assessment tool to determine whether personnel are ment? Medical literature and/or specialists in the field
using the instrument(s) uniformly. To eliminate the are consulted to answer this question. If the interven-
impact of different laboratory procedures, a central- tion is unlikely to achieve this difference in outcomes,
ized laboratory for analysis of specimens is often used. then the trial is not feasible. If the difference selected
Another method is to have a centralized group review is so small that it is unlikely to change clinical
and analyze assessments conducted at the trial site(s). practice, the trial will be inefficient or superfluous.
When the determination of a trial outcome (endpoint) The ‘‘clinically-important’’ difference is adjusted
involves medical judgment, a centralized endpoints by the level of inherent error in measurement of
committee is used. The endpoints committee reviews outcome. For clinical outcomes that are parametric
the data and determines whether the outcome assess- measures, which have a definite 0 and are mathemati-
ment has been correctly identified and attributed to cally uniform across the scale of measurements, this is
treatment. The endpoints committee comprises spe- expressed as standard deviation, or the inter-related
cialists in the medical subject of the research. terms, variance, or standard error. The ‘‘clinically-
important’’ difference in outcomes is divided by the
amount of inherent error in measurement of outcomes
Selecting the trial population
to determine effect size of the treatment expected.
Patients are selected for clinical trials using inclusion The statistical alpha level is also incorporated into
and exclusion criteria. For Phase I trials, healthy sample size analysis. Alpha is equivalent to Type I
volunteers are generally enrolled, with the exception error which is defined as the chance of accepting
of drug trials for the treatment of life-threatening the conclusion that treatments are different when the
diseases. In contrast, patients with the disease are two treatments are equal. An alpha level of 0.05 is
enrolled in Phase II and III trials, and the goal is to accepted for medical research. This is equivalent to 5
select patients to participate in the trial who will likely chances in 100 of making the wrong conclusion for
benefit from the treatment. Inclusion criteria are also difference between the treatments.
used to identify patient groups specified by the trial The beta level is known as the chance of a Type
objectives. Exclusion criteria are used to eliminate II error, the chance of concluding that no difference
patients who might be harmed by treatment, who exists between the treatments when difference truly
are unlikely to survive the entire trial period due to does exist. In medical research, beta levels of 0.1 or
nonrelated health problems, or who should not receive 0.2 are generally acceptable. This can be interpreted
the drug treatment due to allergy, concomitant illness, as 10 to 20 chances in 100 that no difference is found
or a contraindication. by the trial when difference truly does exist. Power
of the trial is 1.00 – beta. The concept of power can
be interpreted as the likelihood of finding a difference
Sample size
when difference truly does exist. Thus, power levels
Determination of sample size is a critical aspect of between 80% and 90% are considered sufficient in
clinical trial design. Sample size is based on four medical research.
factors: the expected difference in clinical outcomes Sample size estimation requires consideration of
between the treatments, the level of error in mea- several scientific aspects of the trial. Since all four
surement of clinical outcomes, the alpha level, and factors must be balanced in this calculation, sev-
the power desired for the trial. Table 3.2 depicts the eral potential alternative sample size scenarios are
interrelationships between these four concepts and developed before a decision regarding sample size is
sample size in clinical trials. reached. Planning the appropriate sample size is crit-
The size of the difference between treatments is ical to the success of the trial. An inadequate sample
predicted based on the difference considered ‘‘clini- size may cause the trial to have insufficient power
cally-important’’ and results of previous research. The to detect a significant difference. An excessive sample
question to consider is: How great a difference in the size results in unnecessary costs and risks exposing
outcome is needed for a clinician to consider changing patients unnecessarily to ineffective treatment.
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44 | An Introduction to Pharmacy

Table 3.2 Interrelationships between factors used to determine sample size in clinical trials

Factor in Calculating Sample Size Impact of increasing the factor on Rationale

sample size requirements*

Clinically-important difference ↓ A larger difference between treatments is needed so fewer

between treatments subjects will be needed to determine if the difference exists.

Inherent error in measurement ↑ More error in measurement is less accurate so more subjects
of outcome are needed to overcome the error.

Statistical alpha level ↓ The researchers are willing to accept a greater likelihood of
accepting a difference by chance.

Desired power level ↑ The researchers are less willing to accept that no difference
between treatments exists even when the results indicate it.

∗ Note: For each factor, decreasing the factor will have the opposite impact on sample size requirement.

Feasibility of conducting the trial are used to determine the number of patients required
for recruitment. The rate of estimated enrollment is
Feasibility is dependent on the trial purpose, the
frequently much greater than actual enrollment.24
intended application of trial results, and access to trial
Increasing the number of trial sites can enhance
sites and patients. The question of feasibility comes
access but with substantial cost. Many pharmaceu-
down to overall trial cost and timeline, which are
tical companies outsource this portion of the drug
intertwined with the primary objective and the sample
development process to contract research organiza-
size required to complete the trial. If the trial purpose
tions (CROs) that help identify and provide access to
is extensive and the results are intended to be general- patients. Proper management of outsourcing projects
izable across a broad population, the sample size will can provide a cost-efficient method for new drug
be large. Prevention of disease events may require development, saving a pharmaceutical company time,
long observation periods, significantly lengthening space, and manpower.
trial duration, and, thus, incur greater costs. If the trial
population is transient, it may be difficult to perform
sufficient patient follow-up over long time periods.
Drug product design and blinding
Another aspect of trial purpose that impacts fea- Blinding involves the disguising of drug therapy to
sibility is type of outcome. Outcomes of mortality the patient and health professionals to minimize the
often require lengthy observation periods, depending introduction of bias into the trial. It is often an
on the baseline mortality rate of the trial population. essential characteristic of a controlled trial. Blinding is
Furthermore, outcomes intended to be generalizable categorized as single, double, or triple. Single blinding
across a wide range of patients need broad inclusion indicates that only the patient is unaware of which
criteria and few exclusion criteria to ensure that all treatment group is assigned. Double blinding indicates
relevant types of patients are represented in the trial. that both the patient and the health professional
Lastly, the trial outcome measurements directly affect evaluating the effect and collecting data are unaware
the type and quantity of data required, as well as of trial drug assignment. Triple blinding indicates
additional testing requirements specific to the trial. additional blinding of the Data Safety and Monitoring
Access to trial patients impacts feasibility of con- Board and statisticians, who assess the comparative
ducting the clinical trial. Prior to trial initiation, the safety and efficacy of the treatments during the trial.
number of available patients in a health system is Blinding is achieved by developing dosage forms
estimated, along with the percentage likely to meet of active and placebo (inert ingredients only) or com-
inclusion criteria and agree to enroll. These values parator product that are indistinguishable in size,
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The new drug approval process and clinical trial design | 45

shape, color, odor, weight, and other characteristics. 4 months ± 14 days. Patients taking one or two
Blinding requires some type of manipulation of the tablets daily were dispensed one bottle of 270 dosage
dosage form, and common techniques and considera- units (0.125 mg digoxin or matching placebo tablets),
tions for blinding drug products are presented in Table whereas two bottles were dispensed to patients taking
3.3.25 Ideally, the manufacturer produces a matching three or four tablets daily. Therefore, the package size
placebo (or active comparator) for each drug, using of 270 tablets was sufficient to meet the requirements
a similar formulation but without the active ingredi- of all dosage levels used in the trial for the maximum
ent. However, it may not be economical or timely for 134 day visit window.
the pharmaceutical company to do so. In these cases, Clinical trial drug packaging helps maintain the
the researcher may need to develop matching drug blinding of the drug by ensuring that package style and
products. Irrespective of the technique used, blinding labeling are exactly equivalent between the different
must not significantly alter the drug release character- drugs and their matching placebos (or comparators).
istics, the physical stability of the dosage form, or the Each package is labeled with unique bottle numbers
chemical stability of the active component.26 or patient therapy numbers to ensure that the ther-
In vitro tests for dissolution and potency may apy matches the treatment assignment. A database
be needed to ensure the blinding technique does not is maintained, which provides the correspondence
affect the performance of the dosage form. In addition, between the bottle or therapy number and treatment
the labeling used must ensure that different drugs or assignment. Bottle or therapy number assignments can
dosages used in the trial are indistinguishable. be provided to clinical trial personnel through prede-
When factorial designs are used, blinding of each termined lists or through real-time methods, such as
drug product is required. Although it is sometimes telephone assignment systems, web-based programs,
possible to make all study drugs match, it is more or scanning devices.
common to use a ‘‘double dummy’’ approach, where Complicated dosage regimens must occasionally
a separate matching placebo for each drug product is be accommodated. For example, a patient may receive
used in the trial. For example, a patient may take two induction (ramp-up) dosing, taper dosing, or indi-
placebo products, an active and placebo combination, vidualized dosing with multiple dosage adjustments
or two active drug products. A disadvantage of the during a trial. For oral dosage forms, blister cards
double dummy method is that, for drugs used in mul- can accommodate these alternatives, while helping
tiple daily doses, patients may be required to ingest to minimize dosing errors. For example in a double
a large number of dosage forms each day, which can dummy trial comparing clozapine versus haloperidol,
affect patient adherence to the therapeutic regimen. blister card dosing allowed for combinations of active
and placebo capsules of both drugs to be included
in each daily dosing regimen.28 Patients received
Trial drug packaging
doses based on symptoms of schizophrenia, rang-
Packaging clinical trial drugs involves creativity, as ing from 100 to 1200 mg per day for clozapine or 5 to
well as consideration of the scientific aspects of the 30 mg for haloperidol. Patients received four to nine
study. Drugs are packaged to (1) meet trial design matching capsules daily with combinations of active
requirements, (2) maintain the blinding, (3) min- and placebo capsules of three strengths of clozap-
imize the chances for dosing errors, (4) enhance ine (12.5 mg, 25 mg, or 100 mg) and one strength of
patient adherence to the therapeutic regimen, and haloperidol (5 mg). Patients randomized to clozapine
(5) maintain drug potency/stability. Package sizes (for or haloperidol received matching placebo capsules of
example, count per bottle and number of bottles per the other drug. The use of combinations of active
patient kit) are designed to meet trial requirements of and placebo capsules allowed blinded dosing adjust-
dosage adjustments, clinical visit periods, visit win- ments, as well as induction and taper dosing. Through
dows, and dosing frequency. For example, in the DIG a computerized assignment system, specific cards were
trial,21 patients were dosed from 0.125 mg to 0.5 mg assigned according to the clinical criteria established
(one to four tablets) per day, depending on clinical in the protocol. Once the card was assigned, dosage
response. Patient clinic visits were scheduled for every errors were minimized, because all patients took
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46 | An Introduction to Pharmacy

Table 3.3 Techniques and considerations for blinding of drug products27

Original Dosage Form Technique Considerations

Tablet Removal of markings • Time consuming and manually intensive

• Still must match size/shape/color of tablet
• Process may alter release properties of a film coating

Over-encapsulation • Time consuming and manually intensive

• Patients may open capsule and discover original
dosage form

Grinding and • Properties of new dosage form may be different

re-tableting from original form, affecting patient response
• Complexity in developing new formulation

Grinding and • Properties of new dosage form may be different

encapsulating from original form, affecting patient response
• Assuring consistency in blend of grinded dosage
form while encapsulating
• Manually intensive, unless automated
encapsulating equipment is available

Tablet overcoating • Tablet coatings are developed to match original

dosage form
• Preserves original dosage form
• Pharmaceutical testing (i.e. dissolution) can help
verify similarity to original dosage
• Cannot be used for embossed tablets

Capsules Removal of markings • Time consuming and manually intensive

• Still must match size/shape/color of capsule

Over-encapsulating • Same as above tablets

Grinding and • Capsule shells from original dosage form may be

re-encapsulating visible in manufactured product

Removing ingredients • Manually intensive

from capsule shells and • Time consuming
encapsulating • Capsules may be difficult to open and
contamination by capsule shell pieces may occur

Oral solutions Matching solution without active ingredient • Taste and odor may be unique to active ingredient
• Discoloration of active ingredient over time may occur
and cause unblinding

Injectables Matching solution without active ingredient • May be difficult to obtain in same packaging and labeling
• Differences in odor or color

Blinding just prior to • Unblinded pharmacy personnel prepare injectable

administration dosage form
• Additional opportunity for communication of actual
treatment to trial personnel

Topical, including skin Matching product without active ingredient • Difficult to match packaging, unless prepared by
patches manufacturer
• Odor, texture, or color may differ between products
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The new drug approval process and clinical trial design | 47

the same number of capsules daily, regardless of clinical personnel, as well as signed on the final page
dosage levels. of the document. A copy of this legal document is
Blister card packages can also help improve adher- given to the patient, as well as maintained in patient
ence with orally-administered drugs, because dosage records throughout the trial.
times can be specified on the cardboard overlays. In April 2003, the Health Insurance Portability
In addition, the blister packs provide direct and and Accountability Act of 1996 (HIPAA) was
timely feedback to patients and clinical trial per- implemented. This act provides that patients be
sonnel regarding adherence to the treatment regimen. informed of their rights to maintain the privacy of
Pharmaceutical potency and stability are further con- their health information. Data collection for clinical
siderations for clinical trial drug packaging. Any drug trials is impacted by HIPAA, in that patients must
product not stored in the original manufacturer’s be informed of their rights and provide written
packages should be subjected to periodic, scheduled consent to researchers to access their medical records.
testing (potency, dissolution) to verify stability during Researchers must verify that they will not allow
the clinical trial. data collected during the trial to be distributed with
patient-identifiable information. HIPAA requirements
Regulations governing the conduct can be addressed within the informed consent process.
of clinical trials More information is available at http://www.hhs.gov
Prior to initiation of any trial among human subjects, /ocr/privacy.
approval must be obtained from the investigator’s
Good clinical practice monitoring
local institutional review board (IRB). Composed
of experts and laymen with varying backgrounds, FDA regulations governing the conduct of clinical
IRB committees critically review clinical protocols to trials, referred to as Good Clinical Practices (GCP),
ensure patient safety and institutional, regulatory, and are specified in 21 CFR Parts 50, 56, 312, and 314.
professional acceptability. IRBs also assess the trial In addition, the International Conference on Harmo-
protocol regarding scientific validity and whether the nization has established guidelines to assure patient
study involves unwarranted risks to the patients. The safety during clinical trials at an international level,
IRB also determines if the protocol includes appro- which can be found at http://www.ich.org. GCP train-
priate patient populations and whether inducements ing is necessary for all personnel involved in the
to participate in the trial are reasonable and nonco- conduct of a clinical trial.
ercive. Approval signals that the IRB has determined In addition to addressing patient safety, GCP
the trial is appropriate and does not involve undue regulations help protect against fraud and falsifica-
risks to participants. IRB approval must be renewed tion of trial data. There are significant incentives to
annually for the trial to continue. healthcare professionals to ensure that patients are
A critical aspect of clinical trial conduct is enrolled and complete all follow-up visits and that
informed consent from participants. Participants positive trial results are achieved. These incentives
must be informed of all aspects of the trial, including include direct financial gain, because some trial spon-
the rationale and previous research, potential risks sors reimburse investigators or institutions based on
and benefits, treatment alternatives, the likelihood per capita enrollment and/or follow-up visit. In addi-
of being randomized to a particular treatment, tion, future funding may be discontinued if results are
discomforts associated with the trial, their own negative. Sometimes, clinical researchers even have
ability to voluntarily disenroll at any time, and their financial investments in the company sponsoring the
rights for future treatment should they be affected trial. There are also academic pressures to achieve
adversely by the trial. Informed consent documents positive results, as trials with positive results tend
must be at a reading level understandable by patients. to more likely be published in prestigious journals.
IRB committees review and approve these documents. Failure to attempt to publish negative results has
In addition to written informed consent, the trial been considered a form of scientific misconduct.29
must be verbally discussed with the patient. Each Fraud and falsification of data have been identified in
page must be initialed and dated by the patient and published literature.30,31
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48 | An Introduction to Pharmacy

The GCP monitoring of clinical trials involves coded to a common glossary, so that, although clini-
outside reviewers who monitor trial conduct and data cians may use different descriptors for similar events,
collection. Reviewers are specially trained to match the events can be consolidated. The FDA has adopted
trial data with source documentation (that is, data the Medical Dictionary for Drug Regulatory Affairs
that are not collected as part of the trial) to identify (MedDRA) as the standard coding system for adverse
fraud and falsification of data. GCP monitoring is event reports. Adverse events can be categorized by
required for any trial used to gain FDA approval or type of event, severity, relatedness to study treatment,
change the labeling or advertising of a drug product. intervention used to address the adverse event, and
FDA inspections of study sites are also conducted outcome of the adverse event. Comparisons of inci-
after completion of the trial to verify the appropriate dence rates (the number of events per person-years)
conduct of the trial and the veracity of the results. between drug treatment groups are specified in clinical
The FDA requires that all trial records be maintained trial publications. Adverse event data from a minimal
and accessible at the trial sites for a minimum of two number of patients are required for NDAs. How-
years after marketing or changing labeling of a drug ever, the limited number of patients exposed at the
product. If marketing or change in labeling is not approval stage, usually about 3000–5000, is insuffi-
pursued, records must be maintained for two years cient for determination of rare adverse events. Thus,
after completion of the study and FDA notification. post-marketing studies of adverse events are used
to identify rare events.32 The reporting of unusual
Monitoring and reporting adverse events adverse events to the FDA during clinical trials helps
during clinical trials provide additional data on rare events.
Safety data are important outcomes of clinical trials. For trials over one year in duration, monitoring
Due to randomization, blinding, and placebo control, of the results of the trial is conducted periodically. An
trials can provide unbiased reports of prevalence and impartial group, such as a Data Safety and Monitoring
incidence rates of adverse events. FDA regulations Board (DSMB), provides this oversight. Monitoring
specify how adverse events should be reported. Seri- usually includes both clinical efficacy and adverse
ous adverse events (SAEs) are defined as those that events. Interim reports are provided to the DSMB
result in death, are life threatening, cause hospital- group in a blinded format, so that, although the
ization or prolong hospitalization, cause cancer or treatment groups are compared, the DSMB cannot
congenital abnormalities, or require extensive treat- determine which group is better or worse in terms of
ment to prevent hospitalization. Unexpected adverse efficacy or adverse events. The DSMB has the power
events are defined as events not previously identified to recommend discontinuance of the trial and will do
as associated with the drug by nature of the event, so if there is clear evidence that it may be detrimental
to patients assigned to one of the treatment groups if
its severity, or its frequency. Unexpected SAEs must
the trial continues. This may be due to strong evidence
be reported to the FDA, by telephone or facsimile
of efficacy or safety differences between the groups.
safety reports, within 7 calendar days of disclosure
Interim statistical analyses provided in DSMB reports
to the trial sponsor. SAEs must also be reported to
are preplanned and included in the overall adjustment
site investigators, who are required to report them
for statistical testing.33
to their local IRB. SAEs are summarized in the IND
annual report submitted to the FDA. Furthermore,
SAEs resulting in termination from the trial must also
Overview of statistical analysis of clinical
be included in the IND annual report. All clinical
trial data
and subjective information relevant to the event are It is not possible to provide comprehensive descrip-
reported in the SAEs. For ongoing SAEs, follow-up tions of statistical methodologies in this chapter; the
reports are also completed. reader should refer to statistical textbooks for further
Other adverse events (AEs) are also collected reg- information.34,35 However, certain general statistical
ularly during clinical trials. Although these are less issues are discussed in brief.
severe, they provide important information regarding Good clinical research will always be conducted
the impact of drug therapy. Adverse events are usually using an intention to treat analysis (ITA).36 This
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The new drug approval process and clinical trial design | 49

means that, even if the patient has stopped taking the theoretical underpinnings for the test. The number of
medication, did not complete the assigned treatment, subgroup analyses should be minimized and, if results
or has been switched to an active alternative therapy, of subgroup analyses are published, these limitations
the data from the patient are included in the original should be clearly stated as speculative.
treatment group to which the patient was randomized.
The impact of intention to treat analysis is to lessen
the likelihood of finding a difference between the Summary
treatments. However, the intention to treat analysis
is more analogous to what happens outside of the New drug products must be shown as safe and
clinical trial situation. Patients typically do not fully effective before they are approved by the FDA for
comply with therapy or may change therapies. Thus, marketing in the United States. Other countries have
intention to treat analysis is a key statistical feature regulatory authorities similar to the FDA that oversee
of clinical trials. new drug approvals. This chapter, focused on drug
Adjustment for multiple comparisons is another approval in the United States, outlined the various
statistical consideration of clinical trials. The adjust- stages involved in new drug development, including
ment involves lowering the statistical boundary at the milestones of Investigational New Drug Appli-
which the researcher will consider the results sig- cation and New Drug Application submission. The
nificantly different. When the same data are used costs associated with the development of new drug
for multiple statistical tests, such as in provision of products are substantial, and the most significant
multiple reports to the DSMB, there is an increased expenditures occur during clinical testing. Thus, the
likelihood that a significant difference will be found design and conduct of clinical trials are critical to
by chance. If one considers alpha = 0.05 to be accept- successful drug product development. Several consid-
able, this means the researcher is willing to accept erations in clinical trial design have been highlighted.
one chance in 20 that a significant finding will be in The reader is encouraged to refer to specific FDA
error. By doing multiple tests, for example four tests guidance documents and other referenced materials
on the same data, the alpha level changes to four for further information.
chances in 20 or one chance in five. A conservative
adjustment of alpha for multiple tests is Bonferroni
correction, which involves dividing the alpha level by References
the number of tests. For example, performing four
1. Cato A et al. Current challenges and future directions of
tests at an overall alpha = 0.05 would change to alpha drug development. In: Cato A et al. eds. Clinical Drug
= 0.0125, thus the researcher would not consider Trials and Tribulations. New York: Marcel Dekker,
the result significant unless the statistical finding was 2002: 1–19.
2. Adams CP, Brantner VV. Spending on new drug devel-
p ≤ 0.0125.
opment. Health Economics 2010; 19(2): 130–141.
Another statistical consideration in clinical trials 3. Grabowski HG et al. Returns on research and develop-
is subgroup analysis. Once the data are obtained, ment for 1990s new drug introductions. Pharmacoeco-
researchers sometimes reanalyze data from differ- nomics 2002; 20(Suppl.3): 11–29.
4. Wax PM. Elixirs, diluents, and the passage of the 1938
ent perspectives; for example, dividing the data into
Federal Food, Drug and Cosmetic Act. Ann Intern Med
several different patient groups. Preplanned compar- 1995; 122(6): 456–461.
isons, such as those in secondary objectives, are 5. Matthews SJ, McCoy C. Thalidomide: a review of
acceptable. However, results of comparisons con- approved and investigational uses. Clin Ther 2003;
25(2): 342–395.
ducted post-hoc should be interpreted cautiously,
6. Goyan JE. Science: part of the problem, most of
especially if based on trends in the data, as the find- the answer. Drug Intell Clin Pharm 1983; 17(7-8):
ings may be misleading. Some potential causes of the 566–569.
deceptive findings are (1) the trial was not designed 7. Calabrese L, Fleischer AB. Thalidomide: current and
potential clinical applications. Am J Med 2000; 108(6):
to assure there was adequate sample size for the sub-
487–495.
group analysis, (2) potentially confounding variables 8. Craig 3rd, SP, Eakin AE. Structure-based inhibitor
were not measured or controlled, and (3) insufficient design. Vitam Horm 2000; 58: 149–169.
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9. Lato SM, Ellington AD. Screening chemical libraries 22. Lepor H et al. The efficacy of terazosin, finasteride, or
for nucleic-acid-binding drugs by in vitro selection: a both in benign prostatic hyperplasia. Veterans Affairs
test case with lividomycin. Mol Divers 1996; 2(1-2): Cooperative Studies Benign Prostatic Hyperplasia Study
103–110. Group. N Engl J Med 1996; 335(8): 533–539.
10. Lednicer D. Exploration of a chemical series as a drug 23. Elwood M. Critical Appraisal of Epidemiological Stud-
discovery strategy. Drug Des Deliv 1987; 2(1): 69–78. ies and Clinical Trials, 2nd edn. New York: Oxford
11. Lakings DB. Nonclinical drug development: pharmacol- University Press, 2000.
ogy, drug metabolism, and toxicology. In: Guarino RA, 24. DeSantis P et al. A guide to successfully recruiting
ed. New Drug Approval Process. New York: Marcel patients for cardiovascular clinical trials. Prog Cardio-
Dekker Inc., 2000: 17–54. vasc Nurs 1997; 12(3): 24–31.
12. Lu C et al. A phase I study of topotecan/paclitaxel alter- 25. Carney CF et al. Comparator drugs for clinical trials.
nating with etoposide/cisplatin and thoracic irradiation Pharm Eng 1997; 17(2): 48–56.
in patients with limited small cell lung cancer. Clin 26. Felton LA, Wiley CJ. Blinding controlled-release tablets
Cancer Res 2003; 9(6): 2085–2091. for clinical trials. Drug Dev Ind Pharm 2003; 29(1):
13. FDA (2011). CDER Approval Times for Priority and 9–18.
Standard NMEs and New BLAs* CY 1993–2008. 27. Carney CF et al. Clinical material manufacturing pro-
http://www.fda.gov/downloads/Drugs/Development cess verification/validation. Pharm Eng 1995; 15(3):
ApprovalProcess/HowDrugsareDevelopedandApproved/ 42–46.
DrugandBiologicApprovalReports/UCM123959.pdf 28. Rosenheck R et al. A comparison of clozapine and
(accessed 2 August 2011). haloperidol in hospitalized patients with refractory
14. FDA (2011). Prescription Drug User Fee Act (PDUFA). schizophrenia. Department of Veterans Affairs Coop-
http://www.fda.gov/ForIndustry/UserFees/Prescription erative Study Group on Clozapine in Refractory
DrugUserFee/default.htm (accessed 2 August 2011). Schizophrenia. N Engl J Med 1997; 337(12): 809–815.
15. Johnson J et al. Accelerated approval of oncology prod- 29. Chalmers I. Underreporting research is scientific mis-
ucts: the Food and Drug Administration experience. conduct. JAMA 1990; 263(10): 1405–1408.
Natl Cancer Inst 2011; 103: 636–644. 30. Bivens LW, Macfarlane DK. Fraud in breast-cancer
16. Shulman SR, Manocchia M. The US orphan drug pro- trials. N Engl J Med 1994; 330(20): 1461.
gramme 1983–1995. Pharmacoeconomics 1997; 12(3): 31. Buyse M et al. The role of biostatistics in the prevention,
312–326. detection and treatment of fraud in clinical trials. Stat
17. FDA (2013) Novel New Drugs Summary 2012. Med 1999; 18(24): 3435–3451.
Available at http://www.fda.gov/downloads/Drugs/ 32. Ahmad SR. Adverse drug event monitoring at the Food
DevelopmentApprovalProcess/DrugInnovation/ and Drug Administration. J Gen Intern Med 2003;
UCM337830.pdf (accessed 17 February 2013). 18(1): 57–60.
18. Chaudhry MU, Simmons DL. Case of the month. Hep- 33. Rademaker AW. A guide to sample size and interim
atic and renal failure in a patient taking troglitazone analysis in clinical trials. Contemp Urol 1994; 6(2):
and metformin. J Ark Med Soc 2001; 98(1): 16–19. 43–44.
19. Sedlacek HH et al. The research and development 34. Norleans MX. Statistical Methods for Clinical Trials.
project. In: Ways to Successful Strategies in Drug New York: Marcel Dekker Inc., 2001.
Research and Development. New York: VCH Pub- 35. Cleophas TJ et al. Statistics Applied to Clinical Tri-
lishers, 1996: 49–90. als, 2nd edn. Boston: Kluwer Academic Publishers,
20. Spilker B. Establishing clinical trial objectives. In: Guide 2002.
to Clinical Trials. New York: Raven Press, 1991: 10–14. 36. Sabin CA et al. A practical guide to applying the
21. Digitalis Investigation Group. The effect of digoxin on intention-to-treat principle to clinical trials in HIV infec-
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Engl J Med 1997; 336(8): 525–533.
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4
Information resources in pharmacy and
the pharmaceutical sciences

Introduction 51 Acknowledgments 61

Locating appropriate types of information References 61

resources 51

Introduction appropriate type of literature used. Whereas an expert

may go directly to a database, a less experienced
This chapter describes many significant information pharmacy student who is asked to find primary
resources used by the pharmacy professional stu- literature to write a paper on a therapeutic or phar-
dent, the pharmaceutical sciences graduate student, maceutical topic may first need to get general back-
the pharmacist, and the pharmaceutical scientist. It is ground information from a tertiary resource, such
not possible to be comprehensive, since there is a vast as a textbook, handbook, or subject encyclopedia
array of resources, which is growing exponentially. either online or in print. Once the student is famil-
This chapter arranges the resources in three categories: iar with the basics and the professional vocabulary,
the original research literature or primary literature, he or she will frequently perform a search in either
which comprises the largest volume of the literature; the PubMed/Medline database or the International
the secondary literature, which provides access to the Pharmaceutical Abstracts database to located rele-
primary literature; and the tertiary literature, which vant review articles (secondary sources) and orig-
sums up the best practice based on the primary liter- inal research (primary sources). Fortunately, these
ature. Pharmacy practitioners and PharmD students databases often provide links to the full text of the
use the literature to provide evidence-based medicine journal article. A basic search statement for these
or the integration of the best research evidence into databases should include synonyms for the search
their practice or studies. Pharmaceutical scientists and terms, including professional or scientific terms. The
their graduate students use the literature to support terms can be combined using the OR logical operator.
research in such fields as pharmacology, toxicology, The search can be refined by adding a term, using the
medicinal chemistry, and pharmaceutics. AND operator. For example, if a student is looking
for primary literature on possible future improve-
Locating appropriate types of ments in HPV vaccines, they could try searching for:
information resources (future OR advances OR second generation) AND
(HPV vaccines OR papillomavirus vaccines). Nesting
The nature and depth of the question and the level the parallel terms using parentheses will result in the
of experience of the researcher will determine the most relevant articles. Additional limits, such as a
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52 | An Introduction to Pharmacy

date range and language, can easily be applied to the devised by the Institute for Scientific Information (ISI),
search. which is now part of Thomson Reuters, which mea-
A subject specialist often pursues one or more sures the ‘‘impact’’ of a journal. The Impact Factor
topics over a longer period and can create a series of a journal for a given year is the average number of
of search alerts in a database or set up RSS feeds to times articles published in that journal in the preced-
receive timely, updated search results from a special- ing two years is cited by others. Although this provides
ized database. More information on search updates a general guide, the Impact Factor has its critics.
can be found in the section on Databases. Experts, as well as those new to a field, follow
the primary literature in a few publications related to
their area of interest. Scanning the titles of the research
Primary literature articles, reviewing the abstracts of key articles, and
The first formal reports of scientific or clinical findings reading those closely related to a particular area of
are found in journals. Journals can be distinguished research is the traditional approach to keep up to date
from trade magazines by the lack of advertisements. on the general trends, as well as progress in one’s own
Some primary literature, however, can be found specific area. This can be done by subscribing to print
in several trade magazines under sections entitled journals or simply accessing the websites of the jour-
‘‘Peer-reviewed reports.’’ The peer review process is a nals of interest on which the titles and abstracts are
rigorous evaluation of manuscripts submitted to the generally available without charge. In addition, ‘‘open
journal. After concluding a study, authors write up access’’ journals allow non-subscribers access to the
their findings in a format consistent with the journal’s full-length detailed articles. The Directory of Open
‘‘instructions for authors.’’ The editor of the jour- Access Journals (http://www.doaj.org/) provides an
nal assigns two or more reviewers who are experts up-to-date list. In some cases, journals allow open
in the particular area of research. The reviewers are access to non-subscribers after a period of time, dur-
volunteers from the scientific community who elect ing which only subscribers can view full-length articles
to participate in the peer-review process. In addition on-line.
to the reviewers’ recommendations to the editor on Of the thousands of journals spanning the areas of
whether to publish the manuscript, they provide feed- clinical and pharmaceutical research, as well as related
back to the authors, such as how to make the study areas, pharmaceutical scientists often publish in:
design more clear to the reader and any additional
experiments to allow the conclusions to be stronger. Journal of Medicinal Chemistry (Eaton, PA; American
The peer-review process can take several months Chemical Society)
before the reviewers, authors, and editor agree on Journal of Natural Products (Washington, DC; Amer-
the final text for publication. The process is designed ican Chemical Society and American Society of
so only those manuscripts with clear scientific merit Pharmacognosy)
pass peer-review and are published. Each journal has Journal of Pharmacology and Experimental Thera-
its own criteria for acceptance of manuscripts, which peutics (Baltimore, MD; Williams and Wilkins)
can include whether the manuscript reports results Pharmaceutical Research (New York, NY; Kluwer
within the area of research covered by that journal Academic Publishers)
and whether the contribution is important to the
scientific community. Clinical pharmacists refer to major medical and
The discrimination of the peer-review process is pharmacy journals:
not uniform among all journals. For someone new to
a field, it is difficult to discern which journals pro- American Journal of Health-System Pharmacy
vide the clearest reports that are reproducible and for (Bethesda, MD; American Society of Health-
which the interpretation of the results is thorough System Pharmacists)
without being too speculative. It is prudent to consult JAMA – The Journal of the American Medical
an expert in the field to determine which journals are Association (Chicago, IL; American Medical
best. Additionally, a general ranking system has been Association)
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Information resources in pharmacy and the pharmaceutical sciences | 53

Journal of the American Pharmacists Association Reviews/systematic reviews

(Washington, DC; American Pharmacists As individual articles, the findings in the primary
Association) literature are often more useful to those working
New England Journal of Medicine (Boston, MA; in that specialty than to those new to the field.
Massachusetts Medical Society) A review article that integrates the information from
individual articles from the primary literature may be
Clinical pharmacists also refer to journals that
more useful to someone outside the field or new to
focus on a particular disease state or patient popula-
the field, as reviews provide the perspective gained
tion:
from many authors over many years. Reviews pro-
vide a good starting place for a literature search into
Circulation (Dallas, TX; American Heart Associa-
a new area. When beginning a literature search, one
tion)
can often ‘‘refine’’ his or her search of a database to
American Journal of Veterinary Research (Chicago,
identify only review articles. Additionally, there are
IL; American Veterinary Medical Association)
Diabetes (Alexandria, VA; American Diabetes Asso- an increasing number of journals consisting of only
ciation) review articles, such as Trends in Pharmacological
Pediatrics (Evanson, IL; American Academy of Pedi- Sciences (Amsterdam; Elsevier) and Advanced Drug
atrics) Delivery Reviews (Amsterdam; Elsevier).
Systematic reviews are those with a more struc-
A guide to journals and trade magazines recom- tured methodology to collect and evaluate the primary
mended for the collections of libraries associated literature relevant to a particular research question.
with schools/colleges of pharmacy has been devel- The most common type of systematic review in phar-
oped and is updated by the Libraries/Educational macy literature is the meta-analysis. Using carefully
Resources Section of the American Association selected sets of data from the primary literature and
of Colleges of Pharmacy (http://www.aacp.org weighting their findings according to a protocol, the
/governance/SECTIONS/libraryeducationalresources meta-analysis can use the much larger pool of data
/Pages/LibraryEducationalResourcesSpecialProjects- to produce quantitative findings. The use of statis-
andInformation.aspx). The 2013 list has 693 entries. tical measures and the large number of data can
When searching for primary resources, patents often produce a clearer answer from many some-
and dissertations should also be considered. The pur- times contradictory findings in the primary literature.
pose of a patent is to protect intellectual property, not More information on meta-analysis can be found
disclose research findings. So, information claimed in in Cochrane Handbook for Systematic Reviews of
patents should not be considered equal to that found Interventions.1
in peer-reviewed research articles. Similarly, disser-
tations have not undergone the rigorous peer-review
Databases
process; however, they can be quite useful to find
details of studies that are too lengthy to include in a Bibliographic databases provide access to original
journal article. research articles or the primary literature and cover
a wide range of specialties, depth, and breadth of
the literature. It is important for the searcher to
Secondary literature-reviews and consider the goal when selecting a database. If the
databases searcher is unsure of where to begin or how to
Secondary literature is created by experts in the sub- structure the search, he or she should consult the
ject field. These resources are organized to either librarian or information specialist. In the absence
describe or evaluate the original primary literature and of a resource person, there are subject guides and
to provide useful access to this literature. Secondary tutorials available online that can assist the searcher.
literature consists of review articles, including sys- A basic Google search will include non-peer reviewed
tematic reviews and meta-analyses and bibliographic and non-scholarly resources, so it is more effective to
databases, such as PubMed. search professional scholarly databases. Occasionally,
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54 | An Introduction to Pharmacy

a Google Scholar search is useful in searching a new of organizations, including the American Pharma-
interdisciplinary area. cists Association, the American College of Clinical
For comprehensive research on clinical or Pharmacy, the American Association of Colleges of
therapeutic topics, the searcher may begin with Pharmacy, and ASHP.
PubMed, which is available to anyone with an The Cochrane Library provides reliable and rea-
internet connection. This database is produced sonably up-to-date information on the effects of
by the National Center for Biotechnology Infor- interventions in healthcare. These interventions may
mation at the US National Library of Medicine be either therapeutic or diagnostic. There are six
(http://www.pubmed.gov). If access to subscription separate databases in the Cochrane Library, which
databases is unavailable, this may be the only afford- may be searched separately or together. The well
able option. PubMed has an excellent thesaurus of known Cochrane Systematic Reviews database pro-
professional terms, or a controlled vocabulary named vides access to the full text of the reviews and the
MeSH, which stands for Medical Subject Headings. protocols for proposed reviews. There is a Feed-
Common search terms are ‘‘mapped’’ to the MeSH back tool that allows users to provide comments and
terms, which are also searched by PubMed. For criticisms of Cochrane Reviews and Protocols. The
example, if the term ‘‘tylenol’’ is entered in the Cochrane Collaboration publishes a list of accepted
search box, acetaminophen is also automatically comments. These comments can be used to further
searched. Another useful tool, which requires free improve and update both Cochrane Reviews and Pro-
registration, is My NCBI. A My NCBI account tocols. Abstracts of non-Cochrane systematic reviews,
allows the researcher to run search alerts and set with a commentary on their overall quality, are avail-
up preferences, such as preferred display formats able in the Database of Abstracts of Reviews of
and colored highlighting of the search terms. While Effects. The Cochrane Central Register of Controlled
signed into My NCBI, a researcher can save a search Trials merges the trials listed in Medline, Embase, and
in many of the NCBI health databases, including other published and unpublished sources. The biblio-
PubMed, and schedule email updates or alerts to run graphic information on publications on the methods
on a monthly, weekly, or even a daily basis. Email used in the conduct of controlled trials is available
will only be received if there are new search results. in the Cochrane Methodology Register. Economic
References can also be saved by topics in online evaluations of healthcare interventions are identi-
Collections. An author may create a bibliography fied and appraised in the NHS Economic Evaluation
of his or her own work, which can be linked to the Database. Free registration for saved search alerts and
NIH Manuscript Submission System. The data from RSS feeds from the Cochrane Library is available to
PubMed is also available through several commercial the residents of several countries. Cochrane provides
vendors, such as the Medline database. Although a monthly Journal Club publication that introduces a
the data are the same, the search platforms are recent Cochrane Review, with a podcast summarizing
proprietary and can give the searcher varying results the review, discussion questions, and key figures and
while using the same search strategy. tables in the form of PowerPoint slides. You can also
International Pharmaceutical Abstracts (IPA) is a learn more about the Cochrane Library through vari-
database that is focused on pharmacy and pharmaceu- ous social media, including Facebook. The Cochrane
tical science and is produced by Thompson Scientific Library also includes the Cochrane Handbook for
in cooperation with the American Society of Health- Systematic Reviews of Interventions,1 which provides
System Pharmacists (ASHP). The database indexes a thorough methodology for evaluating the clinical
and abstracts more than 800 pharmacy and phar- research literature and strict guidelines for creating a
maceutical science related journals and covers drug Cochrane systematic review.
use and development, as well as pharmacy related Other heavily used databases in pharmacy and
topics, including pharmacy education and ethics. IPA pharmaceutical sciences include such specialized
is also useful for finding articles on herbs and nat- databases as BIOSIS Previews (Biological Abstracts);
ural products. In addition to peer reviewed articles, SciFinder Scholar (Chemical Abstracts and related
IPA includes meeting abstracts from the meetings chemical databases); Toxline and other TOXNET
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Information resources in pharmacy and the pharmaceutical sciences | 55

databases, from the US National Library of Medicine; additional value by allowing students, clinicians, and
and Embase, a comprehensive, fee-based health sci- researchers to make notes, link to related resources,
ence database from Elsevier, which indexes and assess learning through online self tests, and share
abstracts many non-English language journals and these with inter-professional teams and their peers,
focuses heavily on pharmaceutical issues. BIOSIS colleagues, or instructors. The ability to add more
Previews, SciFinder Scholar, and Embase have frequent updates to the material online, including
specialized indexing terms to help the researcher videos, will aid the evolution of this literature.
dig deeply into the life science, chemical, and Advantages to tertiary literature include ease of
pharmaceutical literature. In addition to indexing access and well vetted standards of best practice.
journal articles, they also include report, review, A major disadvantage still remaining is that the
patent, and meeting abstracts. The Toxnet databases resources take years to compile and, therefore, can
are a combination of bibliographic and full text contain dated material.
databases, which encompass both secondary and
tertiary toxicological literature. There is more on Textbooks
these full text databases in the section on Toxicology As electronic access is making it possible to use the
in the Tertiary literature section. best chapters or sections from multiple resources, the
Important comprehensive citation databases, use of textbooks is evolving. Textbooks are often
which allow the researcher to find which articles cited provided as part of electronic packages from vendors,
a seminal article, include SciVerse Scopus and Web such as AccessPharmacy from McGraw Hill. Elec-
of Science. Citation searching allows the searcher tronic book readers also provide greater access and
to see the evolution of an idea and emerging fields convenience. New editions of classic textbooks are
of research. SciVerse Scopus from Elsevier includes valuable for students. They are also useful to profes-
the data from the Embase database and is quite sors or subject specialists, who can read a new edition
comprehensive in the sciences and social sciences. to see the recent changes in their area. Dipiro’s Phar-
SciVerse Scopus also provides links to scientific macotherapy: A Pathophysiologic Approach,2,3 and
websites and patents from five patent offices in Goodman and Gilman’s The Pharmacological Basis
its search results. Web of Science from Thomson of Therapeutics4 are all available both in print, as well
Reuters began several decades ago with the print as electronically through AccessPharmacy. The online
indexes named Science Citation Index, Social Science resources include additional online updates. The clas-
Citation Index, and Arts and Humanities Citation sic title Foye’s Principles of Medicinal Chemistry5 is
Index from the Institute for Scientific Information available through a variety of ebook vendors, as well
and has evolved into an extensive, multifunctional set as in print.
of databases. In both databases, the researcher can
save searches and set up search alerts or RSS feeds. Nomenclature
To locate comprehensive information concerning a
drug, the researcher should know the nonproprietary
Tertiary literature
name. Most databases use this name in its controlled
Tertiary literature provides an introduction to the vocabulary and may map the brand name to the
research literature regarding the practice of pharmacy nonproprietary or generic name. For research into
and the pharmaceutical sciences. It introduces key the early development of drugs the chemical names,
research findings and accepted concepts. It is usu- CAS registry numbers or investigational names are
ally written by clinical or research specialists within also useful. The two most commonly used resources
the subject area. These resources are particularly use- for naming conventions are the USP Dictionary of
ful to the pharmacy professional and pharmaceutical USAN and International Drug Names6 and the World
science graduate students. They comprise textbooks, Health Organization’s International Nonproprietary
government monographs, encyclopedias, and other Names (INN).7 The researcher should be aware that
familiar reference works. As we move from print the INN name is sometimes different from the US
to electronic formats, these resources can provide Adopted Name.
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56 | An Introduction to Pharmacy

The American Drug Index8 is published annu- Convention is a representative group of volunteers
ally and includes over-the-counter drugs, combination from the various stakeholders – healthcare prac-
products, and drugs currently available in the United titioners, industrial scientists, and educators. The
States. There is a convenient list of manufacturers USP/NF is revised yearly and supplemented by
and distributors included, along with other useful updates. The Pharmacists Pharmacopeia14 contains
information at the end of the drug monographs. the information from the USP/NF most relevant to
The Merck Index: An Encyclopedia of Chemicals, practicing pharmacists, along with additional helpful
Drugs, and Biologicals9 provides chemical, nonpro- resources, and is updated less often.
prietary, and generic names, as well as graphic chem- The Japanese Pharmacopeia is published by
ical structures, CAS Registry Numbers, and chemical the Japanese government through its Pharmaceu-
formulas. There is a comprehensive cross index to the ticals and Medical Devices Agency (PMDA). It is
monographs. The monographs also include useful ref- available in both Japanese and English versions.
erences to articles, patents, and other tertiary sources More information on the Japanese Pharmacopeia
on preparation and to comprehensive descriptions of can be found at the PMDA website (http://www.
the drug, such as the monograph of the drug in the pmda.go.jp/english/pharmacopoeia/about.html).15
Profiles of Drug Substances, Excipients and Related The European Directorate for Quality of Medicines
Methodology.10 There are also many supplementary and Healthcare (EDQM) publishes the European
tables and organic name reactions. The online version Pharmacopeia.16 (More information is available at
includes structure searching as well. http://www.edqm.eu/). The International Conference
Index Nominum: International Drug Directory11 on Harmonisation of Technical Requirements for
is a valuable resource for researchers searching for for- Registration of Pharmaceuticals for Human Use
eign drug substances. Information on over 5300 drugs (ICH) is working with the regulatory authorities of
includes the therapeutic category and manufacturer or the United States, Japan, and Europe to find and
country. There is also information on approximately encourage commonalities among these three major
10,000 manufactures around the world. pharmacopeias.
Japanese Accepted Names for Pharmaceuti- Other countries have well-recognized pharma-
cals12 is a free online database maintained by copeias, such as the British Pharmacopeia17 (BP),
the Japanese National Institute of Health Sciences published by British Pharmacopoeia Commission Sec-
(http://jpdb.nihs.go.jp/jan/index.aspx). It is search- retariat of the Medicines and Healthcare products
able by the CAS Registry Number, the chemical Regulatory Agency. Martindale: The Complete Drug
name, or the Japanese Accepted Name. Reference22 is the new name for Martindale’s Extra
Pharmacopeia, which lists more than 6000 drugs
Pharmacopeias and resources for drug found internationally.
and excipient standards Standards for excipients can be found in these
A pharmacopeia is a list of drugs and drug products pharmacopeias. In addition, the Handbook of
that describes the purity, strength, method of prepa- Pharmaceutical Excipients,18 although not an official
ration, and other information. Pharmacopeias are pharmacopeia, is a widely used resource for standards
issued or authorized by governments or international and functionality of excipients. Additionally, since
agencies. The United States Pharmacopeia/National many excipients are also food additives, they can be
Formulary13 (USP/NF) is compiled by a non- found in the Food Chemicals Codex,19 published by
governmental organization, the United States the United States Pharmacopeial Convention. Finally,
Pharmacopeial (USP) Convention (http://usp.org), the ‘‘GRAS list’’ is a listing of additives that are gen-
and recognized by the Federal Food, Drug, and erally recognized as safe (http://www.fda.gov/Food/
Cosmetic (FDC) Act as the official pharmacopeia of FoodIngredientsPackaging/GenerallyRecognizedas
the United States. It contains a list of those drugs, SafeGRAS/GRASSubstancesSCOGSDatabase/default.
drug products, dietary supplements, excipients, and htm). The list can be found in searchable form in
other relevant compositions for which standards the Select Committee on GRAS Substances (SCOGS)
have been agreed to by the USP Convention. The database. Each of more than 370 entries provides
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Information resources in pharmacy and the pharmaceutical sciences | 57

the opinion of the Select Committee and the year in providing drug and pharmaceutical information
which the opinion was rendered. from Mexico; Rote Liste,25 with complete coverage
of drugs and medicines available in Germany; and
Drug information on prescription products Vidal: le dictionnaire,26 a compendium of French
The most popular resources for finding basic back- drug and consumer healthcare products.
ground information on drugs include the following The Orange Book: Approved Drug Products with
titles: The American Society of Health-System Phar- Therapeutic Equivalence Evaluations27 is often sim-
macists publishes the AHFS Drug Information: Amer- ply referred to as the Orange Book. It is available for
ican Hospital Formulary Service,20 a well recognized free at the US Food and Drug Administration web-
reference on prescription drugs. It is organized by site (http://www.fda.gov/cder/ob). This government
therapeutic category, with a general overview of the resource is searchable by active ingredient, proprietary
category, including drug interactions, before the indi- name, or by patent number. Therapeutic equivalence,
vidual listings of the drugs. The succeeding individual drug approval date, and marketing status (prescrip-
drug monographs include the uses, dosage and admin- tion, nonprescription, or discontinued) are listed on a
istration, cautions, pharmacokinetics, chemistry, and summary page for each drug formulation, as well as
stability. Preparations and comparative pricing are patent and exclusivity information.
included in the online version of this resource. Mobile Trissel’s Handbook on Injectable Drugs28 sum-
versions of this resource are also available. marizes information on parenteral drug stability and
Most pharmacies have traditionally had a loose- compatibility for clinicians. In the most recent edition,
leaf copy of Drug Facts and Comparisons21 on their there are 372 monographs arranged alphabetically by
shelves. Updated monthly, it is a reliable current nonproprietary name. There is also an Appendix with
resource. The drug monographs are arranged by parenteral nutrition formulas.
therapeutic category and class hierarchy. The online The Drug Topics Red Book29 covers both
version, Facts and Comparisons eAnswers, includes prescription and nonprescription products. Each
a variety of tools, including clinical calculators, drug drug entry includes product and supplier names, the
identifiers, and the ability to view comparative data National Drug Code number, route of administra-
tables and side-by-side monograph summaries of two tion, strength and quantity, and Average Wholesale
or more drugs. There is also a mobile version of the Price and Direct Price. This book is used primarily
databases. by pharmacists and pharmacy students for drug
DRUGDEX is part of the MICROMEDEX price information. Additionally, there are many
online suite of databases from Thomson Reuters and lists, including manufacturers’ addresses and phone
is often available at hospital pharmacies and health numbers, state boards of pharmacy, and a product
centers. DRUGDEX Evaluations monographs are identification guide with color photos.
remarkably thorough and well referenced. Dosing
information, pharmacokinetics, cautions, and clinical Drug information on compounded
applications are well covered. Although DRUGDEX preparations
focuses on prescription drugs, it also includes infor- Like manufactured drug products, compounded
mation on some investigational and nonprescription preparations must be safe and efficacious for the
drugs. There is also a mobile version. entire period of their use. Existing drugs are prepared
Martindale: Tthe Complete Drug Reference22 is a or compounded in new dosage forms, sometimes for
comprehensive listing of worldwide drugs, including new routes of administration designed to meet the
herbal medicines. It is also available electronically, needs of individual patients. In addition to safety and
through a variety of vendors, and is included in the efficacy, often information on stability, solubility, and
MICROMEDEX Healthcare Series. permeability is required to prepare a new formulation
Other international drug compendia include or evaluate an existing formulation. The United
CPS: Compendium of Pharmaceutical Specialties,23 States Pharmacopeia14 and the Pharmacists’ Pharma-
from the Canadian Pharmaceutical Association; copeia30 contain official monographs of compounded
Diccionario de Especialidades Farmaceuticas,24 preparations that have been evaluated by experts in
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58 | An Introduction to Pharmacy

the field to meet the quality and purity standards for Herbal medicines and natural products
the period prior to the ‘‘beyond use date.’’ Additional Herbal medicines and natural products are very pop-
formulations can be found in standard texts, such as ular with consumers, who often perceive the terms
The Art Science and Technology of Pharmaceutical ‘‘natural’’ or ‘‘herbal’’ as connoting safety. Hence,
Compounding.31 Formulations specific for certain there is active research in this area, and students and
patient populations are found in references such as pharmacists need to be well informed. Luckily, there
Plumbs’ Veterinary Drug Handbook32 and Pediatric are a variety of well known textbooks and tertiary
Drug Formulations.33 Although many texts provide databases on this subject. Trease and Evans’ Pharma-
formulation and preparation information, one must cognosy37 is a classic, basic textbook, now in its 16th
generally search the primary literature to find the edition. It focuses on the use of plants in medicine,
limited data on efficacy of these specialized dosage covering plant taxonomy, commercial production,
forms. International Pharmaceutical Abstracts (IPA) biological activity, and phytochemical examination
is the preferred database for finding such informa- and investigation of herbal products. Tyler’s Honest
tion. IPA is also a useful database to find stability Herbal: A Sensible Guide to the Use of Herbs and
information for those drugs and drug preparations Related Remedies38 provides well-referenced mono-
not listed in Trissel’s Stability of Compounded graphs on herbs and their efficacy and safety. It is
Formulations.34 Journals that often contain new for- a good starting point for researchers and useful for
mulations along with stability data are International consumers, although consumers may view the stan-
Journal of Pharmaceutical Compounding (Edmond, dards for rating efficacy as too conservative. Leung’s
OK; IJPC) and American Journal of Health-System Encyclopedia of Common Natural Ingredients Used
Pharmacy (Bethesda, MD; American Association of in Food, Drugs, and Cosmetics39 is a more extensive
Health-System Pharmacists). resource covering the source, chemical composition,
pharmacology and biological activity, uses, and com-
mercial preparation of each natural ingredient. It
Drug information on nonprescription
is extensively referenced, with appendices providing
products
glossaries of abbreviations and botanical terms and
Although there is some information on nonprescrip- morphological descriptions of plant organs.
tion drug products in the prescription drug resources Online resources provide search options and
listed previously in this chapter, the most valuable special features. Two well known natural prod-
resource for this information is the Handbook of uct databases are Natural Standard and Natural
Nonprescription Drugs: An Interactive Approach to Medicines Comprehensive Database. Natural Stan-
Self-Care,35 which is available both in print and in dard provides evidence-based information about
PharmacyLibrary, the new electronic package from alternative and complementary therapies and has
the American Pharmacists Association. The hand- a variety of databases. Each therapy is graded
book is arranged into sections beginning with the according to the evidence for its effectiveness in
practitioner’s role in self-care, followed by sections treating a particular medical condition. Natural
on diseases, with chapters arranged in each section Standard databases include Foods, Herbs, and Sup-
by body systems; a section on home medical equip- plements; Comparative Effectiveness; and Genomics
ment; and a section on complementary and alterna- and Proteomics. Natural Medicines Comprehensive
tive medicine. To help pharmacy students develop Database from Therapeutics Research Center covers
problem-solving skills, case studies are provided in natural medicines sold in North America and has
each section. Chapter updates are available for the evidence-based comprehensive monographs on these
online version. medicines, as well as a natural product effectiveness
The Physicians’ Desk Reference for Nonprescrip- checker. Checkers for interactions and depletions,
tion Drugs, Dietary Supplements and Herbs36 is a patient education handouts, and Continuing Educa-
useful supplement to the Handbook of Nonprescrip- tion Programs are also available with both databases.
tion Drugs: An Interactive Approach to Self-Care.35 Both natural product databases have mobile and
It is available in print and electronically. print versions and provide RSS feeds.
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Information resources in pharmacy and the pharmaceutical sciences | 59

Drug interactions, side effects and adverse TOXNET set of databases. It focuses on the levels
reactions of the drug in breast milk and infant blood and the
Patients and pharmacy practitioners are very con- possible adverse effects on the nursing infant.
cerned about interactions, side effects, and adverse Another special topic is covered by Food-
reactions. These also concern pharmaceutical scien- medication Interactions,44 available either as a spiral
tists developing new products. bound book or a mobile version. More than 1000
Meyler’s Side Effects of Drugs: An Encyclopedia drug monographs are arranged alphabetically and
of Adverse Reactions and Interactions40 has a long cover drug class or action; side effects; renal, hepatic,
history. According to the Preface of the 15th edition cardiac, and pregnancy information; contraindica-
of Meyler’s Side Effects of Drugs: An Encyclopedia of tions; monitoring information; and special dietary
Adverse Reactions and Interactions, Leopold Meyler, precautions and nutritional effects. There are many
a Dutch physician, experienced adverse drug effects tables, including a useful laboratory value table.
in the 1940s, while undergoing treatment for tubercu- Canadian brand names are exclusive to the mobile
losis. He searched for information on this topic and, version.
finding only a nineteenth century tome, he went to Medication safety is a major concern. Drug-
work to fill this significant gap. The first edition of induced Diseases: Prevention, Detection, and Man-
this work was published in Dutch in 1951, and an agement45 provides information for students and
English edition was published in 1952. Editions of healthcare practitioners to address and improve the
Meyler’s Side Effects of Drugs: An Encyclopedia of standard of care regarding drug-induced diseases. This
Adverse Reactions and Interactions are updated by comprehensive textbook introduces the magnitude of
Side Effects of Drugs Annual41 and cover prescrip- the problem and follows up with sections arranged
tion drugs, anesthetics, antiseptics, drugs of abuse, by anatomical region, such as drug-induced gastroin-
herbal medicines, and devices and methods in alter- testinal diseases.
native medicine. Meyler’s Side Effects of Drugs: An
Encyclopedia of Adverse Reactions and Interactions Poisoning and toxicology
is available both in print and electronic formats. Two well know textbooks on toxicology are Casarett
Drug Interactions Analysis and Management42 and Doull’s Toxicology: The Basic Science of
is written by two well-known authorities in this Poisons46 and Goldfrank’s Toxicologic Emergen-
area, Philip D. Hansten, PharmD and John R. Horn, cies.47 Casarett and Doull’s Toxicology covers the
PharmD. The focus is on the management of drug various aspects of the subject, including toxicoki-
interactions and gives the reader options to avoid netics, carcinogenicity, mutagenicity, developmental
patient harm and decrease risk. Suggestions regarding toxicology, target organ toxicity, toxic agents,
monitoring and alternative drugs are recommended environmental toxicology, food toxicology, analytic
when appropriate. Specific information on each inter- toxicology, clinical toxicology, and occupational
action also includes risk factors, the mechanism of toxicology. Goldfrank’s Toxicologic Emergencies
action, a clinical evaluation of cited reports, closely presents in-depth information on antidotes, general
related drugs that may interact in a similar manner, principles, and techniques to evaluate and manage
and references. Each interaction is also assigned a Sig- toxic exposures, biochemical toxicology, organ
nificance Number, which is based on the intervention system principles, and classes of compounds. Case
needed to minimize risk. studies and study questions are given, and the
An important specialty resource is Drugs in Preg- answers are provided at the end of the book.
nancy and Lactation: A Reference Guide to Fetal and TOXNET is a set of databases made avail-
Neonatal Risk.43 This resource provides fetal risk able by the US National Library of Medicine
and breast feeding risk summaries, which include ani- (http://toxnet.nlm.nih.gov/). They provide indexing
mal reproduction data, placental transfer, reports of and abstracting and full text information concerning
human pregnancy exposure, and a list of references toxicology, hazardous chemicals, environmental
for more than 1200 drugs. A related database is the health, and toxic releases. Databases may be searched
Drugs and Lactation Database (LactMed), one of the individually or as a set. The Hazardous Substances
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60 | An Introduction to Pharmacy

Databank (HSDB) contains more than 5000 chemical titles are Ident-a-drug Reference,49 which identifies
records and is enhanced with additional material the drug by the color, shape, size, and imprint
on nanomaterials, regulatory requirements, and code, and the IDENTIDEX System, a part of
emergency handling procedures. Other TOXNET MICROMEDEX.
databases include the Chemical Carcinogenesis
Research Information System (CCRIS), Integrated Consumer drug information
Risk Information System (IRIS), GENE-TOX, It is important to know where to find reliable and
and the previously described LactMed database. accurate consumer drug information, especially
The National Cancer Institute provides data on since consumers frequently use the internet to find
mutagenicity and tumor promotion and inhibition information. There are many such resources on the
in CCRIS. IRIS contains data in support of human internet. MedlinePlus from the US National Library
health risk assessment and is compiled by the US of Medicine (http://www.medlineplus.gov) includes
Environmental Protection Agency (EPA). GENE- a vast array of features for the consumer, including
TOX, created by the US EPA, contains genetic information on drugs and supplements and a medical
toxicology (mutagenicity) test data on more than dictionary with pronunciation. Drugs.com includes
3000 chemicals and recommends proper testing an Interactions Checker. WebMD includes a useful
protocols and evaluation procedures. Pill Identifier tool.
An example of expanded access to drug infor-
Formulation and manufacturing mation on the internet is the Drug Information Por-
Many of the standard textbooks on formulation and tal (http://druginfo.nlm.nih.gov), which provides a
manufacturing are now quite dated. There is a need search interface to information on more than 20,000
for additional educational material in this area. The drugs from US government agencies, including the
National Institute of Pharmaceutical Technology and National Library of Medicine. There is information
Education (http://nipte.org/), which is dedicated to for researchers, clinicians, students, and consumers.
fundamental research and education in pharmaceu- Two popular print resources include the Pill
tical product development and manufacturing, has Book50 and the Complete Guide to Prescription and
developed a draft curriculum in this area; develop- Nonprescription Drugs.51 The Pill Book includes
ment of educational resources is a planned activity information on affordable generic alternatives, side
of the group. In the meantime, the Encyclopedia effects, adverse effects, drug–drug and drug–food
of Pharmaceutical Technology48 has monographs on interactions, addictiveness, safe handling of injecta-
many of the aspects related to formulation and the bles, and when to call the physician. Aside from
various pharmaceutical manufacturing processes. For the usual drug information, the Complete Guide to
detailed information on drug substances necessary for Prescription and Nonprescription Drugs includes
pre-formulation research, Britain’s Profiles of Drug the length of time before a drug starts working and
Substances, Excipients, and Related Methodology10 warnings regarding premature discontinuation of a
provides comprehensive monographs. Additionally, drug. At the beginning of the book, there is a list
PharmaHub (http://pharmahub.org/) has an increas- of commonly used drugs to treat specific diseases or
ing array of useful databases and process modeling conditions.
software for formulation and manufacturing.
Personalized medicine
Product identification As pharmacists become more focused on the indi-
Emergency and other medical personnel need to be vidual patient, pharmacogenetics is becoming more
able to quickly identify capsules or tablets. Many important than ever before. Two valuable resources
resources include sections on identifying drug or in this area are Ginsberg and Willard’s Essentials of
related products. These include the Physician’s Desk Genomic and Personalized Medicine52 and Catania’s
Reference, the Red Book, and several online and An A–Z Guide to Pharmacogenomics.53 Essentials
mobile resources, including Facts and Comparisons of Genomic and Personalized Medicine provides an
eAnswers and Lexi-Comp. The two most well-known overview of the field, with translational approaches
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Information resources in pharmacy and the pharmaceutical sciences | 61

to bring the information into the clinical world. An PharmaHUB at http://pharmahub.org, were created
A–Z Guide to Pharmacogenomics introduces the ter- to facilitate the collaborative creation and sharing of
minology and techniques related to this growing field pharmaceutical engineering and science information
to students and professionals who have a basic under- and modeling tools. The PharmaHUB website
standing of molecular biology. states that their goal is to ‘‘support innovations in
product and process development and manufacturing
methodology for pharmaceutical products.’’55 This is
Professional associations an area in which the amount of data can be massive,
Associations for almost every specialty of pharmacy and these data have been isolated in individual
in the various regions of the United States and around research groups or institutes until now. Sharing the
the world can be found at the Virtual Pharmacy data will allow faster progress in the research area.
Library (http://www.pharmacy.org/) by clicking on
the Associations tab. The list of more than 100 For further information
pharmacy-related associations is complete, with links
to each association’s website. The American Association of Colleges of Phar-
macy Libraries/Educational Resources Section’s Basic
Resources for Pharmacy Education (http://www.aacp.
Emerging trends org/governance/SECTIONS/libraryeducationalresour
The majority of electronic books are still simply ces/Pages/LibraryEducationalResourcesSpecialProjects
copies of the original print versions. Although they andInformation.aspx) provides a benchmark to use
can be accessed from anywhere at any time, they in selecting many of the resources listed herein and
are still rather static. According to the 2011 Hori- is a good place to explore for more references in a
zon Report,54 the product of collaboration between specific pharmacy related field. An excellent book
the EDUCAUSE Learning Initiative (ELI) and the on pharmaceutical resources is Bonnie Snow’s Drug
New Media Consortium, this is rapidly changing, Information: A Guide to Current Resources.56
and the newer electronic books with added features
will become more in demand than the print. Social
features will connect the reader to other researchers,
Acknowledgments
enabling collaboration. Self-directed, interactive expe-
The previous version of this chapter was written by
riences and activities are beginning to be provided.
three colleagues at the University of the Sciences in
Videos and other audiovisual resources will integrate
Philadelphia: Leslie Ann Bowman, Mignon S. Adams
into these electronic resources. Links to supporting
and Amy Christopher. Although we have chosen to
materials can enrich the reading experience. Cloud
organize our material in our own way, reviewing their
tags will make locating useful chapters or sections
version has provided a valuable point of reference.
vastly simpler.
Mobile resources have been used by pharmacy
professional students, pharmacists, and faculty for
References
several years. According to the 2011 Horizon Report,
‘‘Internetcapable mobile devices will outnumber com- 1. Higgins J et al. Cochrane Handbook for Sys-
puters within the next year.’’ With the spread of smart tematic Reviews of Interventions. Chichester,
phones and other devices, students and scientists will England/Hoboken NJ: Wiley-Blackwell, 2008.
2. DiPiro JT. Pharmacotherapy: A Pathophysiologic
demand more resources and applications compatible
Approach, 8th edn. New York: McGraw-Hill Medical,
with the platforms they have chosen. One example 2011.
is PubMed on Tap, which allows the user to search 3. Katzung BG et al. Basic and Clinical Pharmacology,
PubMed and manage references from the iPod Touch, 11th edn. New York/London: McGraw-Hill Medical,
2009.
iPhone, or iPad.
4. Goodman LS et al. Goodman and Gilman’s the Pharma-
Data planning and management is becoming cological Basis of Therapeutics, 11th edn. New York:
a major thrust in the sciences. Websites, such as McGraw-Hill, 2006.
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62 | An Introduction to Pharmacy

5. Foye WO et al. Foye’s Principles of Medicinal Chem- 24. Rodrı́guez Vásquez A, Domı́nguez Frı́as G. Diccionario
istry, 6th edn. Philadelphia: Lippincott Williams and De Especialidades Farmacéuticas, 56th edn. Mexico:
Wilkins, 2008. Thomson, 2010.
6. USP Dictionary of USAN and International 25. Bundesverband der Pharmazeutischen Industrie (Ger-
Drug Names 2011. Rockville MD: United States many), Rote Liste Service. Rote liste: Arzneimittelverze-
Pharmacopeial Convention, 2011. ichnis für Deutschland (einschließlich EU-Zulassungen
7. International Nonproprietary Names (INN) for Phar- und bestimmter Medizinprodukte). Frankfurt am Main:
maceutical Substances: Lists 1–101 of Proposed INN Verlag Rote Liste, 2009.
and Lists 1–62 of Recommended INN, Cumulative List 26. Roguet I, ed. Vidal De La Famille: Le Dictionnaire Des
no. 13. Geneva: World Health Organization, 2009. Médicaments, 15th edn. Issy-les-Moulineaux: Vidal,
8. Wilson CO. American Drug Index. Philadelphia: Lip- 2010.
pincott, 2011. 27. Department of Health and Human Services
9. O’Neil MJ. The Merck Index: An Encyclopedia of (2011). Orange Book: Approved Drug Prod-
Chemicals, Drugs, and Biologicals. Whitehouse Station ucts with Therapeutic Equivalence Evaluations.
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10. Brittain HG, ed. Profiles of Drug Substances, Excip- 28. Trissel LA. Handbook on Injectable Drugs, 16th edn.
ients, and Related Methodology. Vol. 35. Amster- Bethesda MD: American Society of Health-System Phar-
dam/Boston: Elsevier Academic Press, 2010. macists, 2011.
11. Pharmasuisse, ed. Index Nominum: International Drug 29. Thomson Corporation. Red Book: Pharmacy’s Funda-
Directory, 20th edn. Stuttgart: MedPharm, 2011. mental Reference. Montvale NJ: Thomson PDR, 2010.
12. Japanese National Institute of Health Sciences. 30. United States Pharmacopeial Convention. Pharmacists’
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http://www.jpdb.nihs.go.jp/ Pharmacopeial Convention, 2009.
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13. United States Pharmacopeial Convention. The maceutical Compounding, 3rd edn. Washington DC:
United States Pharmacopeia: The National Formu- American Pharmacists Association, 2008.
32. Plumb DC. Plumb’s Veterinary Drug Handbook, 7th
lary. Rockville MD: United States Pharmacopeial
edn. Hoboken NJ: Wiley-Blackwell, 2011.
Convention, 2010.
33. Nahata MC, Pai VB. Pediatric Drug Formulations, 6th
14. United States Pharmacopeial Convention. USP Phar-
edn. Cincinnati OH: Harvey Whitney Books, 2011.
macists’ Pharmacopeia. Rockville MD: United States
34. Trissel LA. Trissel’s Stability of Compounded Formula-
Pharmacopeial Convention, 2009.
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ation, 2009.
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35. Berardi R. Handbook of Nonprescription Drugs an
16. Council of Europe. European Pharmacopoeia: Pub-
Interactive Approach to Self-care, 16th edn. Washing-
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ton DC: American Pharmacists Association, 2009.
ration of a European Pharmacopoeia (European Treaty
36. Physicians’ Desk Reference, 65th edn. Montvale NJ:
Series No. 50). Vol. 1, Vol. 2. Strasbourg: Council of Medical Economics Company Inc., 2011.
Europe, 2007. 37. Evans WC et al. Trease and Evans Pharmacognosy,
17. British Pharmacopoeia Commission. British Pharma- 16th edn. Edinburgh: Saunders/Elsevier, 2009.
copoeia 2011. London: Stationery Office, 2010. 38. Foster S, Tyler VE. Tyler’s Honest Herbal: A Sensible
18. Rowe RC et al. Handbook of Pharmaceutical Excipi- Guide to the use of Herbs and Related Remedies, 4th
ents. Washington DC: Pharmaceutical Press, 2006. edn. New York: Routledge, 2009.
19. United States Pharmacopeial Convention. Food Chem- 39. Khan IA, Abourashed EA. Leung’s Encyclopedia of
icals Codex: By Authority of the United States Phar- Common Natural Ingredients used in Food, Drugs, and
macopeial Convention. Rockville MD: United States Cosmetics, 3rd edn. Hoboken NJ: John Wiley and Sons
Pharmacopeial Convention, 2010. Inc., 2010.
20. American Society of Health-System Pharmacists. AHFS 40. Aronson JK et al. Side effects of drugs. In: Aronson
Drug Information 2011. Bethesda MD: American Soci- JK, ed. Meyler’s Side Effects of Drugs: The Interna-
ety of Health-System Pharmacists, 2011. tional Encyclopedia of Adverse Drug Reactions and
21. Facts and Comparisons. Drug Facts and Comparisons. Interactions, 15th edn. Oxford: Elsevier, 2006.
St. Louis: Wolters Kluwer Health, 2011. 41. Dukes MNG. Excerpta Medica Foundation. In: Aron-
22. Sweetman SC, ed. Martindale : The Complete Drug son JK, ed. Side Effects of Drugs Annual. Amsterdam:
Reference, 37th edn. London/Chicago: Pharmaceutical Elsevier, 2011.
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23. Repchinsky C, ed. CPS 2011: Compendium of Pharma- and Management. St. Louis MO: Wolters Kluwers
ceuticals and Specialties; the Canadian Drug Reference Health/Facts and Comparisons, 2010.
for Health Professionals. Ottawa ON: Canadian Phar- 43. Briggs GG et al. Drugs in Pregnancy and Lactation, 9th
macists Association, 2011. edn. Philadelphia: Wolters Kluwer Health, 2011.
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44. Pronsky ZM. Food Medication Interactions, 16th edn. 51. Griffith HW et al. Complete Guide to Prescription and
Birchrunville PA: Food-Medication Interactions, 2010. Nonprescription Drugs. New York: Penguin Group,
45. Tisdale JE et al. Drug-Induced Diseases: Prevention, 2011.
Detection, and Management, 2nd edn. Bethesda MD: 52. Willard HF, Ginsburg GS. Essentials of Genomic and
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47. Goldfrank LR, Flomenbaum N. Goldfrank’s Toxico- 54. New Media Consortium and EDUCAUSE. 2011 Hori-
logic Emergencies, 9th edn. New York: McGraw-Hill zon Report. http://www.net.educause.edu/ir/library/pdf
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5
Pharmaceutical Chemistry

Inorganic pharmaceutical chemistry 65 Conclusions and perspectives 121

Organic pharmaceutical chemistry 79 Prodrugs 122

Structural determinants of drug action 92 Fundamentals of medical radionuclides 124

Natural products 96 Drug nomenclature 131

Structure–activity relationships and drug design 106 History 133

Pharmaceutical profiling 115 References 138

Inorganic pharmaceutical extranuclear electrons. The difference between the

atomic number and the atomic weight of a given
chemistry
isotope of an element defines the number of neutrons
in the nucleus. Atomic weights in the tables are not
Inorganic chemicals have been used in pharmacy and
whole numbers because they represent the weighted
medicine for many reasons, ranging from therapeutic
average of the atomic weights of all isotopes present.
agents to nutritional supplements to pharmaceutical
necessities. In this section a review of some chemical
principles and properties of elements is followed by
• The electrons are arranged in major quantum
groups (energy levels or orbitals) occupying the
a discussion of the wide variety of useful inorganic
space about the nucleus. Each electron is assigned
chemicals.
four quantum numbers:
• The principal quantum number, n, describes the
relative position of an energy level with respect to
Basis of chemical reactions
the other energy levels present.
Although many subatomic particles have been • The subquantum number, l, describes the dif-
identified, only the protons and neutrons of the ferent electron distributions possible for a given
nucleus of an atom and the extranuclear electrons value of n.
will be considered here. • The magnetic quantum number, ml , is best
Each atom of an element is described uniquely described as the magnetic contribution to the
by two pure numbers: its atomic number and its angular momentum due to the movement of the
atomic weight. The atomic number gives the number electrons in space.
of protons present in the nucleus and therefore • The magnetic spin quantum number, ms , is the
its positive charge. Because the ground-state atom magnetic component contributed by the spin of the
must be neutral, this in turn defines the number of electron.
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66 | An Introduction to Pharmacy

The permitted values for n are 1, 2, 3, . . . , and for between the two entities. A crystal of sodium chloride
l are 0, 1, 2, . . . (n − 1), for ml are −l, . . . 0, . . . consists of equal numbers of sodium and chloride
+l, and for ms ± 1/2. Returning to the subquantum ions held in place by the interaction of the spherically
number l, when l is 0 the electrons occupying the sub- symmetrical positive cation field and the spherically
orbital are known as s electrons; when l is 1, they’re symmetrical negative anion field. These ionic (electro-
known as p electrons; when l is 2, they’re known as static) compounds are characterized by high boiling
d electrons; and when l is 3, they’re known as f elec- and melting points, and most are water soluble.
trons. Thus, if two electrons occupy suborbital 0 of If two reacting atoms have similar electronega-
major quantum group 3, they are represented as 3s2 . tivities, such as two hydrogen atoms, a sharing of
In assigning electrons to the atom the Aufbau electrons takes place. One electron is donated to the
principle is used. It is an application of quantum the- bond from an incompletely filled suborbital of each
ory, Hund’s rules, and the Pauli exclusion principle. atom. A covalent bond is formed by the overlap of the
Simply stated, a given entering electron must occupy two atomic orbitals involved. With the formation of
the lowest unoccupied energy level of the atom. In the bond, a molecule results. The bonding electrons
other words, each electron must have a unique set of are no longer restricted to their atomic orbitals; they
quantum numbers. now are free to move in an orbit between the two
As a result of the above process, all atoms, except atoms in what is known as a molecular orbital.
hydrogen and the inert gases, have one or more
When the electronegativities of the two atoms
completely occupied lower major quantum groups
involved in the formation of a covalent bond are not
and have the suborbitals of their highest major
identical, the atom with the higher electronegativity
quantum group only partially filled. The electrons
tends to attract the electrons of the molecule more
of this outer, partially filled energy level give each
strongly than its partner. This leads to polarization
element its distinct chemical properties. These are the
of the molecule, resulting in a dipole. The extent of
valence electrons.
polarization is directly proportional to the difference
Chemical reactions entail the removal of valence
in electronegativities. Such bonds are said to have
electrons, adding electrons to a partly filled valence
partial ionic character.
shell, or sharing a pair of valence electrons between
In practice, only the most electropositive atoms
two atoms. Most atoms attempt to achieve a rare-gas
reacting with the most electronegative atoms result in
outer shell (ns2 or ns2 np6 ) by these processes. The
purely electrostatic compounds, and only atoms with
energy required for the removal of the electron of
equal electronegativities form purely covalent bonds.
least energy is known as the first ionization potential.
It is unique for each element. The metals have low Those bonds formed from elements between these
ionization potentials and therefore readily form extremes have partial covalent or partial electrostatic
cations. Nonmetals have high ionization potentials. character.
The attraction of a nucleus for electrons is termed Atoms with orbitals occupied by an unshared pair
its electronegativity. Metals have low electronega- of electrons can share this electron pair with an atom
tivities (they are electropositive), whereas nonmetals lacking two or more electrons in its valence shell.
(especially the halogens) have high electronegativities. The bond formed is said to be a coordinate covalent
This allows the latter to attract additional electrons bond. Once this bond has been formed, it cannot be
to form anions. distinguished from an ordinary covalent bond; the
When atoms with widely differing electronegativi- difference lies only in the manner of formation. The
ties react (e.g., sodium at 0.93, with chlorine at 3.98), formation of the ammonium ion from an ammonia
an electron transfer takes place. The one valence elec- molecule, which has an unshared electron pair,
tron of sodium (3s1 ) enters the incompletely filled and a hydrogen ion, which has an empty s orbital,
(3s2 3p5 ) valence shell of the chlorine atom. Sodium illustrates this type of reaction.
now has an inert-gas (Ne) electron structure with a +1 Covalent compounds have low melting and
charge. The chlorine achieves the argon structure with boiling points, and usually are insoluble in water.
a −1 charge. There is no formal electron-pair bond Solubility in water can be induced by introducing an
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Pharmaceutical Chemistry | 67

acid or base group into the molecule. Reaction with

Table 5.1 Conjugate acid–base pairs
base or acid will then give a soluble salt.
Other types of bonding also exist. Those of Acid Base Acid Base
interest are weakly bonded; the compounds formed
decompose more readily than the electrostatic and H2 O OH− H2 SO4 HSO−
4
covalent types. Hydrogen bonding (bridging) is an
H3 O+ H2 O HSO4 − SO2−
4
example of this type of bonding, and is common
among many molecules. Dipole–dipole bonding also NH+ NH3 H3 PO4 H2 PO−
4 4
is possible, resulting in very weak associations.
Complexes are compounds or ions formed when RNH+
3 RNH2 H2 PO4 − HPO2−
4
an atom or cation’s central unit acts as a center about
HCl Cl− [A](H2 O)6 ]3+ [A](H2 O)5 (OH)]2+
which anions or molecules (ligands) arrange them-
selves. The central unit is said to have a coordination
H2 CO3 HCO−
3 [A](H2 O)5 (OH)]2+ [A](H2 O)4 (OH)2 ]+
number equal to the number of ligands forming the
complex. The maximum number of ligands that can HCO−
3 CO−
3 H3 BO3 ·H2 O [B(OH)4 ]−
arrange themselves about the central unit is known as
its maximum coordination number and is a function
of the size of the central unit. Usual maximum Some conjugate pairs of pharmaceutical interest are
coordination numbers are 2, 4, 6, or 8. The number given in Table 5.1. It is evident that acids and bases
of ligands that can coordinate with the central unit can be cations, neutral molecules, or anions. Some
also is a function of ligand size. Thus, even though structures can be members of two different conjugate
the maximum coordination number of aluminum pairs, as an acid in one and as a base in the other.
is 6, only four of the relatively large chloride ions A strong acid is an acid that loses its proton easily;
can be accommodated as ligands, for example, a weak acid holds its proton tenaciously. The con-
[AlF6 ]3− vs. [AlCl4 ]1− . The bonding involved in the jugate base of a strong acid is a weak base, whereas
formation of complexes can be coordinate covalent that of a weak acid is a strong base. In neutralization,
or electrostatic. Bonds depending on permanent the proton goes to the strongest of the bases present.
dipoles are also common, such as with hydrates. The percent ionization and the ionization constant
are measures of the strength of a given acid.
Acids, bases, and buffers Acids and bases are used in pharmacy for
analytical procedures, as buffer systems, and to
Acids and bases dissolve insoluble medicinals. To accomplish the
Acid–base theories range from the limited, classic latter the insoluble compound must have a functional
Arrhenius theory to the comprehensive theory of group capable of acting as a strong base or as an acid.
Lewis. In between are the Franklin solvent system of Lidocaine Hydrochloride Injection USP and Niacin
acids and bases and the Brønsted proton donor theory. Injection USP are examples. The former is prepared
Because physiological functions involve aqueous by reacting lidocaine with hydrochloric acid; the
media, and because pharmaceuticals are frequently diethylamino group is a stronger base than either
dispensed in aqueous solution, the Brønsted theory the water molecule or the chloride ion. Lidocaine
is convenient for use in pharmacy. A molecule or ion goes into solution as a cation. Niacin Injection USP
that can provide a proton (proton donor) is an acid; is prepared by reacting niacin with either sodium
one that can accept a proton (proton acceptor) is a carbonate or sodium hydroxide; the carboxyl group
base. On accepting a proton, a base becomes an acid; loses its proton to the carbonate or hydroxyl ion, and
on losing its proton, the acid becomes a base. An acid the niacin goes into solution as an anion.
and its base are related by the presence or absence of a In neutralization, as above, the pharmacist must
proton, and are known as a conjugate pair. The trans- be cognizant of two requirements that are not
fer of a proton from the acid of one conjugate pair to important in ordinary chemical neutralizations. The
the base of another conjugate pair is neutralization. counterion being introduced – chloride ion and
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68 | An Introduction to Pharmacy

sodium ion, respectively, in the above examples – Gastric antacids

must be compatible physiologically with the body The present official magnesium antacids include
fluids. Also, because strong acids or bases are being Magnesium Hydroxide, Milk of Magnesia, Magnesia
used, there can be no excess acid or base because of Tablets, Alumina and Magnesia Oral Suspension
the corrosive nature of these reagents. (and Tablets), Magnesium Carbonate, Magnesium
Acids and bases are also necessary for the
Carbonate and Sodium Bicarbonate for Oral Sus-
preparation of effervescent mixtures, a medicinal
pension, Magnesium Oxide, Magnesium Phosphate,
dosage form sometimes used to render a medicinal
and Magnesium Trisilicate (and Tablets). The official
more palatable for oral administration. Sodium
aluminum antacids include Aluminum Hydroxide
bicarbonate is used as the carbon dioxide source.
Gel, Dried Aluminum Hydroxide Gel (and Capsules
Solid acids such as citric acid, tartaric acid, or
and Tablets), Aluminum Phosphate Gel, Dihy-
sodium dihydrogen phosphate are used, frequently
droxyaluminum Aminoacetate (and Magma, and
in combination. Reaction rate is very important in
Capsules and Tablets), Dihydroxyaluminum Sodium
these formulations. Sodium bicarbonate must have
Carbonate (and Tablets), Alumina, Magnesia, and
the correct particle size; if too fine, the reaction is too
Calcium Carbonate Oral Suspension (and Tablets),
violent, and if too coarse, the reaction is too slow.
Alumina and Magnesium Trisilicate Oral Suspension
To lower the activity of the acid, a normal salt of the
(and Tablets), and the Alumina and Magnesia prepa-
acid is included in the mixture as a diluent.
rations already listed. The calcium antacids include
Some acids and bases listed in the compendia at
Precipitated Calcium Carbonate (and Tablets), Cal-
present are Calcium Hydroxide, Potassium Bicar-
cium Carbonate and Magnesia Tablets, and Calcium
bonate, Potassium Hydroxide, Sodium Bicarbonate,
and Magnesium Carbonates Tablets. Magaldrate, an
Sodium Carbonate, Sodium Hydroxide, Strong
aluminum magnesium hydroxide sulfate, is official,
Ammonia Solution, Acetic Acid, Hydrochloric Acid
as is its Oral Suspension and Tablets. Miscellaneous
and Diluted Hydrochloric Acid, Nitric Acid, Sulfuric
official antacids include Milk of Bismuth, Sodium
Acid, Phosphoric Acid and Diluted Phosphoric Acid.
Bicarbonate, and Potassium Bicarbonate.
Stability and storage problems of these com-
pounds must be considered. All strong bases are There are other gastric antacid dosage form
subject to reaction with carbon dioxide if proper monographs, some including simethicone (an anti-
closures are not maintained. Volatile compounds, flatulent), and they are Magnesium Oxide Capsules
such as ammonia and hydrogen chloride, must (and Tablets); Basic Aluminum Carbonate Gel;
be sealed tightly at all times, as must hygroscopic Dried Basic Aluminum Carbonate Gel Capsules
compounds such as sodium hydroxide. (and Tablets); Alumina and Magnesium Carbonate
Oral Suspension (and Tablets); Alumina, Magnesium
Buffers Carbonate, and Magnesium Oxide Tablets; Alumina,
Magnesia, and Simethicone Oral Suspension (and
Buffers are used to maintain the pH of a medicinal
Tablets); Calcium Carbonate Oral Suspension; and
at an optimal value. A buffer is a solution of a weak
Magaldrate and Simethicone Oral Suspension (and
acid and its conjugate base, the base being provided
Tablets). A monograph for Magnesium Hydroxide
by one of its soluble salts.
Paste, which contains about 31g of magnesium
hydroxide per 100g, describes a suspension that is an
intermediate in the manufacture of Milk of Magnesia
Physiological control of pH
and other suspensions of magnesium hydroxide.
Brønsted acids and bases have been used for many
years to maintain and adjust the pH of body fluids.
By far the greatest interest has been in development Systemic alkalizers and acidifiers
of gastric antacids. However, an adequate number Sodium Bicarbonate USP and Potassium Bicarbonate
of suitable reagents are available for systemic pH USP are used as systemic alkalizers. Because the
adjustments. bicarbonates are unstable to heat, chemical problems
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Pharmaceutical Chemistry | 69

arise in the sterilization of bicarbonate solutions. oxidation states, etc., as given in Tables 5.2 through
5.12, can yield valuable clues to their behavior.
2HCO− 2−
3 ↔ CO3 + CO2 + H2 O The transition elements have incompletely filled
18-electron outer shells, and each can exist in several
To depress the forward reaction, the solution can different oxidation states. In most cases the shift
be saturated with carbon dioxide. To prevent the between two electron states is relatively easy; for
loss of the gas, which would result in the permanent example,
formation of the strong carbonate base, the ampules
used must be sealed tightly before sterilization, and Fe2+ ↔ Fe3+ + e−
must be made of glass sufficiently strong to withstand
As a result, the transition elements can act as electron
the gas pressure developed during sterilization. On
sinks and are active in those systems involved in
cooling, the reverse reaction becomes dominant.
oxidation or reduction reactions.
Ammonium Chloride USP, Monobasic Sodium
On the other hand, an element such as zinc
Phosphate USP, and Calcium Chloride USP are
achieves a completely filled outer 18-electron shell
employed as systemic acidifiers.
on becoming zinc ion. In the 2+ oxidation state this
shell becomes stable. Unlike the tightly held spherical
8-electron shell, the 18-electron shell is mushy, and
Electrolytes and essential trace elements
is deformed or polarized easily by external fields.
It is instructive to review the physical and chemical In turn, it can cause polarization of other moieties.
properties that make possible the respective roles of This ion is not found in redox systems but rather in
electrolytes and essential trace elements in pharmacy. systems such as carbonic anhydrase, which aid in the
Examination of orbital electron structures, ionic radii, splitting or forming of molecules.

Table 5.2 Elements of group I-A

Element Hydrogen Lithium Sodium Potassium Rubidium Cesium Francium

Symbol H Li Na K Rb Cs Fr

Atomic number 1 3 11 19 37 55 87

Atomic weight 1.008 6.941 22.99 39.10 85.47 132.91 (223)

Orbital electrons 1s1 [He]2s1 [Ne]3s1 [Ar]4s1 [Kr]5s1 [Xe]6s1 [Rn]7s1

Oxidation states 1+, 1− 1+ 1+ 1+ 1+ 1+ 1+

Atomic radius (Å) 0.37 1.50 1.86 2.31 2.44 2.62 –

Ionic radius (Å) 1.36 (1−)a 0.60 (1+) 0.95 (1+) 1.33 (1+) 1.48 (1+) 1.69 (1+) 1.76 (1+)

Ionic (hydrated) radius (Å) – 3.40 2.76 3.32 2.28 2.28 –

Ionization potential (eV) 13.527 5.39 5.14 4.34 4.18 3.89 –

Electronegativityb 2.1 0.98 0.93 0.82 0.82 0.79 0.7

% of earth’s crust 0.127 6.5 × 10−3 2.8 2.6 3.1 × 10−2 7 × 10−4 –

a Hydride ion; figure in parentheses is the oxidation state.

b Pauling scale.
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70 | An Introduction to Pharmacy

Table 5.3 The elements of groups I-B and II-B

Element Copper Silver Gold Zinc Cadmium Mercury

Symbol Cu Ag Au Zn Cd Hg

Atomic number 29 47 79 30 48 80

Atomic weight 63.54 107.87 196.97 65.38 112.4 200.59

Orbital electrons [Ar]3d10 4s1 [Kr]4d10 5s1 [Xe]4f 14 5d10 6s1 [Ar]3d10 4s2 [Kr]4d10 5s2 [Xe]4f 14 5d10 6s2

Oxidation states 1+, 2+ 1+, 2+ 1+, (2+), 3+ 2+ 2+ 1+, 2+

Atomic radius (Å) 1.40 1.70 1.70 1.40 1.60 1.50

Ionic (crystal) radii (Å) 0.96 (1+) 1.26 (1+) 1.37 (1+) – – 1.27 (1+)

0.72 (2+) 0.89 (2+) 0.99 (3+) 0.88 (2+) 1.09 (2+) 1.16 (2+)

Ionization potential (eV) 7.724 7.574 9.223 6.92 8.99 10.42

Electronegativity 1.90 1.93 2.54 1.65 1.69 2.00

% of earth’s crust 10−4 10−8 10−9 1.3 × 10−2 1.5 × 10−5 ∼10−6

Table 5.4 The elements of group II-A

Element Beryllium Magnesium Calcium Strontium Barium Radium

Symbol Be Mg Ca Sr Ba Ra

Atomic number 4 12 20 38 56 88

Atomic weight 9.012 24.31 40.08 87.62 137.3 226.03

Orbital electrons [He]2s2 [Ne]3s2 [Ar]4s2 [Kr]5s2 [Xe]6s2 [Rn]7s2

Oxidation states 2+ 2+ 2+ 2+ 2+ 2+

Atomic radius (Å) 0.90 1.70 1.74 1.92 1.98 –

Ionic (crystal) radius (Å) (coordination number 6) 0.31 (2+)a 0.65 (2+) 0.99 (2+) 1.13 (2+) 1.35 (2+) 1.43 (2+)

Ionization potential (eV) 9.3 7.6 6.1 5.7 5.2 5.252

(II)b 18.2 15.0 11.9 11.0 9.95 10.099

Electronegativity 1.57 1.31 1.00 0.95 0.89 0.9

% of earth’s crust 6 × 10−4 2.1 3.6 0.03 0.025 1.3 × 10−10

a Coordination number 4.
b Second ionization potential.
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Pharmaceutical Chemistry | 71

Table 5.5 The elements of group III-A

Element Boron Aluminum Gallium Indium Thallium

Symbol B Al Ga In Tl

Atomic number 5 13 31 49 81

Atomic weight 10.81 26.98 69.72 114.8 204.37

Orbital electrons [He]2s2 2p1 [Ne]3s2 3p1 [Ar]3d10 4s2 4p1 [Kr]4d10 5s2 5p1 [Xe]4f 14 5d10 6s2 6p1

Oxidation states 3+ (1+), 3+ 1+, 2+, 3+ 1+, 3+ 1+, 3+

Atomic radius (Å) 0.82 1.25 1.26 1.44 2.0

Ionic (crystal) radius (Å) – – 1.90 (1+) 1.90 (1+) 1.64 (1+)

(coordination number 6) 0.20 (3+)a 0.675 (3+) 0.76 (3+) 0.94 (3+) 1.03 (3+)

Ionization potential (eV) 8.30 5.95 6.0 5.8 6.1

(II)b 25.15 18.82 20.4 18.8 20.3

(III)c 37.92 28.44 30.6 27.9 29.7

Electronegativity 2.04 1.61 1.81 1.78 1.62

% of earth’s crust 3 × 10−4 8.13 1.5 × 10−3 10−5 ∼10−4

a Coordination number 4.
b Second ionization potential.
c Third ionization potential.

Unlike the incompletely filled shells of the transi- Injection and Lactated Ringer’s and Dextrose Injec-
tion elements or the 18-electron shell of the zinc ion, tion (with Half-Strength and Modified variations), a
8-electron-shell ions ordinarily are stable and are not series of monographs are found with the designation
deformed easily by external fields. Those 8-electron Multiple Electrolytes in each title; these monographs
outer-shell ions with a high charge (e.g., calcium) have offer choices of cations from Na+ , K+ , Ca2+ , Mg2+ ,
intense charge densities in the volume surrounding and NH+ 4 ; of anions from chloride, acetate, citrate,
the ion. This results in strong interactions with the lactate, gluconate, phosphate, and sulfate; plus a
fields of other moieties to form strong permanent choice of carbohydrate nutrient from invert sugar and
associations. However, an 8-electron shell effectively dextrose. These monographs indicate an awareness of
screens the single charge of ions such as sodium. They the importance of inorganic cations (including magne-
are therefore chemically inert with very weak interac- sium) and anions, and provide a variety of choices to
tions with other ions. This explains their simple roles allow treatment of patients on an individualized basis.
in the body fluids as osmotic regulators, etc. In addition to providing official standards for
There are a fair number of monographs for various infusions used as parenteral rehydration
parenteral infusions intended to supply electrolytes, solutions or electrolyte replenishers, USP has a
water, and carbohydrates as nutrients. In addition generic monograph for Oral Rehydration Salts, a dry
to monographs in the USP for Ringer’s and Dextrose mixture of sodium chloride, sodium bicarbonate (or
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72 | An Introduction to Pharmacy

Table 5.6 Transition elements

Group III-B Group IV-B

Element Scandium Yttrium Lanthanum Titanium Zirconium Hafnium

Symbol Sc Y La Ti Zr Hf

Atomic number 21 39 57 22 40 72

Atomic weight 44.96 88.91 138.9 47.90 91.22 178.5

Orbital electrons [Ar]3d1 4s2 [Kr]4d1 5s2 [Xe]5d1 6s2 [Ar]3d2 4s2 [Kr]4d2 5s2 [Xe]4f 14 5d2 6s2

Oxidation states 3+ 3+ 3+ 2+, 3+, 4+ 2+, 4+ (2+), 4+

Atomic radius (Å) 1.51 1.8 1.87 1.36 1.45 1.44

Ionic radii (Å) 0.81 (3+) 0.93 (3+) 1.15 (3+) 1.00 (2+) – –

(coordination number 6) 0.75 (4+) 0.86 (4+) 0.85 (4+)

Ionization potential (eV) 6.7 6.5 5.6 6.82 6.84 ∼5.5

Electronegativity 1.54 1.53 1.3 – – –

% of earth’s crust 0.44 0.022 4.5 × 10−4 0.629 0.028 –

sodium citrate), potassium chloride, and dextrose to Topical agents

be dissolved and used to treat chronic diarrhea.
In recent years there has been an increased
Oxidizing germicides
awareness of the importance of minerals in the diet Hydrogen Peroxide, Sodium Hypochlorite, Iodine,
and of the value of mineral supplements. Generally, and/or their various solutions are cited in the USP.
gluconates, like other organic salts, are less irritating Hypochlorous acid, the active moiety in sodium
to the gastrointestinal tract; thus, the following metal hypochlorite solution, owes its germicidal activity to
gluconates are found in the USP: Zinc, Sodium, Cop- both oxidizing and chlorinating activity.
per, Magnesium, and Manganese. The USP includes
a monograph for Selenious Acid Injection, which can Precipitating germicides
provide a source of selenium as a mineral supplement. Silver Nitrate, Silver Nitrate Ophthalmic Solution,
In a new USP section entitled Nutritional Sup- and Toughened Silver Nitrate are listed in the USP,
plements are monographs for Mineral Capsules and as is Ammoniated Mercury. Zinc Acetate, Zinc
Mineral Tablets. The minerals present in these dosage Chloride, Zinc Sulfate, and Zinc Undecylenate are
forms are potassium, calcium, magnesium, phospho- also official. Only two boron compounds are cited in
rous, zinc, iron, manganese, copper, molybdenum, the NF: Boric Acid and Sodium Borate. The antimony
fluorine, chromium, iodine, and selenium. compounds listed are Antimony Potassium Tartrate
When it is necessary to administer trace elements USP and Antimony Sodium Tartrate USP.
parenterally, the monograph entitled Trace Elements
USP describes a sterile solution that may be used Astringents
to administer zinc, copper, chromium, manganese, Aluminum ion in solution is an excellent local
selenium, iodine, and molybdenum. astringent over wide concentration ranges. It is also
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Pharmaceutical Chemistry | 73

Table 5.7 The elements of group IV-A

Element Carbon Silicon Germanium Tin Lead

Symbol C Si Ge Sn Pb

Atomic number 6 14 32 50 82

Atomic weight 12.01 28.08 72.59 118.69 207.2

Orbital electrons [He]2s2 2p2 [Ne]3s2 3p2 [Ar]3d10 4s2 4p2 [Kr]4d10 5s2 5p2 [Xe]4f 14 5d10 6s2 6p2

Oxidation states 4− to 4+ 4− to 4+ 2+, 4+ 2+, 4+ 2+, 4+

Atomic radius (Å) 0.77 1.17 1.22 1.41 1.54

Ionic (crystal) radii 2.6 (4−) 2.71 (4−) 0.87 (2+) 0.93 (2+) 1.20 (2+)

(coordination number 6) 0.3 (4+)a 0.54 (4+) 0.67 (4+) 0.83 (4+) 0.91 (4+)

Ionization potential (eV) 11.264 8.149 8.09 7.30 7.38

Electronegativity 2.55 1.90 2.01 1.58 1.87

% of earth’s crust 2.7 × 10−2 27.7 7 × 104 6 × 10−4 1 × 10−3

a Coordination number 4.

Table 5.8 The elements of group V-A

Element Nitrogen Phosphorus Arsenic Antimony Bismuth

Symbol N P As Sb Bi

Atomic number 7 15 33 51 83

Atomic weight 14.01 30.97 74.92 121.75 208.98

Orbital electrons [He]2s2 2p3 [Ne]3s2 3p3 [Ar]3d10 4s2 4p3 [Kr]4d10 5s2 5p3 [Xe]4f 14 5d10 6s2 6p3

Oxidation states 3−, 1+, 3+, 5+ 3−, 3+, 5+ 3−, 3+, 5+ 3−, 3+, 5+ 3−, 3+, 5+

Atomic radius (Å) 0.70 1.06 1.21 1.41 1.5

Ionic (crystal) radii (Å) 1.32 (3+) 0.58 (3+) 0.72 (3+) 0.90 (3+) 1.17 (3+)

(coordination number 6) 0.27 (5+) 0.52 (5+) 0.60 (5+) 0.74 (5+) 0.90 (5+)

Ionization potential (eV) 14.48 11.10 10.5 8.5 8.0

Electronegativity 3.04 2.19 2.18 2.05 2.02

% of earth’s crust 4.6 × 10−8 0.12 5 × 10−4 10−4 2 × 10−5

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74 | An Introduction to Pharmacy

Table 5.9 Transition elements

Group V-B Group VI-B

Element Vanadium Niobium Tantalum Chromium Molybdenum Tungsten

Symbol V Nb Ta Cr Mo W

Atomic number 23 41 73 24 42 74

Atomic weight 50.94 92.91 180.95 52.00 95.94 183.85

Orbital electrons [Ar]3d3 4s2 [Kr]4d4 5s1 [Xe]4f 14 5d3 6s2 [Ar]3d5 4s1 [Kr]4d5 5s1 [Xe]4f 14 5d4 6s2

Oxidation states 2+, 3+, 4+, 5+ 2+, 3+, 4+, 5+ 2+, 3+, 4+, 5+ 2+, 3+, 4+, 6+ 2+ . . . 6+ 2+ . . . 6+

Atomic radius (Å) 1.22 1.34 1.34 1.18 1.30 1.30

Ionic (crystal) radii (Å) 0.40 (5+) 0.70 (5+) 0.73 (5+) 0.76 (3+) 0.79 (4+) 0.80 (4+)

(coordination number 6) 0.58 (6+) 0.73 (6+) 0.74 (6+)

Ionization potential (eV) 6.71 6.79 ∼6 6.77 7.38 7.98

Electronegativity – – 1.33 1.66 2.2 2.36

% of earth’s crust 0.021 – – 2 × 10−2 ∼5 × 10−4 ∼1.5 × 10−4

Table 5.10 The elements of group VI-A

Element Oxygen Sulfur Selenium Tellurium Polonium

Symbol O S Se Te Po

Atomic number 8 16 34 52 84

Atomic weight 16.00 32.06 78.96 127.6 (209)

Orbital electrons [He]2s2 2p4 [Ne]3s2 3p4 [Ar]3d10 4s2 4p4 [Kr]4d10 5s2 5p4 [Xe]4f 14 5d10 6s2 6p4

Oxidation states 2−, 1− 2−, 2+, 6+ 2−, 4+, 6+ 2−, 4+, 6+ 4+, 6+

Atomic radius (Å) 0.66 1.04 1.16 1.37 1.53

Ionic (crystal) radii (Å) (simple anion) 1.26 (2−) 1.70 (2−) 1.84 (2−) 2.07 (2−) 1.08 (4+)

(coordination number 6) – 0.43 (6+) 0.56 (6+) 0.57 (6+) 0.81 (6+)

Ionization potential (eV) 13.61 10.36 9.75 9.0 –

Electronegativity 3.44 2.58 2.55 2.1 2.0

% of earth’s crust 46.6 0.052 10−7 10−7 10−14

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Pharmaceutical Chemistry | 75

Table 5.11 The elements of group VII-A

Element Fluorine Chlorine Bromine Iodine Astatine

Symbol F Cl Br I At

Atomic number 9 17 35 53 85

Atomic weight 19 35.45 79.90 126.90 (210)

Orbital electrons [He]2s2 2p5 [Ne]3s2 3p5 [Ar]3d10 4s2 4p5 [Kr]4d10 5s2 5p5 [Xe]4f 14 5d10 6s2 6p5

Oxidation states 1− 1−, 1+, 3+, 5+, 7+ 1−, 1+, (3+), 5+ 1–, 1+, (3+), 5+, 7+ –

Atomic radius (Å) 0.64 0.99 1.14 1.33 –

Ionic (crystal) radii (Å) (halide anion) 1.19 1.67 1.82 2.06 –

(coordination number 6) 0.022 (7+) 0.41 (7+) 0.53 (7+) 0.67 (7+) 0.76 (7+)

Ionization potential (eV) 17.42 13.01 11.84 10.44 –

Electronegativity 3.98 3.16 2.96 2.66 2.2

% of earth’s crust 8 × 10−2 3 × 10−2 1.6 × 10−4 3 × 10−5 –

mildly antiseptic. Aluminum Chloride USP was once Aluminum Subacetate Topical Solution USP is
used in this application, but the high acidity of its essentially a solution of the above ions prepared from
solutions caused problems. The acidity results from aluminum sulfate using carbonate ion (CaCO3 ) as
ionization of the hexa-aquo ion, the base. Aluminum Sulfate, Ammonium Alum, and
Potassium Alum are found in the USP and are also
[Al(H2 O)6 ]3+ + H2 O ↔ [Al(OH)(H2 O)5 ]2+ + H3 O+ used as astringents. Alum can be either the potassium
or ammonium form. It is shaped into a pencil form to
and is approximately that of acetic acid. Today, the be used as a styptic.
mixture of two compounds (aluminum hydroxychlo- Iron(III) and aluminum ions are very similar.
ride, aluminum chlorhydrate, aluminum chlorhydrol) Iron(III) is astringent, and preparations of ferric salts
obtained by partial neutralization of aluminum for such use formerly were recognized. Although it
chloride is used. is efficient in this capacity, its staining property is
a major disadvantage. Lime water, a saturated solu-
[Al(H2 O)6 ]3+ + OH− → [Al(OH)(H2 O)5 ]2+ + H2 O tion of fresh calcium hydroxide, is used as a local
astringent. Bismuth subnitrate and the other bismuth
[Al(OH)(H2 O)5 ]2+ + OH− → [Al(OH)2 (H2 O)4 ]+ subsalts are used as astringents and protectives.
+H2 O
Protective agents
The reaction is stopped before complete conversion To possess good adhering properties, protective
to the dihydroxy hydrate. The resulting solution (or agents must be in very finely powdered form. They
dried product) retains the excellent astringent (and must also be relatively inert, insoluble compounds. A
deodorant) properties of the aluminum ion, but the wide range of compounds are suitable as protective
pH of the solution’s approximate neutrality (5 to 6). agents. They are usually used externally, but some
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76 | An Introduction to Pharmacy

Table 5.12 Transition elements

Group VII-B Group

VIII – First
Triad

Element Manganese Technetium Rhenium Iron Cobalt Nickel

Symbol Mn Tc Re Fe Co Ni

Atomic number 25 43 75 26 27 28

Atomic weight 54.94 (98) 186.2 55.85 58.93 58.71

Orbital electrons [Ar]3d5 4s2 [Kr]4d5 5s2 [Xe]4f 14 5d5 6s2 [Ar]3d6 4s2 [Ar]3d7 4s2 [Ar]3d8 4s2

Oxidation states 2+, 3+, 4+, 6+, 7+ 2+, 3+, 4+, 6+, 7+ 3+, 4+, 5+, 6+, 7+ 2+, 3+ 2+, 3+ 2+, 3+

Atomic radius (Å) 1.17 1.27 1.25 1.17 1.16 1.15

Ionic (crystal) radii (Å) 0.81 (2+) – 0.81 (3+) 0.75 (2+) 0.79 (2+) 0.83 (2+)

(coordination number 6) 0.40 (6+) 0.56 (7+) 0.69 (5+) 0.69 (3+) 0.69 (3+) 0.70 (3+)

Ionization potential (eV) 7.43 7.23 7.87 7.83 ∼8.5 7.6

Electronegativity 1.55 1.9 1.9 1.85 1.88 1.91

% of earth’s crust 0.085 Zero (?) 10−7 5 2.3 × 10−3 8 × 10−3

applications involve the gastrointestinal tract. Some Inorganic pigments

are slightly soluble (e.g., ZnO) and give some The most important innocuous pigments are the
astringent action; others (e.g., kaolin) have adsorbent iron oxides. They give colors throughout the visible
action. spectrum. Three variables are involved: particle size,
Zinc Oxide, Calamine (and Calamine Lotion oxidation state, and degree of hydration.
and Phenolated Calamine Lotion), and Zinc Stearate
(all USP) are used for their protective and slightly Acid Conjugate base
astringent properties. Calamine is the calcined
H2 SO4 HSO−
native zinc oxide ore. The iron oxide impurity gives 4

calamine a flesh color that is cosmetically more HNO3 NO3 −

appealing. Zinc stearate, a mixture of fatty acid zinc
soaps, has an unctuous feel. White Lotion USP is HF F−

used for its astringent and protective powers.

H3 PO4 H2 PO−
4
Magnesium trisilicate, basic aluminum carbonate,
and chalk are used as protective compounds, as are H2 S HS−
the various insoluble bismuth subsalts. Talc is used
HS− S2−
because of its smooth, unctuous feel. Kaolin and
bentonite are used as they also have some absorptive NH+ NH3
4
properties; titanium dioxide is used as a solar screen.
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Pharmaceutical Chemistry | 77

Miscellaneous inorganic applications Carbon dioxide absorbers

Artificial atmospheres When, as in general anesthesia, a patient rebreathes
air, dangerous levels of carbon dioxide build up. To
Five gases are official: Nitrogen, Oxygen, Helium,
prevent this, carbon dioxide absorbers are used. Soda
Carbon Dioxide, and Nitrogen(I) Oxide (nitrous Lime NF is prepared by fusing calcium hydroxide with
oxide or laughing gas). Nitrogen is used as a sodium hydroxide, potassium hydroxide (or both)
diluent for oxygen and may be used as a protective with sufficient diatomaceous earth to yield a hard,
atmosphere for easily oxidized medicinals. non-friable product. For Barium Hydroxide Lime
Helium, because of its low density compared USP, barium hydroxide is substituted for the alkali
to nitrogen, is used to prepare a gaseous mixture hydroxide. The particles formed must be large enough
composed of 20% oxygen and helium. This mixture to allow free passage of air, but small enough to give a
is used to alleviate respiration difficulties. Because of large surface area for absorption. The particles must
the low solubility of helium in blood, the same mix- be hard to prevent dust formation with handling.
ture is used as an atmosphere for those performing Entrainment of absorber dust in the breathed air could
cause serious alkali burns in the respiratory tract. A
under high atmospheric pressures (deep-sea divers,
colored indicator is included in the preparation to
caisson workers). When ordinary air is used, rapid
indicate when the carbon dioxide capacity is depleted.
decompression causes bubbles of gaseous nitrogen
to form in the blood; the resulting painful, and
Respiratory stimulants
sometimes fatal, condition is known as the bends.
Carbon dioxide is used as a respiratory stimulant,
Oxygen is used when respiratory problems exist.
usually with 5 to 7% oxygen. Because it is the
Ordinarily, it is diluted with nitrogen or helium;
normal respiratory stimulant it is of no value where
100% oxygen should not be used continuously. In
the respiratory center is already depressed. Carbon
hyperbaric oxygen therapy, oxygen is breathed inside dioxide also is used as an inert gas in the headspace
a tank at up to 3atm (atmospheres) of pressure. over medicinals in sealed containers.
Although the amount of oxygen carried by the Ammonium Carbonate NF is used as a respiratory
hemoglobin is little affected, the higher oxygen stimulant. The name is a misnomer as it is a mixture of
pressure increases the amount of dissolved oxygen in ammonium bicarbonate and ammonium carbamate.
the plasma (Henry’s law). At room temperature it decomposes to ammonia and
It is possible to produce oxygen that is medic- carbon dioxide, two respiratory stimulants.
inally useful on site, as in a hospital or nursing
home, by the use of oxygen concentrators. There NH4 HCO3 +NH2 CO2 NH4 → 3NH3 +2CO2 +H2 O
are two types of membranes that are used in the
The substance must be stored in tightly sealed
concentrators: permeable plastic membranes and
containers. Aromatic Ammonia Spirit USP is pre-
molecular sieves. The monograph for Oxygen 93
pared from ammonium carbonate, strong ammonia
percent USP sets standards for the oxygen produced
solution, various aromatic oils, alcohol, and water.
by the molecular-sieve process.
Light-resistant containers must be used.
Nitrogen(I) oxide usually requires 20 to 25%
oxygen during administration. It is used for surgical Expectorants
procedures of short duration. Xenon has a general
Water vapor, an excellent expectorant, is currently
anesthetic action but is too rare for use. Magnesium
considered the best. Ammonium chloride and
ion has anesthetic action; however, the anesthetic carbonate, and ammonium and potassium iodides
dose and the toxic dose of magnesium are too close are used commonly as expectorants. Hydroiodic acid
for it to be used as a general anesthetic. Magnesium syrup was official at one time. If the iodides are used
Sulfate Injection USP is used as an anticonvulsant in solution, they must be protected by an antioxidant
and central nervous system depressant. such as sodium thiosulfate.
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78 | An Introduction to Pharmacy

Laxatives, enemas, and irrigation solutions is defined as a sterile solution that, after the chemical
Cathartics are divided into classes according to mode reactions between citric acid and the other two
of action. With the exception of sulfur, the inorganic compounds are completed and the resulting solution
cathartics are saline (osmotic, bulk) laxatives. For is sterilized, is suitable for use as a urinary-bladder
laxative action, one or both of the ions of the salt must irrigant; its acidic pH is conducive to dissolving any
not be absorbed, or be absorbed with difficulty. This bladder calculi in patients such as those using an
creates an osmotic imbalance in the intestinal tract indwelling catheter.
that the body attempts to correct by secreting water
Radiopaques and imaging agents
into the intestine. The large volume of fluid in the
intestine acts as a mechanical stimulus for peristalsis. Radiopaque compounds are capable of interfering
The commonly used salts of monohydrogen with the passage of X-rays. This interference is
phosphate, monohydrogen tartrate, tartrate, and directly proportional to atomic number. The soft
citrate ions are absorbed slowly, but in laxative tissues of the body are composed of atoms of very
doses their osmotic action is rapid and effective. low atomic number (1, 6, 7, 8, 15, and 16) that do
They are swept out of the intestinal tract before not interfere sufficiently to be discerned. To make
appreciable absorption can take place. Sulfate ion is visible the soft tissues, the lumen of organs, and body
relatively non-absorbable and is used either as the channels, atoms of high atomic number must be used.
magnesium or sodium salt (Epsom salt and Glauber’s Because of the toxicity of these elements, the
salt, respectively). choices are limited. Only two, barium and iodine
Insoluble laxatives, such as Milk of Magnesia, (atomic numbers 56 and 53, respectively) have proved
must be dissolved in the stomach before they can useful. Barium Sulfate USP and Barium Sulfate for
exert a laxative effect. The soluble magnesium sulfate Suspension USP are used for studies of the intestinal
and citrate of magnesia are used widely as laxatives. tract. Iodine is incorporated into organic molecules
However, soluble magnesium salts frequently are not designed to concentrate in the organ or cavity to
recommended as laxatives because of the danger of be studied, such as Iopanoic Acid USP designed for
absorbing free magnesium ion. Dibasic Sodium Phos- visualization of the gall bladder. Each molecule of
phate, Sodium Phosphates Oral Solution, Sodium the acid has three iodine atoms.
Citrate and Citric Acid Oral Solution, Potassium The introduction and development of magnetic
Sodium Tartrate, Milk of Magnesia, and Sodium resonance imaging as a means of acquiring images of
Sulfate are cited officially. parts of the body by noninvasive methods has made
PEG 3350 and Electrolytes for Oral Solution USP medical diagnoses simpler and more scientific. The
(Polyethylene glycol 3350, NaHCO3 , NaCl, Na2 SO4 , use of gadolinium (element 64) in various complexes
and KCl) is a dry mixture that is to be dissolved such as a cationic diethylenetriamine pentaacetic acid
at the time of use and then consumed within a complex with a meglumine anion has dramatically
prescribed time so as to function as a cathartic and facilitated the visualization of intracranial lesions by
accomplish oral colonic lavage in preparation for a paramagnetic enhancement.
barium enema or a colonoscopic examination.
Sulfur, when ingested, has an irritant laxative Structural repairs
effect. The element is thought to be reduced to hydro- Occasionally, temporary or permanent replacement
gen sulfide by reducing agents present in the intestinal of body support structures is necessary. The materials
fluid. Hydrogen sulfide is a mild intestinal irritant. used should be chemically inert and insoluble in the
Sodium Phosphates Enema USP is a mixture of body fluids, they must be non-toxic, and they must
dibasic and monobasic sodium phosphates or dibasic have the strength to withstand any physical stress
sodium phosphate and phosphoric acid in water to to which they are subjected. Tantalum has been
give a solution of pH 5 to 5.8. used as a bone replacement for temporary braces
Some solutions are used for irrigating various of long bones, and to close openings in the skull.
parts of the body. For example, Citric Acid, Magne- Silver has found similar applications. It reacts slightly
sium Oxide, and Sodium Carbonate Irrigation USP with body fluids, but as insoluble silver chloride is
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Pharmaceutical Chemistry | 79

the principal product, this is not a serious threat. Functional groups

Mercury amalgams of gold and silver are used for
Functional groups are specific combinations of atoms
dental fillings, but this venerable use of mercury is
linked through covalent bonds. A functional group
being questioned because of possible chronic toxicity.
Zinc-eugenol cement is also used for dental fillings. or set of functional groups may also be referred to
Plaster of Paris is used for temporary support as a chemical moiety. Functional groups are responsi-
structures, especially for broken bones. The formula, ble for characteristic physicochemical properties of a
CaSO4 · 1/2H2 O, suggests a hemihydrate, but there molecule, including synthetic reactivity and biological
is experimental evidence indicating the existence of activity. Several common functional groups, includ-
local gypsum (CaSO4 ·2H2 O) nuclei in anhydrous ing phenol, ether, alcohol, alkene, and amine, are
calcium sulfate. illustrated below with the opioid analgesic morphine.
Plaster of Paris is also used for taking dental
impressions; because it expands slightly on setting, it Functional groups of morphine
fills all spaces completely to give a true surface replica.
Phenol
HO

Organic pharmaceutical chemistry

Tertiary amine
Ether O
Introduction N
CH3
The purpose here is to provide a brief introductory
overview of organic chemistry concepts that are very HO
Alcohol
relevant to the very small subclass of organic com-
Alkene
pounds called pharmaceutical agents. It is assumed
that the reader has basic knowledge of organic chem-
istry at the typical one-year college level in the United Metabolism and enzymatic reactions usually result
States and has access to basic and advanced books for in transformation or addition of functional group(s).
follow-up as need be. Detailed treatments of many For example, esterase enzymes convert ester func-
of the important concepts introduced are provided tional groups of substrates into corresponding alco-
elsewhere. hols and carboxylic acids. The enzymatic reactions
Organic chemicals used as drugs can be clas- involved in the biosynthesis of the neurohormone
sified into three main categories based on chemi- epinephrine from amino acid tyrosine provide an
cal, pharmacological, and therapeutic properties. For example of a series of enzymes working in tandem,
example, consider the drug metoprolol. It can be with each one carrying out a functional group trans-
classified as an aryloxypropanolamine (chemical), formation, as depicted in Fig. 5.1. Metabolism is
beta-2 (β 2 ) adrenergic receptor antagonist (pharma- classified into two categories, known as phase I and
cological), and antihypertensive agent (therapeutic), phase II. Phase I metabolism results in creation of
depending on context. polar functional group, which then acts as substrate
Here, we will briefly examine functional in phase II conjugation reaction. Phase I reactions are
groups, acid–base concepts, stereochemistry, inter- commonly carried out by cytochrome P450 oxidase
molecular forces of attraction, and quantitative enzymes via a monooxygenase reaction:
structure–activity relationship studies as they relate
to organic pharmaceutical agents such as metoprolol.
RH + O2 + 2H+ → ROH + H2 O
Expatiations on pharmacological and therapeutic
effects are carried out in other chapters. The
chemical classification of metoprolol as an ary- Phase II conjugations are catalyzed by a vari-
loxypropanolamine indicates the various functional ety of transferase enzymes, including glutathione S-
groups present on the molecule, i.e., aryl, oxygen transferase, sulfotransferase and glucuronosyltrans-
(ether), and propanol (alcohol) amine. ferase. It can be illustrated with:
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80 | An Introduction to Pharmacy

OH OH
COOH HO COOH HO HO HO
A B C D
HO NH2 HO NH2 HO NH2 NH2 NH
HO HO
L-tyrosine L-dopa Dopamine Norepinephrine Epinephrine

Figure 5.1 Biosynthesis of epinephrine. (A) Tyrosine hydroxylase, (B) aromatic L-amino acid decarboxylase, (C) dopamine
beta-hydroxylase, (D) phenethanolamine-N-methyltransferase.

O In 1923, Brønstead and Lowry developed a defini-

Sulfotransferase
tion of acids and bases which expands the Arrhenius
R OH R O S OH definition. According to their theory, an acid is any
3’-Phosphoadenosine-
5’-phosphosulfate substance capable of donating a hydrogen ion (pro-
O
ton), and a base is a substance capable of accepting a
In many cases, enzyme names reflect the func- proton. Their relation is expressed by
tional group transformation that they help catalyze. A
HA  H+ + A−
decarboxylase enzyme removes carboxyl group from
substrate. Likewise, an esterase cleaves ester bond to where HA is the acid and A− is the base.
give corresponding carboxylic acid and alcohol. A conjugate acid–base pair refers to a pair of sub-
stances related by loss or gain of a proton. Examples
O O are shown below.
R′
Esterase In addition to neutral molecules, cations and
R O R OH + R′ OH anions can also function as acids or bases. An acid will
not release a proton unless a base that is capable of
accepting it is present. In this way, acid–base behav-
A central concept in drug design is the pharma-
ior involves interaction between two sets of conjugate
cophore. A pharmacophore is a three-dimentional
acid–base pairs, as depicted below.
arrangement of functional groups that is responsible
for a particular biological activity. The pharma- A1 + B2  B1 + A2
cophore contains the complementary spatial and
where A1 is acid1 , B1 is base1 , A2 is acid2 , and
electrostatic arrangement of functional groups for
B2 is base2 . The above relationship is termed a pro-
binding to a biological target, such as a receptor.
tolytic reaction or protolysis. A1 and B1 constitute one
This concept again illustrates the importance of
acid–base pair, and A2 and B2 the other. A proton is
functional groups.
given up by A1 and is transferred to B2 ; A1 becomes
B1, and B2, upon accepting the proton, becomes A2 .
An example occurs when the acid hydrogen sulfide is
Acids and bases dissolved in water:

According to Arrhenius, an acid is a substance that H2 S + H2 O  H3 O+ + HS−

acid1 base2 acid2 base1
produces hydrogen ions (H+ ) in aqueous solution,
whereas a base produces hydroxyl ions (OH− ) in H3 O+ , hydronium ion is an ionic species that is always
the same solution. There is no complementary rela- formed when an acid is dissolved in water. It is
tionship between an acid and a base besides the generally written as H+ (hydrogen ion).
formation of water when hydrogen ions neutralize When a base such as sodium hydroxide (NaOH) is
hydroxyl ions. In the Arrhenius definition of acids dissolved in water, the protolytic reaction that occurs
and bases, the opposite nature of their characters is is as follows:
emphasized. There is no account for their behavior in
OH− + H2 O  H2 O + OH−
non-aqueous media. base1 acid2 acid1 base2
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Pharmaceutical Chemistry | 81

Protolysis is not limited to dissimilar conjugate attributed to a higher hydroxide ion concentration in
acid–base pairs. H2 O can behave both as an acid the former.
and a base. Because of this, H2 O is referred to as an The incomplete or partial ionization of acids may
amphoteric or amphiprotic substance. When sodium be considered a reversible reaction:
acetate is dissolved in water, the following acid-base
reaction occurs: HA  H+ + A−

CH3 COO− + H2 O  CH3 COOH + OH− where HA is the acid and A− is its conjugate base.
base1 acid2 acid1 base2
An equilibrium expression based on the law of mass
action may be applied to the reaction
In an aqueous solution of ammonium chloride, the
reaction is:
Ka = [H+ ] [A− ]/[HA] (5.1)
NH+
4 + H2 O  NH3 + H3 O
+

acid1 base2 base1 acid2 where Ka is the ionization or dissociation constant

and the brackets signify concentrations. For weakly
Although the proton concept of acids and bases is ionized acids in a specified solvent and at a constant
widely applicable, it does not indicate the reason for temperature, Ka is constant irrespective of the con-
proton transfer nor does it explain how substances centrations. For increasingly stronger acids, higher Ka
such as sulfur trioxide, boron trichloride, or carbon values occur.
dioxide (none of which is capable of donating a Although the strength of an acid is commonly
proton) can behave as acids. In 1923, Lewis provided measured in terms of the ionization or dissociation
the definition of acids and bases which avoids the constant (equation), the process of ionization is not
deficiencies of the proton theory. The theory defines that simple. A proton does not simply detach itself
an acid as an electron pair acceptor and a base as an from one molecule unless it is accepted simultaneously
electron pair donor. by another molecule. When an acid is dissolved in
water, the water acts as a base, accepting proton
Ionization of acids and bases from the acid. The lone pair of electrons to form the
Ionization is a process in which an atom or molecule covalent bond with proton comes from water. This
is converted into an ion by the addition or removal of reaction can be written as
charged particles. Acids and bases are generally clas-
sified as strong or weak depending on whether they HA + H2 O  A− + H3 O+
acid1 base2 base2 acid2
ionize extensively or slightly in an aqueous solution.
For example, if 1 N aqueous solutions of hydrochloric Applying the law of mass action to the reaction gives
acid and acetic acid are compared, it is found that the
former is a better conductor of electricity, reacts more [H3 O+ ] [A− ]
Ka = (5.2)
readily with metals, and catalyzes certain reactions [HA] [H2 O]
more efficiently. However, both solutions neutralize
identical amounts of base. A similar comparison is Because change in the concentration of H2 O is negli-
found with 1 N solutions of sodium hydroxide and gible, a constant taking this into consideration can be
ammonia; the former is more reactive than the latter written as
though both solutions will neutralize the same quan- [H3 O+ ] [A− ]
tity of acid. For two acids, the difference in hydrogen Ka = (5.3)
[HA]
ion concentration is attributed to the differences in
their properties. Hydrochloric acid is ionized to a Equations (5.1) and (5.3) are equivalent because
greater extent; thus, it contains a higher concentra- [H3 O+ ] is numerically equal to [H+ ].
tion of hydrogen ions than acetic acid at equivalent Acids capable of donating more than one
concentrations. Similarly, the difference in strength proton are termed polyprotic. The ionization of
between sodium hydroxide and ammonia solutions is polyprotic acids is stepwise and can be illustrated by
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82 | An Introduction to Pharmacy

considering the equilibria involved in the ionization of

Table 5.13 Dissociation constants of several
sulfuric acid.
weak acids and bases

H2 SO4 + H2 O  HSO−
4 + H3 O
+
Substance Formula K

HSO− 2−
4 + H2 O  SO4 + H3 O
+ Acetic acid CH3 COOH 1.8 × 10−5

Acrylic acid CH4 O2 5.5 × 10−5

Application of the law of mass action to the series of
reaction gives
Ascorbic acid H2 C6 H6 O6 HC6 H6 O−
6 K 1 : 6.8 × 10−5 K 2 :
2.8 × 10−12
[HSO− −
4 ] [H3 O ]
K1 = (5.4)
[H2 SO4 ] Bromoacetic acid HC2 H2 BrO2 1.3 × 10−3

+ Benzoic acid HC7 H5 O2 6.3 × 10−5

[SO2−
4 ] [H3 O ]
K2 = − (5.5)
[HSO4 ] Boric acid H3 BO3 5.9 × 10−10

To obtain the overall ionization constant K, the two Chromic acid H2 CrO4 HCrO− K 1 : 1.5 × 10−1 K 2 :
4
expressions for their ionization constants are multi- 3.2 × 10−7
plied together
Chloroacetic acid HC2 H2 ClO2 1.4 × 10−3

K = K1 K2 (5.6)
Chlorous acid HClO2 1.1 × 10−2

According to Le Chatelier’s principle, each subse- Cyanic acid HOCN 3.5 × 10−4
quent ionization is suppressed by the hydronium ion
formed in the preceding stage. Successive dissociation Dichloroacetic acid HC2 HCl2 O2 5.5 × 10−2
constants decrease in value, and subsequent species
Trichloroacetic acid HC2 Cl3 O2 3.0 × 10−1
are more negatively charged. This can be seen in Table
5.13, in which K1 for phosphoric acid is 100,000
Diethylammonium (C2 H5 )2 NH+
2 1.4 × 10−11
times greater than K2 , which is in turn approximately ion
100,000 times greater than K3 . Although successive
dissociation constants are always smaller, the differ- Dimethyl- (CH3 )2 NH+
2 1.7 × 10−11
ence is not always as large as observed for phosphoric ammonium ion

acid. For example, succinic acid has K1 of 6.4 × 10−5

Ethylenedi- NH2 CH2 CH2 NH+ 1.9 × 10−11
and K2 of 2.3 × 10−6 . ammonium ion
3

The ionization of a weak base (B) can be illustrated

by examining the ionization of the conjugate acid. Fluoroacetic acid HC2 H2 FO2 2.6 × 10−3
We can then define Ka in a similar manner as done
Formic acid HCHO2 1.8 × 10−4
previously for weak acids.
Hydrogen peroxide H2 O2 2.2 × 10−12
HB+  H+ + B
Hydrosulfuric acid H2 S 1.0 × 10−7

HB+ + H2 O  B + H3 O+ Hydroselenic acid H2 SeHSe− K 1 : 1.3 × 10−4 K 2 :

1.0 × 10−11

where HB+ is the conjugate acid and B is the base.

[B] [H3 O+ ]
Ka = (5.7)
[HB+ ] [H2 O]
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Pharmaceutical Chemistry | 83

With [H2 O] being constant, this expression can be The numerical value of Kw varies with temperature; at
rewritten as 25◦ C, it is approximately equal to 1 × 10−14 mol2 L−2 .
Autoprotolysis of pure water yields one hydro-
[B] [H3 O+ ]
Ka = (5.8) nium ion for each hydroxyl ion produced; therefore,
[HB+ ]
[H3 O+ ] equals [OH− ]. At 25◦ C each has a value of
An example is ammonia (NH3 ). We can define Ka by 1 × 10−7 mol/L (1 × 10−7 × 1 × 10−7 = Kw = 1 ×
examining ionization of the conjugate acid, ammo- 10−14 ). A solution in which [H3 O+ ] is equal to [OH− ]
nium ion. This reaction can be written as is termed a neutral solution.
When an acid is added to water, hydronium-ion
NH+
4 + H2 O  NH3 + H3 O
+ concentration increases, and the equilibrium between
hydronium and hydroxyl ions is momentarily dis-
The equilibrium expression for this reaction is turbed. To restore equilibrium, some hydroxyl ions
originally present in the water combine with some of
[NH3 ] [H3 O+ ] the added hydronium ions to form un-ionized water
Ka = (5.7a)
[NH+
4 ] [H2 O] molecules until the product of the concentrations of
the two ions is reduced to 10−14 . When equilibrium
With [H2 O] being constant, this expression can be is restored, the concentrations of the two ions are
rewritten as no longer equal. For example, if the hydronium-ion
[NH3 ] [H3 O+ ] concentration is 1 × 0.01 N, when equilibrium is
Ka = (5.8a) established, the concentration of the hydroxyl ion
[NH+ 4]
will be 1 × 10−12 (the product of the two concentra-
A trend to remember, based on the equilibrium tions being equal to 10−14 ). Because [H3 O+ ] is much
equation, is that as Ka of the conjugate acid of a greater than [OH− ], the solution is acidic. Similarly,
base increases, [B] and [H3 O+ ] increase and [HB+ ] the addition of an alkali to pure water momentar-
decreases. Alternatively, as base strength increases, ily disturbs the equilibrium between hydronium and
Ka decreases and pKa increases. hydroxyl ions. To restore equilibrium, some of the
hydronium ions originally present in the water com-
Ionization of water bine with part of the added hydroxyl ions to form
Water is a poor conductor of electricity although it un-ionized water molecules. The process continues
can ionize through autoprotolysis: until the product of the hydronium and hydroxyl
ion concentrations again equals 1 × 10−14 . Because
2H2 O  H3 O+ + OH− [OH− ] is much greater than [H3 O+ ], the solution is
basic or alkaline.
Application of the law of mass action to the reaction
above gives Relationship of Ka and Kb
There is a particularly interesting and useful relation-
[H3 O+ ] [OH− ]
K= (5.9) ship between the strength of an acid and its conjugate
[H2 O]2
base or a base and its conjugate acid. For illustration
where K is the equilibrium constant for the reaction. purposes, consider the strength of the weak base NH3
Because the concentration of H2 O (molecular water) and its conjugate acid NH+ 4 in water. The behavior of

is very much greater than either the hydronium ion or NH3 in water is expressed by
the hydroxylion concentration and undergoes negligi-
−
ble change, it is considered to be constant and can be NH3 + H2 O  NH+
4 + OH
multiplied by K to give a new constant, Kw , known as
the ion product of water, and equation (5.9) becomes
−
[NH+4 ] [OH ]
Kb = (5.11)
Kw = [H3 O+ ] [OH− ] (5.10) [NH3 ]
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84 | An Introduction to Pharmacy

The behavior of NH4 + as an acid is represented by Electronegativity and dissociation constants

Electronegativity is the ability of an atom or func-
NH+
4 + H2 O  NH3 + H3 O
+
tional group to attract electron density. Electronega-
tivity of an atom is affected by its atomic number and
the distance of its valence electrons from the nucleus.
[NH3 ] [H3 O+ ] A bond between two atoms with different electroneg-
Ka = (5.12)
[NH+ 4]
ativity results in unequal distribution of electrons and,
therefore, dipole.
Multiplying the two equations gives Table 5.13 gives the dissociation constants of sev-
eral weak acids and bases in water at 25◦ C. It shows
−
[NH3 ] [H3 O+ ] [NH+
4 ] [OH ] great variation in strengths of acids and bases. The
Ka Kb = + (5.13)
[NH3 ] [NH4 ] effects of various substituents on the strength of acids
and bases depend on the electronegativity of the sub-
It is clear that stituent. For example, the substitution of a proton on
acetic acid with a chlorine atom increases the degree
Kw = Ka Kb (5.14) of ionization of the acid. Substitution with two chlo-
rine atoms further increases the degree of ionization.
Substitution with three chlorine atoms yields a still
where Kw is the ion product of water as defined in
stronger acid. Acetic acid ionizes primarily because
equation (5.10).
the oxygen atom adjacent to the hydrogen atom of
The utilization of this relationship, which is stan-
the carboxyl group has a stronger affinity for electrons
dard for any conjugate acid–base pair, is evident from
than the hydrogen atom. Therefore, when acetic acid
the following deductions: (1) the strength of an acid
is dissolved in water, polar water molecules have
may be expressed in terms of the Ka or Kb of its
a stronger affinity for the hydrogen of acetic acid
conjugate base, or vice versa; (2) the Ka of an acid
than the hydrogen atoms of other water molecules.
may be calculated if the Kb of its conjugate base is
Acetic acid ionizes as a consequence of this differ-
known, or vice versa; and (3) the stronger the acid,
ence in affinities. When chlorine is introduced into
the weaker its conjugate base or vice versa.
an acetic acid molecule, forming ClCH2 COOH, the
Bases capable of accepting more than one
electrons in the molecule are attracted to the chlorine
proton are termed polyprotic and can be illus-
because of its relatively high electronegativity; the
trated by
bond between the hydrogen and the oxygen in the car-
− −
boxyl group is thereby weakened through inductive
SO2−
4 + H2 O  HSO4 + OH effects, and the degree of ionization increases. Alter-
HSO−
4 + H2 O  H2 SO4 + OH
−
natively, substituting chlorine into the molecule of
ammonia reduces the strength of the base because of
Application of the law of mass action to the its decreased affinity for hydrogen ions. Dissociation
series of reactions combined with the concepts out- constants for strong acids and bases cannot be deter-
lined in equations (5.4) and (5.5) gives the rela- mined in water because they do not obey the law of
tionship between the various Ka and Kb values for mass action.
sulfuric acid:
Ionic strength and dissociation constants
Kw = Ka1 × Kb2 × Ka2 × Kb1 (5.15) Ionic strength of a solution is a measure of con-
centrations of ions in that solution. When an ionic
Ka1 and Ka2 refer to the equilibrium constants given compound is dissolved in an aqueous solution, it dis-
by equations (5.4) and (5.5), and Kb1 and Kb2 refer sociates into ions. Most solutions of pharmaceutical
to the reaction of SO2− 4 and HSO− 4 with water, interest are in a concentration range wherein the ionic
respectively. strength of the solution can have a marked effect on
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Pharmaceutical Chemistry | 85

ionic equilibria and observed dissociation constants. in which [K+ ] is the concentration of base added.
One method of correcting dissociation constants for equation (5.17) is then rearranged to give
solutions with ionic strength up to about 0.3 is to

calculate the apparent dissociation constant or pKa as Z = [A− ] = [K+ ] + [H3 O+ ] − [OH− ] (5.18)
√
 pKa + 0.51(2Z − 1) μ When a weak monoprotic acid is added to water,
pKa = √ (5.16)
1+ μ it can exist in the un-ionized form, HA, and in the

ionized form, A− . After equilibrium is established,
in which pKa is the calculated thermodynamic disso- the sum of the concentrations of both species must be
ciation constant, Z is the charge on the acid, and μ is equal to Ca , the stoichiometric concentration of acid
the ionic strength. added, or

Example: Calculate the pK2 for succinic acid at an
ionic strength of 0.5, given pK2 is 4.78. The charge Ca = [HA] + [A− ] = [HA] + Z (5.19)
on the acid species is −1.
Solution: [HA] can be replaced using equation (5.3) to give
√
 4.78 + 0.51(−2 − 1) 0.5
pK2 = √ = 4.14 [H3 O+ ]Z
1 + 0.5 Ca = +Z (5.20)
Ka
Experimental determinations of dissociation which can be rearranged to
constants
The dissociation constant of a weak acid or base Z[H3 O+ ]
Z − Ca − (5.21)
can be obtained using a variety of methods including [Ka ]
conductivity measurements, absorption spectrometry,
and partition coefficients. The most widely used According to equation (5.20), if Z, which is
method is the potentiometric pH measurement. The obtained experimentally using equation (5.18), is plot-
simplest method involving potentiometric pH mea- ted against Z[H3 O+ ], a straight line results with slope
surement is based on the measurement of hydronium equal to −1/Ka , and an intercept equal to Ca . In
ion concentration of a solution containing equimolar addition to obtaining an accurate estimate for the dis-
concentrations of acid and its conjugate base. When sociation constant, the stoichiometric concentration
equimolar concentrations of HA and A− are present, of the substance being titrated is also obtained. This
Ka is related to the pH of the solution (the pKa of is of importance when the substance being titrated
the acid is equal to the pH of the solution). Although cannot be purified, or has an unknown degree of sol-
this method is simple and rapid, the dissociation vation. Similar equations can be applied for obtaining
constant obtained is not of sufficient accuracy for the dissociation of a weak base.
some purposes. The dissociation constants for diprotic acids can
To obtain the dissociation constant of a weak acid be obtained by defining P as the average number of
with high degree of accuracy and precision, a dilute protons dissociated per mole of acid or
solution of the acid (about 10−3 to 10−4 M) is titrated
with a strong base, and the pH of the solution is taken P = Z/Ca (5.22)
at many points. The resulting data can be handled in
a variety of ways, perhaps the best of which is the and
method proposed by Benet and Goyan. The proton
[H3 O+ ]2 P K1 [H3 O+ ] (1 − P)
balance equation for a weak acid, HA, titrated with a = K1 K2 + (5.23)
(2 − P) (2 − P)
strong base such as KOH, would be
A plot of equation (5.23) should yield a straight line
[K+ ] + [H3 O+ ] = [OH− ] + [A− ] (5.17) with slope equal to K1 and intercept K1 K2 . Dividing
the intercept by the slope yields K2 .
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86 | An Introduction to Pharmacy

Micro dissociation constants It can be seen that unless k1 or k2 is very much smaller
The dissociation constants for polyprotic acids as than the other, the observed macro constant is a com-
determined by potentiometric titrations are gener- posite of the two and cannot be assigned to one or the
ally known as macro or titration constants. As car- other acidic group in a nonambiguous way. Methods
boxylic acids are stronger acids than protonated for determining k1 are given by Riegelman (1962),
amino groups, there is no difficulty in assigning Niebergall (1972), and their coworkers. Once k1 , K1
K1 and K2 to carboxyl and amino groups, respec- and K2 have been determined, all of the other micro
tively, of a substance such as glycine hydrochloride. constants can be obtained from equations (5.24)
In other chemicals or drugs such as phenolamine, in and (5.25).
which the two acidic groups are the phenolic and Hydronium ion concentrations may vary enor-
protonated amino groups, determining dissociation mously. For a strong acid, that value is approximately
constants is more difficult. This is because, in general, 1, whereas for solution of a strong base, it is approxi-
both groups have dissociation constants of similar mately 1 × 10−14 . Due to the inconvenience in dealing
magnitude. Therefore, there will be two ways of los- with small numbers, Sorenson, in 1909, proposed
ing the first proton and two ways of losing the second, that the hydronium ion concentration be expressed in
resulting in four possible species in solution. This can terms of logarithm (log) of its reciprocal. He assigned
be illustrated using the convention of assigning a plus the symbol pH to this value. Mathematically, it is
(+) to a positively charged group, a zero (0) to an written as
uncharged group, and a minus (−) to a negatively 1
charged group. For example, consider a phenol- pH = log (5.26)
[H3 O+ ]
propanolamine. The +0 represents the fully proto-
nated phenolpropanolamine, +− the zwitterions, 00 Since the log of 1 is zero, the equation can be
the uncharged molecule, and 0−, the anion. The total rewritten as
ionization scheme can therefore be written as
pH = −log[H3 O+ ] (5.27)
– +
O H
N
from which it is evident that pH also may be defined as
OH H H
+– the negative log of the hydronium ion concentration.
This type of notation is used to indicate the negative
+ – logarithm of the term that is preceded by p, which
O H O
H N NH2 gives rise to the following:
OH H H OH
+0 0–
pOH = −log[OH− ] (5.28)

pK = − log K (5.29)
O
H NH2
OH Taking the logarithms of equations (5.10) and (5.14)
00
gives
+–
k1 k3
pKa + pKb = pKw (5.30)
+0 0–
pH + pOH = pKw (5.31)
k2 k4
00
The relationship of pH to hydronium-ion and
The micro constants are related to the macro con-
hydroxyl-ion concentrations may be seen in
stants as
Table 5.14.
K1 = k1 + k2 Examples:
K2 = k3 + k4 (5.24)
1. Calculate the pH corresponding to a hydronium
K1 K2 = k1 k3 = k2 k4 (5.25) ion concentration of 1 × 10−6 M.
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Pharmaceutical Chemistry | 87

Table 5.14 Hydronium ion and hydroxyl ion concentrations

pH Normality in terms of hydronium ion Normality in terms of hydroxyl ion

0 1 10−14

Acidity increases

1 10−1 10−13

2 10−2 10−12

3 10−3 10−11

4 10−4 10−10

5 10−5 10−9

6 10−6 10−8

Neutral 7 10−7 10−7

8 10−8 10−6

9 10−9 10−5

10 10−10 10−4

11 10−11 10−3

12 10−12 10−2
Alkalinity
increases 13 10−13 10−1

14 10−14 1

Solution: Solution:
1 pH = − log (4.9 × 10−6 )
pH = log
1 × 10−6 log 4.9 = 0.69
= log 1,000,000 or log(1 × 106 ) log 10 −6
= −6.00
log(1 × 106 ) = 6 = −5.30 = log (4.9 × 10−6 )
pH =6 pH = −(−5.30) = 5.30

2. Calculate the pH corresponding to a hydronium The following example illustrates the conversion
ion concentration of 4.9 × 10 −6 M. of pH to exponential notation.
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88 | An Introduction to Pharmacy

3. Calculate the hydronium ion concentration corre- term is reached. The following examples show the
sponding to pH of 2.3. denominator, D, to be used for various types of acids.

H3 A: D = [H3 O+ ]3 + K1 [H3 O+ ]2
Solution:
+K1 K2 [H3 O+ ] + K1 K2 (5.35)
1
pH = log HA: D = [H3 O+ ] + Ka (5.36)
[H3 O+ ]
1 The numerator in all instances is Ca multiplied by the
2.3 = log
[H3 O+ ] term from the denominator that has [H3 O+ ] raised to
or the power of n−j. Therefore, for diprotic acids such
as chromic, maleic, fumaric, and tartaric acids,
2.3 = − log [H3 O+ ] [H3 O+ ]2 Ca
[H2 A] = (5.37)
−2.3 = log [H3 O ] + [H3 O+ ] 2 + K1 [H3 O+ ] + K1 K2
[H3 O+ ] = 1/(200) = 5.0 × 10−3 K1 [H3 O+ ]Ca
[HA− ] = (5.38)
[H3 O+ ] 2 + K1 [H3 O+ ] + K1 K2
Species concentration
K1 K2 Ca
When a weak acid, Hn A, is added to water, n + [A2− ] = (5.39)
[H3 O+ ]2 + K1 [H3 O+ ] + K1 K2
1 species, including the un-ionized acid, can exist.
After equilibrium is established, the sum of the con- Example: Calculate the concentration of each tartaric
centrations of all species must be equal to Ca , the acid species in a 2.5 × 10−3 M solution of tartaric
stoichiometric concentration of acid. Therefore, for a acid at pH 5.6. Assume that K1 = 9.6 × 10−4 and K2
triprotic acid, H3 A: = 1.3 × 10−1 .
Equations (36–38) have the same denominator,
Ca = [H3 A] + [H2 A− ] + [HA2− ] + [A3− ] (5.32) D, which can be calculated as

D = [H3 O+ ]2 + K1 [H3 O+ ] + K1 K2
In addition, the concentrations of all acidic and
basic species in the solution vary with pH and can = 1 × 10−12 + 9.6 × 10−4 × 1.0 × 10−6
be represented solely in terms of equilibrium con- + 9.6 × 10−4 × 1.3 × 10−1
stants and the hydronium-ion concentration. This = 1 × 10−12 + 9.6 × 10−10 + 1.248 × 10−4
relationship is expressed as
= 1.248 × 10−4

[Hn A] = [H3 O+ ]n Ca /D (5.33) Therefore,

[H3 O+ ]2 Ca
[H2 A] =
D
[Hn−j A−j ] = [H3 O+ ]n−j K1 , . . . , Kj Ca /D (5.34) 1 × 10−12 × 2.5 × 10−3
=
1.248 × 10−4
in which n represents the total number of dissociable = 2.00 × 10−11 M
hydrogen on the parent acid, j is the number of K1 [H3 O+ ]Ca
protons dissociated, Ca is the stoichiometric concen- [HA− ] =
D
tration of acid, and K represents the acid dissociation 9.6 × 10−4 × 1.0 × 10−6 × 2.5 × 10−3
constant. The term D is from [H3 O+ ] and K, starting =
1.248 × 10−4
with [H3 O+ ] raised to the nth power. The last term = 1.923 × 10 −8
M
is the product of all the dissociation constants. The K 1 K2 Ca
[A2− ] =
intermediate terms can be generated from the last D
term by substituting [H3 O+ ] for Kn to obtain the 9.6 × 10−4 × 1.3 × 10−1
=
next-to-last term, then substituting [H3 O+ ] for Kn−1 1.248 × 10−4
to obtain the next term, and onward until the first =1 M
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Pharmaceutical Chemistry | 89

Proton-balance equation and SO2−

4 with the release of one proton to give the
In the Bronsted–Lowry theory, the total number of following PBE:
protons released by acidic species must equal the total
number of protons consumed by basic species. This [H3 O+ ] + [HSO− − 2−
4 ] = [OH ] + [SO4 ] (5.42)
observation results in a very useful relationship known
as the proton-balanced equation or PBE. PBE forms
the basis of a unified approach to pH calculations, Drug stability
for it is an exact accounting of all proton transfers
A broad field of study is the investigation of the
occurring in a solution. When HBr is added to water,
effects of hydrogen ion concentration on the reactiv-
it dissociates yielding Br− for each proton released.
ity of pharmaceutical systems. Evidence for enhanced
Thus, Br− is a species formed by the release of a
stability of systems when they are maintained within a
proton. In all aqueous solutions,
narrow pH range, as well as of progressively decreas-
2 H2 O  H3 O+ + OH− ing stability as the pH departs from the optimum
range, is abundant. Proton gain or loss by a substrate
where H3 O+ is formed by proton consumption and molecule that reduces or increases the reactivity of
OH− is formed by proton release. Therefore, the PBE the molecule could result in stability or instability of
for the above reaction is a system. When a substance that is desired to remain
unchanged is converted to one or more unwanted
[H3 O+ ] = [OH− ] + [Br− ] (5.40)
substances, instability is said to occur. Instability may
Guidelines for generating PBE are as follows: happen in aqueous solutions through the catalytic
effects of acids and bases. With acids, this happens
by transferring a proton to the molecule, and with
1. Start with the species added to water.
bases, it occurs by accepting a proton. There are
2. Place all species that can form when protons are
countless specific examples of the effect of hydrogen
released on the right side of the equation.
ion concentration on the stability of medicinals. The
3. Place all species that can form when protons are
consumed on the left hand side of the equation. illustrations exhibited below show the importance
4. Multiply the concentration of each species by the of pH adjustment of solutions, especially ones that
number of protons gained or lost to form that require sterilization.
species. During a 60-minute exposure at a temperature
5. Add [H3 O+ ] to the left side of the equation and of 37.7◦ C, if the pKa of a molecule is less than 5.5,
[OH− ] to the right side of the equation. neutral and alkaline solutions can be highly unstable.
Minimum hydrolytic decomposition of solutions of
Example: When H3 PO4 is added to water, the cocaine occurs in the pH range 2 to 5. In one study
species H2 PO− a solution of cocaine hydrochloride, initially at pH
4 forms with the release of one proton;
HPO2− forms with the release of two protons; PO3− 5.7, remained stable for two months (although the
4 4
forms with the release of three protons, which gives pH dropped to 4.2 during this time) while another
the following PBE: solution buffered to about pH 6 underwent approxi-
mately 30% hydrolysis. Likewise, solutions of pro-
[H3 O+ ] = [OH− ] + [H2 PO−
4] caine hydrochloride containing some hydrochloric
+2[HPO2− 3− acid showed no appreciable decomposition when dis-
4 ] + 3[PO4 ] (5.41)
solved in water alone, with 5% of it hydrolyzed,
Example: When sodium bisulfate (NaHSO4 ) is whereas when buffered to pH 6.5, from 19 to 35%
added to water, it dissociates into one Na+ and one underwent decomposition by hydrolysis. Solutions of
HSO− 4 . The sodium is neglected in the PBE because it thiamine hydrochloride may be sterilized by auto-
does not form the release or consumption of protons. claving without appreciable decomposition if the pH
The species HSO− 4 , however, may react with water is below 5; above this, thiamine hydrochloride is
to give H2 SO4 with the consumption of one proton, unstable.
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90 | An Introduction to Pharmacy

Drug activity Table 5.15 Table showing ionization of a

Drugs may exist in ionized and un-ionized forms as compound at different pH values
a result of being weak acids or bases, and may be
pH – pK a [Base]/[Acid] Percent Percent
active in one form but not the other. Such drugs typi-
un-ionized ionized
cally have optimum pH range for maximum activity.
For example, mandelic, benzoic, and salicylic acids 4 10,000/1 0.01 99.99
have antibacterial activity in the un-ionized form but
have practically no antibacterial activity in the ionized 3 1000/1 0.1 99.9

form. As a result, these substances require acidic envi-

2 100/1 1 99
ronments in order to thrive as antibacterial agents.
For example, sodium benzoate is effective as a preser- 1 10/1 9 91
vative in 4% concentration at pH 7, and in 0.06 to
0.1% concentration at pH 2.3 to 2.4. Other antibac- 0 1/1 50 50
terial agents mostly or entirely act in cationic form.
−1 1/10 91 9
Acridines and quaternary ammonium compounds are
a part of this category.
−2 1/100 99 1

Drug absorption −3 1/1000 99.9 0.1

Two important factors that determine the rate of −4 1/10,000 99.99 0.01
absorption of drugs from the gastrointestinal tract
and subsequently their passage through cellular mem-
branes are the degree of ionization as well as lipid
Salts
solubility. Drugs that are weak organic acids or bases
can exist in significant amounts in the un-ionized A significant percentage of drugs contain acidic or
form which is absorbed by passive diffusion through basic groups which can undergo acid–base reac-
lipophilic cell membranes. Conversely, ionized drugs tions generating salts. Salts are compounds composed
are absorbed poorly or not at all. Rates of absorption of oppositely charged (cationic and anionic) species
of a variety of drugs are related to their ionization bound by strong ionic interactions. About half of
constants and, in many cases, may be predicted quan- the drugs used today are marketed as salts. Salts are
titatively on the basis of this relationship. The degree preferred over the free base species, as they tend to
of the acidic or basic character of a drug, as well as the have greater stability, dissolution, solubility, and ease
pH of the physiological medium in which a drug is dis- of base handling. The selection of the appropriate
solved or dispersed, become important limitations of counterion is an essential study in the pharmaceu-
drug absorption. The pH is important because it deter- tical pipeline because different salts of a drug can
mines the extent to which the drug will exist in ionic have markedly distinct biopharmaceutical proper-
or nonionic form. The difference between pH and pKa ties, including dissolution, stability, bioavailability,
is indicative of how much of the drug is in the ionized and compressibility. Salt choice also has relevance
or un-ionized form, as illustrated in Table 5.15. to patent and regulatory processes. Typically, a single
For example, for a drug containing a carboxylic salt of a drug is approved for marketing and any novel
acid group with pKa of about 4, using the table salt of an approved substance can be classified as a
above, one could determine that the drug is mainly new chemical entity. Sometimes mixtures of different
in the ionized form at physiologic pH (about pH = salt forms of a drug are marketed. This is the case with
7.4). The carboxylic acid group will lose its proton to Adderall, which contains four distinct salts of racemic
form the ionized form, carboxylate. However, in the and dextro-amphetamine. The specific salt combina-
stomach where the contents are more acidic (pH of tion was chosen for pharmacokinetic properties and
about 1 to 2), the drug would remain in its protonated better therapeutic profile. If a more efficient salt of an
(un-ionized) form. approved drug is discovered, it may be patented,
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Pharmaceutical Chemistry | 91

further extending the protected drug lifetime. An equal 1:1 mixture of drug to acid is formed. The salt
example of this is Diclofenac®, which was marketed types can have distinct physical and biopharmaceu-
initially as the sodium salt (Voltaren®). Prior to patent tical properties. Typically, formation of the desired
expiration, new salts with superior topical applicabil- salt can be accomplished by controlling addition and
ity were discovered, patented, and marketed. crystallization conditions.
When acidic drugs (like ibuprofen) are ionized One of the major reasons for salt formation is
as anions, they form salts with cations like Na+ , to obtain crystalline solid form of the drug. A crys-
K+ , and Ca2+ . These salts are commonly prepared by tal is a solid form of a compound (or mixture) held
treating the un-ionized acid species with an equivalent in an ordered lattice by non-covalent intermolecular
amount of the counterion containing base, such as interactions. Most salts and some free (un-ionized)
KOH, in solution. Basic drugs like morphine become forms of drugs can exist as crystalline materials.
protonated and are prepared by treating un-ionized Pharmaceutically relevant crystallography includes
form (freebase) with an equivalent quantity of acid, crystallization techniques, salt formation, polymor-
such as HCl gas. phism, and cocrystallization. A detailed discussion
of crystallography techniques is outside the scope of
R – COOH + NaOH → R – COO− Na+ + H2 O
this section. The more common methods used for
crystallization include solution crystallization, solid
R3 N + HCl → R3 NH+ Cl−
and solvent state grinding, melt, sublimation, and
The general rule for optimal salt formation is that thermal treatment. More recent innovative techniques
the pKa of the counterion should be two pKa units or include capillary crystallization, laser-induced crystal-
more above the pKa of the drug for acidic drugs, or lization, sonocrystallization, and heterogeneous crys-
below for basic drugs. This pKa difference is required tallization. By far the most common method used for
for proton transfer to be energetically favorable. crystal formation is solution crystallization, whereby
A pharmaceutical salt is composed of an electri- crystals are grown from a supersaturated solution of
cally neutral ratio of complementary charged drug drug in a solvent or solvent mixture. Crystal forma-
and counterion. Factors influencing selection of coun- tion can be influenced by solvent choice, rate and
terion include the acidity or basicity of the ionizable method of generating supersaturation, presence of
group, intended usage, counterion safety (FDA GRAS additives, and temperature.
[generally regarded as safe]), route of administra- Amorphates are non-crystalline solids that lack
tion, and formulation properties. Choosing the right the long-range structural order of crystals but possess
salt is typically a trial-and-error process and can be short-range molecular order. Amorphates are also
a burden on time and resources. The more recent called disordered systems or glassy solids. Although
advent and adoption of high throughput methods for much less common than crystalline drugs, pharma-
salt and polymorph selection has greatly enhanced ceutical interest in amorphates exists. As a result
the selection process. Common counterions for acidic of the less ordered structure, the solubility of many
drugs include Na+ , K+ , Ca2+ , and NH+ 4 . Counter ions amorphous solids represents a lower energy barrier
commonly used with basic drugs include inorganic than corresponding crystals. An example is novo-
−
anions like Cl− , Br− , SO2− 3−
4 , PO4 , NO3 and organic biocin, whose amorphous form exhibits favorable
anions including acetate, formate, oxalate, fumarate, dissolution properties, compared to its crystal state.
maleate, tartrate, citrate, and aspartate. Although use of amorphates may be a promising
Several organic acids like fumaric, maleic, and way to enhance drug pharmacokinetics, limitations
citric possess two or more acidic protons. As such, could include reduced physical and thermodynamic
these compounds may form multiple salt types, based stabilities and higher chemical reactivity.
on the stoichiometric ratio of salt to drug. When two
ratios are possible, the salts are referred to as the
Polymorphism
hemi- and stoichiometric forms. In the hemi-form,
two molecules of drug interact with one of acid (or In addition to salt types, there is a related phe-
vice versa), whereas in the stoichiometric form an nomenon relevant to pharmaceutical chemistry
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92 | An Introduction to Pharmacy

and crystallography, known as polymorphism. Poly- to form intermolecular interactions with the drug. By
morphs are different crystalline forms of a compound. understanding the varieties of interactions involved in
Depending on crystallization conditions, different cocrystals, scientists can begin to choose and/or engi-
polymorphs of a salt may form. Some drugs have neer coformers, yielding cocrystals with the desired
many polymorphic forms. For example, 5-methyl-2- physicochemical properties. This makes selection of
[(2-nitrophenyl)amino]-3-thiophenecarbonitrile has the appropriate conformer an important feature. The
ten known polymorphic forms. As with salt types, physicochemical properties of a drug can be modified
polymorphs may have different physicochemical in unique ways by selecting appropriate conformers.
properties. Several categories of polymorphism exist, For example, cocrystals have been used to deal with
including packing polymorphism, conformational difficulties in solubility, dissolution rate, absorption,
polymorphism, and pseudopolymorphism. Structures and physical stability. Examples include celecoxib and
involved in packing polymorphism tend to be rigid, nicotinamide, caffeine and theophylline, and carba-
and these molecules orient themselves differently mazepine and saccharin. Cocrystal technology greatly
in the crystalline lattice (unit cell) of different expands the possible solutions to physicochemical
polymorphs without conformational change. In limitations and gives scientists an additional strategy
conformational polymorphism, structures are more to optimize biopharmaceutical properties.
flexible and adopt different molecular conformations
in different polymorphs. Lastly, pseudopolymor-
phism includes the phenomena of solvates and Structural determinants of drug
hydrates. In these cases, water or solvent molecules action
are incorporated into the crystalline lattice. Different
stoichiometric ratios and packing structures give rise Lipophilicity is a very important factor influencing
to the distinct pseudopolymorph forms. the pharmacokinetic parameters of drug absorption
Unlike salt formation, polymorphism can be and distribution. To reach a site of action, most
highly variable and complex. A comprehensive drugs must transverse several lipophilic membranes.
understanding of the phenomenon is lacking. An orally absorbed drug must cross the lipid mem-
Reproducibility of particular polymorphs can be brane of small intestine epithelial cells. Although
problematic, and polymorphs may even interconvert absorption can occur by several mechanisms, pas-
during formulation. For these reasons, the most sive diffusion is the most important mechanism for
stable polymorph is typically preferred. most drugs, and lipophilicity is an essential compo-
nent of this process. Following intestinal absorption,
a drug enters the plasma from where it distributes. An
Cocrystals
optimal drug must be both hydrophilic and lipophilic.
The phenomenon of cocrystals is relatively recent in This limitation explains in part why the majority of
drug development. A cocrystal is generally regarded drugs are weak acids or bases. Depending on the site
as a homogenous crystalline material composed of a of action, additional lipophilic barriers may need to
neutral drug and neutral coformer, held together in a be transversed. For example, central nervous system
defined stoichiometry through non-covalent interac- active drugs must cross the highly restrictive lipophilic
tions. Cocrystals, therefore, differ from salt crystals, blood–brain barrier (BBB), and drugs with intracel-
given the absence of proton transfer and ionization, lular targets must cross additional cell membranes.
yet retain a long-range ordered structure. Cocrystals
are not necessarily binary. Ternary and quaternary
Partition coefficient (P)
cocrystals are known, allowing greater possibilities
and complexity in pharmaceutical crystallography. An important measure of the lipophilicity of a drug
Hydrogen bonding seems to be the most impor- is the partition coefficient (P). P is typically deter-
tant intermolecular interaction in cocrystallization, mined experimentally by partitioning a compound
although other weak intermolecular interactions can between aqueous and lipid (typically octanol) phases.
also occur. Coformers are selected based on ability Octanol was chosen because of its similarities to
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Pharmaceutical Chemistry | 93

biological membrane lipids, i.e., polar head (OH) and individual atoms and functional groups to P. Many
hydrocarbon tail. After mixing, the concentrations of different π values are available.1 Contributions are
drug in the different phases are determined. P is the additive and depend on the molecular environment
ratio of the concentration of drug in lipid to that in of the substituent. Induction, resonance, and steric
the aqueous phase: factors all affect π . It is also affected by conforma-
tion. Intramolecular interactions, like H-bonds, can
[Drug]lipid
P= decrease π by decreasing apolar surface area. All these
[Drug]aqueous
possibilities should be considered when calculating
P is thus a measure of lipophilicity. The log of P (log P) log P from π .
is commonly used. When P < 1, log P is negative and Although log P and log D values may be cal-
the greater the compound solubility in the aqueous culated simply by partition experiments, additional
phase. When P > 1, log P is positive, and the com- methods, such as reverse phase high-performance liq-
pound favors the lipid phase. Log P is typically a good uid chromatography (HPLC), can be used.2 These
predictor for in vivo lipophilicity. Collander observed HPLC methods have the advantage of being both
that the rate of movement of many organic com- quick and accurate, and possess high reproducibil-
pounds across a cellular membrane correlates with ity. During drug discovery it may be necessary to
log P. Furthermore, Hansch and coworkers were able predict log P prior to synthesis. While log P may be
to correlate relative drug potency with log P. Collan- estimated manually by summing the component π
der and Hansch’s observations reveal that in certain values, a more convenient way is the use of one of
cases the biological activity of a drug can be enhanced numerous commercially available software programs.
by designing derivatives with increased log P. How- These user-friendly programs allow for simple and
ever, the enhancement is not infinite, and an optimal rapid estimation of log P or log D, which are now
log P value exists; further increases of log P decrease determined as simply as drawing a chemical struc-
biological response. The reason for this decrease is ture. While undeniably valuable, calculated values
that a drug that is too lipophilic becomes sequestered may deviate significantly (two or more units) from
in any lipid phase it encounters and is unable to cross experimental values. A major rationale for this devi-
membranes and re-enter the aqueous phase. Such ation is the constitutive nature of π values, especially
molecule has inadequate pharmacokinetic properties, in complex or exotic structures. In such cases, the
including poor solubility, absorption and distribution. experimental values from close structural relatives of
Many drugs are acids or bases that, depending the compound should be compared with calculated
on pKa and pH, exist to a significant degree as the values from various software programs to determine
ionized form in physiological environments. Log D the best program for the particular series.
is used to describe the log of the distribution coeffi-
cient of an ionizable drug between 1-octanol and an
Thermodynamic activity
aqueous buffer. Log D is the log P of a compound at a
particular pH. For example, Log D5.5 is the log P of an While studying the narcotic effects of various chem-
ionizable compound at pH 5.5. In general, a drug with icals on tadpoles, Ferguson theorized that at equi-
a basic amine moiety exhibits greater ionization at pH librium, simple thermodynamic principles could be
values below its pKa , resulting in a greater degree of applied to drug activities and that relative saturation
drug in the aqueous phase. At higher pH (above the concentration (termed thermodynamic activity) of a
pKa ) the un-ionized species predominate, with the drug in the external or extracellular phase correlates
typical result of a greater affinity for the lipid phase with narcotic activity. The correlation, known as Fer-
and increase in log D. The opposite trend is observed guson’s principle, has value in classifying the mode of
with acidic drugs as they are un-ionized at pH values action and predicting biological response. It has also
below their pKa and ionized at higher values. been used to classify drugs into structurally specific
Addition of functional groups to a structure can and structurally nonspecific drugs. Thermodynamic
affect log P in somewhat predictable ways. A sub- activities of structurally specific drugs are low, typi-
stitituent constant (π ) exists for the contribution of cally below 0.001. Structurally nonspecific drugs have
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94 | An Introduction to Pharmacy

activities in the range of 0.01 to 1.0, indicating they (Kd ). Kd is the concentration of drug occupying half
are only active at relatively high concentrations. the available binding sites at equilibrium.
In the case of structurally nonspecific drugs, bio-
[Drug] [Receptor]free
logical activity correlates well with physical properties Kd =
[Drug–receptor complex]
of the molecule, such as log P, solubility, vapor pres-
sure, and surface area, rather than specific structural The lower the Kd value, the higher the affinity, for less
features. The biological activity of structurally non- drug is required to occupy the receptor at equilibrium.
specific drugs typically results from accumulation of Kd or the related Ki (equilibrium dissociation constant
the drug in a particular lipophilic region of the cell, obtained by competitive ligand displacement) can be
such as the plasma membrane. A few therapeutic calculated using several in vitro techniques, including
categories of drugs are believed to act, at least par- competitive binding studies followed by Scatchard
tially, through nonspecific mechanisms. These include or Schild analysis. Kd is influenced by entropic and
bacterial disinfectants and certain general anesthetics. enthalpic factors. Attractive forces lead to formation
This mechanism can be used to explain why struc- of enthalpically favored intermolecular interactions
turally diverse molecules such as nitrous oxide, diethyl between ligand and receptor. Binding also results in
ether, halothane, and thiopental all have similar restriction in conformational freedom of the involved
anesthetic effects. parties and this loss of rotational and translational
freedom is entropically unfavored. However, entrop-
ically favorable gains can occur from displacement
Structurally specific drugs and receptors of ordered water molecules constituting the hydra-
tion shells of the drug and receptor or other ordered
Paul Ehrlich conceptualized and proposed the notion
water molecules at the binding site. Assuming that the
of a receptor. With structurally specific drugs, activity
sum of entropic and enthalpic conditions is favorable,
is dependent on the ability to interact with a spe-
binding will decrease the free energy of the system,
cific physiological target, most often a protein such as
facilitating interaction.
an enzyme or receptor. In these instances, biological
Bonds formed in the drug–receptor complex
activity depends on a drug’s chemical structure and
tend to be weak, reversible, non-covalent interac-
thus its pharmacodynamic interactions. Many recep-
tions and include ionic (electrostatic), ion–dipole,
tors are membrane-bound proteins that selectively
dipole–dipole, hydrogen bonding, charge transfer,
bind small molecules called ligands. Binding takes
hydrophobic, and van der Waals. Irreversible cova-
place at a specific site also called the active or bind-
lent bonding occurs only with a few select therapeutic
ing site. Several categories of ligands are recognized,
agents, such as chemotherapeutics, antimicrobials,
including agonists, super agonists, partial agonists,
antivirals, and enzyme inhibitors.
inverse agonists and antagonists. In the case of an
Several models of binding have been proposed
agonist, the ligand–receptor interaction is believed
over the years to account for the observed phar-
to lead to a conformational change, causing receptor
macodynamic activities of drugs. Some are outdated
activation. The active receptor initiates a physiolog-
but proved useful historically in conceptualizing the
ical response, the specifics of which depend on the
binding phenomena. Models of receptor binding are
receptor type and environment. Numerous receptor
constantly being adjusted to fit our evolving under-
categories exist and include ligand gated ion channels,
standing of binding pharmacology. The earliest model
G-protein coupled receptors, hormone receptors, and
of binding is the lock and key hypothesis where
tyrosine kinase receptors.
the receptor and drug were viewed as rigid struc-
tures in which the drug fits neatly into the active
site like a key into a lock. This theory could not
Binding
fully account for the dynamic conformational changes
The biological activity of a structurally specific drug undergone by both drug and receptor. More recent
is related to its affinity for a target receptor. Affinity theories include the zipper and induced fit models.
is typically represented by the dissociation constant In the zipper model the receptor site is viewed as
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Pharmaceutical Chemistry | 95

rigid. The drug is flexible and molds itself to the Hansch linear free-energy model
rigid receptor binding site through a stepwise series The Hansch equation allows biological activity to be
of conformational changes that derive the necessary related to multiple physicochemical properties. As the
energy from binding itself. The more widely accepted equation is typically linear, it is sometimes referred to
induced fit model views both the drug and recep- as the Hansch linear free-energy equation. Since the
tor as flexible. As drug approaches the binding site, equation accounts for the effects of multiple parame-
conformational changes take place in both drug and ters, the results tend to be complicated, but can also be
receptor to facilitate binding. The resulting confor- of greater relevance than models of only one parame-
mational change in the receptor is believed to initiate ter. Hydrophobicity (π , measured by log P), electronic
the biological response. The induced fit model is able features modeled by the Hammett substituent con-
to explain different binding observations, including stant (σ for aromatics and σ I for aliphatics), and
the notion of efficacy as it occurs with ligand-directed steric considerations estimated by Taft’s steric factor
trafficking. While these models have been useful in (Es ) are the most commonly used physicochemical
conceptualizing receptor binding phenomenon, our properties in the Hansch equation. A limitation of the
understanding of binding is evolving and is still Hansch equation is that a large number of derivatives
incomplete. must be measured experimentally prior to deriving
the equation.

Quantitative Structure–Activity Free-Wilson method

Relationship (QSAR) studies The Free-Wilson approach considers the ‘‘overall
As the name implies, QSAR is an attempt to identify effect’’ of a substituent on biological activity. In this
and quantify the physicochemical properties of a drug way, specific physicochemical values are not required,
and relate these to biological activities. When a rela- and only biological activity is measured. To get an
tionship is observed, an equation can be generated. equation, the activity of the parent structure is mea-
This relationship allows medicinal chemists to deter- sured and compared against various derivatives. The
mine significance of a specific property to drug action. equation derived allows activity of substituents to
More importantly, it allows prediction of activity of be predicted. As with the Hansch equation, a major
novel derivatives. In this way, QSAR allows chemists disadvantage in the Free-Wilson approach is that a
to focus synthetic efforts on compounds more likely number of derivatives must be obtained and tested.
to be active, conserving time and resources. In theory, Both also require significant computational power.
any structural, physical, or chemical property of a
drug can be modeled by QSAR. Typically, it is most Topliss scheme
desired to focus on one or two of these properties Topliss scheme is a synthetic flow diagram and is a
at a given time. However, this may not be prac- non-computer method of analog design. The scheme
tical because many properties are interrelated and was designed to enhance the probability of discover-
sometimes multiple properties are considered simul- ing the most active compound in a series of structural
taneously. Essential requirements of QSAR are that derivatives as early as possible. The biological activity
the compounds being studied be structurally related, of a parent or lead compound is first measured. Then
and act via the same receptor and mechanism. the first derivative specified by the scheme is synthe-
Numerous physical, structural, and chemical sized and activity measured. Based on the activity of
properties can be studied by QSAR. The most this compound to the lead (more, equal, or less), a
common include hydrophobic, electronic, and steric synthetic path that amplifies or attenuates tested prop-
properties. This observation is partially due to the erties is followed. In this way each step in the scheme
ease of quantifying these properties, especially for depends on the activity of the previous compound.
individual substituents. Examples of QSAR methods The scheme is particularly useful when difficult or
include Hansch Linear Free-Energy and Free-Wilson expensive synthetic procedures are necessary to obtain
models. derivatives.
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96 | An Introduction to Pharmacy

Bioisosterism (tetravalent), based on the number of bonds (1, 2, 3,

The concept of bioisosterism is central to organic or 4, respectively) they can form.
pharmaceutical chemistry. Bioisostere exchange is a
common strategy in drug discovery. Isosteres are
atoms or functional groups with similar valence struc- Natural products
tures. Since isosteres are not identical, the physic-
ochemical properties that they will impart on a Natural products are chemical compounds found
molecule are not identical. Change in physicochemical in nature. Terrestrial plants, marine organisms and
properties can alter pharmacokinetic and pharmaco- microorganisms are some of the major sources of
dynamic properties of a drug and provide insight on natural products. They are typically end products
the pharmacophore. Bioisosteres are atoms or func- of secondary metabolism, have biological or phar-
tional groups which impart similar biological proper- macological activity and are used for a variety of
ties to a molecule (Fig. 5.2). In this way, bioisosteres purposes. This section will focus on those natural
can be exchanged, optimizing physical or chemi- products that have pharmaceutical importance (Table
cal properties without significant structural change. 5.16). Records show that in practically every coun-
The main use of bioisosteres is to improve pharma- try, certain foods and plants were the basis of early
cokinetic parameters, such as absorption, metabolic medicine.3 More than 5000 years ago, the Sumeri-
stability, or half-life, or to reduce toxicity. An example ans described well-established medicinal uses for such
of bioisosterism is observed with procainamide, the plants as laurel, caraway, and thyme.4 The first Chi-
longer-acting amide derivative of procaine (an ester), nese ‘‘herbal’’ book dates back to ∼2700 BC and
resulting from substitution of an ester oxygen with lists 365 medicinal plants and their uses, including
nitrogen. By doing this substitution, the resulting com- ma-huang, the source of ephedrine.4 A substantial
pound is no longer susceptible to esterases and is thus record of the use of herbs as medicine comes from
longer acting. Common bioisosteres for benzene ring the first Code of Hammurabi (∼1770 BC), which is a
are thiophene and pyridine. Bioisoteres can be uni- series of tablets carved under the direction of the King
valent, bivalent, tervalent (trivalent), or quadrivalent of Babylon and mentions medicinal plants such as

Univalent CH3 NH2 OH F Cl

H2 H
Bivalent C N O S

Tervalent C N S+
H

Quadrivalent

C Si P+

Ring equivalents
C CH S ex) Benzene-thiophene
H

C CH N ex) Benzene-pyridine
H
H2 H
C N O S

Figure 5.2 Bioisoteric atoms and groups.

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Pharmaceutical Chemistry | 97

Table 5.16 Examples of natural products having pharmaceutical importance

Natural product Occurrence Pharmacological use

Caffeine Tea (the leaves of Thea sinensis-Ternstroemiaceae), cocoa Stimulates mental activity
beans (the seeds of Theobroma cacao-Sterculiaceae), and
coffee beans (the seeds of Coffea spp. - Rubiaceae)

Morphine Opium poppy, Papaver somniferum (Papaveraceae) Analgesia

Pilocarpine Pilocarpus spp. (Rutaceae) Parasympathomimetic

Ephedrine Ephedra spp. (Ephedraceae) Peripheral vasoconstrictor

Theophylline Tea (the leaves of Thea sinensis-Ternstroemiaceae), cocoa Bronchodilator

beans (the seeds of Theobroma cacao-Sterculiaceae), and
coffee beans (the seeds of Coffea spp. -Rubiaceae)

Codeine Opium poppy, Papaver somniferum (Papaveraceae) Cough suppressant

Senna anthraquinones Cassia senna and Cassia angustifolia (Leguminosae) Laxative

Ergometrine Ergot, a morbid growth formed when the fungus Claviceps Uterine stimulation
purpurea develops on various plants of the Gramineae +
Cyperacea families.

Capsaicin Capsicum spp. (Solanaceae) Counter-irritant

Emetine Cephaelis ipecacuanha (Rubiaceae) Amoebic dysentery

henbane, licorice, and mint.5 The ancient Egyptians remained an essential component in the management
treated their sick by giving them what they thought of disease around the world. By the early 1900s, it
to be suitable foods. For example, they prescribed was well understood that many diseases were caused
liver, a rich source of vitamin A, for night blind- or aggravated by poor nutrition. In addition, vita-
ness and used moldy breads on wounds.6 Among mins were discovered during studies on deficiency
the ancient Greeks, Hippocrates (∼460–377 BC), diseases such as pellagra (nicotinic acid, a B-vitamin,
who is considered the father of medicine in West- deficiency) and rickets (vitamin D deficiency). By mid-
ern cultures, based most of his protocols for disease 1900s, vitamins were being isolated and synthesized
prevention and treatment on his patients’ diet. Hip- and subsequently used as additives in other foods or
pocrates coined the famous aphorism, ‘‘Food be thy to prepare vitamin supplements. In addition, most
friend and enemy.’’7 However, the most significant people in industrialized countries had achieved an
Greek contribution is often considered to be the five- adequate and nutritious food intake. Therefore, defi-
volume work entitled De Materia Medica written by ciency diseases all but disappeared, and as a result,
Dioscorides (AD 40–90). This work described the there was little continued emphasis on the importance
preparation of approximately 1000 simple drugs pri- of foods and diet in health. At the same time, most
marily from medicinal plants and is considered the industrialized nations also saw a rapid rise in drug
prototype for future pharmacopeias.5 development. Initially, many of these modern drugs
As advances in science continued to improve had their origins in herbal products. Most were just
man’s understanding of physiology and the pharma- isolated, purified products from plant extracts that
cological effects of food and herbals, these products had been used for centuries, such as morphine from
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98 | An Introduction to Pharmacy

the opium plant and digitalis leaf glycosides. Medic- equal to or higher than the Institute of Medicine’s
inal chemists then began to modify these extracted Recommended Dietary Reference Intake; therefore
compounds to produce new synthetic medications. monitoring their use over time has become an impor-
Examples of these synthetic drugs include the opiate tant component of the National Nutrition Monitoring
derivatives such as meperidine, the local anesthetics System.9 Data from National Health and Nutrition
(novocaine, lidocaine) developed from cocaine and the Examination Survey (NHANES) has revealed that
various ephedrine derivatives originally discovered in use of dietary supplement is common, and increasing
Ephedra species.7 among the adult US population aged 20 and over,
This transition from the use of subtle foods and with over 53% reporting use of at least one dietary
herbals to rapidly acting and specific synthetic vita- supplement in 2003 to 2006.10 The US sales of dietary
mins and drugs in disease management, which took supplements estimated to be more than $20 billion,
place primarily in the United States, occurred for with multivitamin were multiminerals being the most
several reasons. First, these agents were more effec- commonly used products.
tive at curing and managing many diseases. Second, There are a number of reasons for the resur-
there was much disdain for ‘‘old-fashioned or folk- gence in popularity of these products: (1) it is now
loric medicine,’’ especially after the hucksterism and well recognized that diet and exercise alone can
quackery that took place at the beginning of the twen- manage many disorders such as mature onset dia-
tieth century. Many fortunes were made during this betes (Type II), cardiovascular disease, and those
era (known as the patent-medicine era) by those pro- of inborn errors of metabolism (e.g., gout, galac-
claiming that certain foods or herbs could ‘‘cure all tosemia, phenylketouria);7 (2) many diseases have
ills.’’ This ultimately led to the formation of the FDA been conquered and only old age, degenerative dis-
and later to laws that regulate dietary supplements orders, which traditional medicine has had limited
and pharmaceuticals based upon sound scientific evi- success with, remain;9 (3) people are realizing that,
dence. Third, there was a belief that human trial and although highly successful, traditional medicine, with
error over the past centuries had discovered most of its scientific basis, is emotionally hollow, esthetically
the plants having medicinal value and little was left meaningless, and spiritually empty; (4) many indi-
to be discovered. Lastly, many pharmaceutical com- viduals have lost faith in science, which is being
panies felt that it was too costly to screen plants for blamed for many ills such as pollution due to pesti-
useful drugs given the low success rate, especially once cides, carcinogens, and other environmental toxins;
advances in science had made it easier and cheaper to and (5) rising medical costs and managed healthcare
design synthetic drugs, which are more patentable.5 have caused the public to lose trust in their healthcare
However, by the end of the past century, we saw providers, drug manufacturers, and the government.11
another major revolution in healthcare. Millions of As a result, people are taking a more active role in
people have begun eating more healthily and using managing/preventing disease and searching for alter-
dietary supplements and herbal products to prevent native ways to attain full health.
disease and promote good health. The Dietary Sup- While this trend toward self-awareness and
plement, Health and Education Act (DSHEA), which increased participation in one’s health is surely a
became law in 1994, and assured the American con- good thing, there are also several concerns. There is
sumer access to dietary supplements, defines dietary much lacking, unsupported, and erroneous informa-
supplement as ‘‘a product (other than tobacco) that tion about herbals and other dietary supplements, and
is intended to supplement the diet; contains one or individuals have a tendency to be less than discerning
more dietary ingredients (including vitamins, miner- or are not adequately educated to appropriately
als, herbs or other botanicals, and amino acids) or evaluate information regarding these therapies. Since
their constituents; is intended to be taken by mouth the reemergence of herbals and dietary supplements is
as a pill, capsule, tablet, or liquid; and is labeled on the primarily consumer driven and lacks much scientific
front panel as being a dietary supplement.’’8 Dietary evidence, many health professionals have regarded
supplements contribute substantially to total nutri- it as mere faddism.7 Unfortunately, this has caused
ent intake, as they can contain nutrients in amounts many healthcare professionals to completely dismiss
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Pharmaceutical Chemistry | 99

these products even though many of their patients fuelled by the many negative outcomes portrayed in
use them for legitimate and useful reasons. This has the media with these products, especially those with
resulted in a communication breakdown between falsely labeled claims. Unlike drug products that must
patients and their healthcare providers. One study be proven safe and effective for their intended use
reported that 75% of individuals using dietary before marketing, there are no provisions in the law
supplements neglect to share this information with for FDA to ‘‘approve’’ dietary supplements for safety
their physicians.12 This is most concerning in light or effectiveness before they reach the consumer. By
of the building evidence of serious herbal–drug law (DSHEA), the manufacturer is responsible for
interactions such as with St. John’s Wort. Table 5.17 ensuring that its dietary supplement products are safe
lists the possible interactions of some popular herbs. before they are marketed. More recently, the FDA has
There are also major safety concerns with these established regulations to require Good Manufactur-
products themselves. For example, early in 1998, a ing Practices (GMPs), necessary for activities related
USP expert advisory panel determined that consumer to manufacturing, packaging, labeling, or holding
use of comfrey could be harmful due to a lack of dietary supplements, thus bringing the industry under
scientific evidence to support its safety and dispel the increased scrutiny and accountability.
information on its hepatic toxicity.13 An additional Although there are many concerns, modern
concern with the use of supplements or supplemented research has strongly supported and further devel-
foods is that they tend to undermine the idea of oped the idea that certain foods and herbals can
healthy eating, which focuses on the whole diet and help maintain good health or serve as medicines
not just single ingredients. Healthy foods commonly (Tables 5.18 and 5.19). The FDA defines special
contain several compounds with therapeutic activity classes of foods including Medical Foods which have
or contain compounds that modify the effect of their exact concentrations of nutrients and appropriate
active constituents on the body. Therefore, eating labeling for use in certain medical conditions (e.g.,
an orange is typically more beneficial than taking a certain hyperalimentations preparations),17 and
vitamin C tablet. In addition, supplements may pro- Foods for Special Dietary Uses (FSDU), which
vide nutrients and active components in a potentially includes hypoallergenic foods, weight-reduction
unbalanced and concentrated form, different than foods, foods for diabetics, reduced sodium foods, and
that used in research studies.14 However, many of the infant formulas.18 In addition, 80% of the world’s
natural compounds within foods are at too low a con- population (primarily in developing countries) still
centration to exert a significant effect, and the only rely on plant-derived medicines.19 Therefore, quality
rational way of getting the recommended amount is healthcare needs to be a combination of these
in supplement form or as a food additive, such as the ‘‘alternative’’ approaches and traditional therapies;
stanol esters in the Benecol products. There are also both have a great utility in maintaining proper health
legal and regulatory concerns on how to promote and and treating disease. With these factors in mind, it is
market these products, to determine exactly which certainly worthwhile for all of those in the healthcare
ingredients have a pharmacological activity, to stan- arena to be aware of and take advantage of the fast
dardize these products so that they will have known flowing information regarding natural products to
amounts of active principles with known activity, to help decide which findings can be used to provide
determine actual efficacy, and to devise appropriate quality healthcare to all patients.
claims.15 The WHO’s World Medicines Situations In addition to the use of natural products, such
Report 2011,16 noted that despite the growing pop- as foods and herbals, to prevent and manage disease,
ularity of natural products or traditional medicines, 25% of all drugs prescribed today are still based
consumer understanding of potential risks of using upon substances derived from plants or plant-derived
them is low, and they are not always aware that synthetic analogs. In fact, in the former Federal
products may be contaminated due to poor man- Republic of Germany, six phytochemicals were
ufacturing practices, or may cause side effects in among the top 100 of the most prescribed drugs in
interaction with other herbs or drugs. Addition- 1990. Some 4.23 million prescriptions were written
ally, the decrease in consumer confidence has been for standardized Ginkgo biloba preparation alone.20
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100 | An Introduction to Pharmacy

Table 5.17 Herb–drug interactions

Herb Drug(s) Possible interactions

Digitalis Antiarrhythmic agents: Quinidine (Quinidine Gluconate, Increased serum digoxin levels have been observed due to a
Quinidine Sulfate), Amiodarone (Cordarone); Calcium decrease in renal and nonrenal clearance and in the volume of
channel blockers: Verapamil (Calan, Verelan) distribution of digoxin.a Caution is warranted when using
digitalis with these pharmaceutical agents.

Ginkgo biloba Antidiabetics/Hypoglycemic agents: Sulfonylureas- Ginkgo has been found to increase plasma insulin
Glyburide (Diabeta), glipizide (Glucotrol), glimepiride concentrations in healthy volunteers,b and to decrease these
(Amaryl), tolbutamide (Orinase), etc. concentrations in subjects with type 2 diabetes.c Interactions
are possible with antidibetics/hypoglycemic agents.

Calcium-channel blocker: Nifedipine (Adalat, Procardia) It is reported that the maximal plasma concentration of
nifedipine was approximately doubled by concomitant use of
ginkgo, resulting in severe and longer-lasting headaches,
dizziness or hot flushes, and increased heart rate.d

Ginseng Anticoagulant: Heparin, warfarin (Coumadin); and Panax ginseng may inhibit the aggregation of platelets,
antiplatelet agents: clopidogrel (Plavix), ticlopidine (Ticlid) reduce platelet adhesiveness, reduce INR, and reduce warfarin
concentrations and increase its clearance.

Antidiabetics/Hypoglycemic agents: Sulfonylureas- Ginseng may significantly reduce blood glucose levels;e
Glyburide (Diabeta), glipizide (Glucotrol), glimepiride therefore caution is warranted as combining ginseng with
(Amaryl), tolbutamide (Orinase), etc. antidibetics may lead to additive effects.

Milk thistle Glucuronidated agents: lorazepam (Ativan), lamotrigine Silymarin in milk thistle has been reported to inhibit
(Lamictal), entacapone (Comtan) beta-glucurondase,f and theoretically may decrease the
clearance of glucuronidated agents.

Saw palmetto Androgenic agents: testosterone (Androderm, Because of the anti-androgenic properties of saw palmetto, its
methyltestosterone (Android, Testred), fluoxymesterone concomitant use may decrease the effectiveness of
(Halotestin), and stanozolol (Winstrol) therapeutic androgens.

St. John’s wort 5HT1 agonists (triptans): Nartriptan (Amerge), rizatriptan Interaction with various triptan medications, via enhanced
(Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig). serotonergic activity, is possible in theory.

Monoamine oxidase inhibitors (MAOIs): Isocarboxazid Hypericin, a constituent of St. John’s wort may inhibit
(Marplan) phenelzine (Nardil), and tranylcypromine monoamine oxidase (MAO) A and B,g thereby potentiating
(Parnate) the effects of MAOIs, possibly leading to clinical toxicity, such
as serotonin syndrome or hypertensive crisis.

Selective serotonin reuptake inhibitors (SSRIs): Citalopram Concomitant use of St. John’s wort may lead to increased
(Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac, adverse effects typically associated with SSRI antidepressants,
Sarafem), Paroxetine (Paxil, Pexeva), and Sertraline (Zoloft) including serotonin syndrome or mania.

a Bhatia SJ, Digitalis toxicity-turning over a new leaf? West J Med. 1986; 145:74–82.
b Kudolo GB, The effect of 3 month ingestion of Ginkgo biloba extract on pancreatic beta-cell function in response to glucose loading in normal

glucose tolerant individuals. J Clin Pharmacol. 2000; 40(6):647–654.

c Kidolo GB, The effect of 3-month ingestion of Ginkgo biloba extract (EGb 761) on pancreatic beta-cell function in response to glucose loading in

individuals with non-insulin-dependent diabetes mellitus. J Clin Pharmacol. 2001; 41(6):600–611.

d Yoshioka M et al. Effects of Ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. Biol

Pharm Bull. 2004; 27(12):2006–2009.

e Sotaniemi EA et al. Ginseng Therapy in Non-Insulin- dependent diabetic patients: effects on psychophysical performance, glucose homeostasis,

serum lipids, serum aminoterminalpropeptide concentration, and body weight. Diabetes Care. 1995; 18(10):1373–1375.
f Kim DH et al. Silymarin and its components are inhibitors of beta-glucuronidase. Biol Pharm Bull. 1994; 17(3):443–445.
g Suzuki O et al. Inhibition of monoamine oxidase by hypercin. Planta Med. 1984; 50(3):272–274.
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Table 5.18 Current FDA qualified health claims

Product Permitted health claim

Dietary supplements containing selenium Some scientific evidence suggests that consumption of
selenium may reduce the risk of certain forms of cancer
or
Some scientific evidence suggests that consumption of
selenium may produce anticarcinogenic effects in the body

Dietary supplements containing vitamin E and/or vitamin C Some scientific evidence suggests that consumption of
antioxidant vitamins may reduce the risk of certain forms of
cancer

Whole or chopped almonds, hazelnuts, peanuts, pecans, Scientific evidence suggests but does not prove that eating
some pine nuts, pistachio nuts, and walnuts 1.5 ounces per day of most nuts such as [name of specific nut]
as part of a diet low in saturated fat and cholesterol may
reduce the risk of heart disease

Dietary supplements containing the omega-3 long chain Consumption of omega-3 fatty acids may reduce the risk of
polyunsaturated fatty acids eicosapentaenoic acid (EPA) coronary heart disease
and/or docosahexaenoic acid (DHA)

Dietary supplements containing vitamin B6, B12, and/or As part of a well-balanced diet that is low in saturated fat and
folic acid cholesterol; folic acid, vitamin B6, and vitamin B12 may reduce
the risk of vascular disease

Dietary supplements containing soy-derived Consumption of phosphatidylserine may reduce the risk of
phosphatidylserine dementia in the elderly
or
Consumption of phosphatidylserine may reduce the risk of
cognitive dysfunction in the elderly

Dietary supplements containing folic acid 0.8 mg folic acid in a dietary supplement is more effective in
reducing the risk of neural tube defects than a lower amount
in foods in common form

This may be attributed to the Commission E, which Society of North America (PSNA), and the Society
was established in 1978 by a German federal agency for Economic Botany (SEB) continue to encourage
(Bundesgeundheitsamt) to determine the safety and and stimulate research in the field of natural
efficacy of herbal products. So far, the Commission products.
has produced about 400 monographs on various phy- Nature remains an extremely rich source of
topharmaceuticals and combination products. These molecular diversity, and therefore, natural products
compendia probably represent the most complete continue to be used for drug discovery. Interest in the
and accurate modern body of scientific information field of marine natural product appears to be growing.
on the subject today. The study of physical, chemical, Marine bioprospecting or exploring the oceans for
biochemical and biological properties of drugs of nat- novel compounds with therapeutic potential from
ural origin has been named Pharmacognosy (Greek, marine organisms is the recent addition to current
Pharmakon-drug; gnosis-knowledge). A number efforts in drug discovery from natural products.
of scientific organizations such as the American In the past, collecting and processing natural com-
Society of Pharmacognosy (ASP), the Phytochemical pounds was both difficult and costly, especially for
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102 | An Introduction to Pharmacy

Table 5.19 Popular herbal medicines–Their bases and source

Herbal Source Active Common uses Common side effects Supporting evidence
product ingredient(s)

Bilberry Vaccinium Vitamins A and C, Improve eyesight, Fresh bilberry fruit may Studies have indicated an
myrtillus flavonoids, increase blood have laxative effects improvement in eyesight, due mainly
anthocyanin, and flow, and to the effects of vitamin A
glucoquinine treatment of
diabetes

Black Actaea Remifemin (brand Menopausal Overdose: nausea, Studies have shown measurable
Cohosh recemosa name of symptoms, dizziness, visual effect on reproductive hormones.
aka. standardized peripheral artery disturbances, nervous Studies have also shown that
Cimicifuga extract) Triterpene disease, and system abnormalities, established breast tumor cell lines
racemosa saponins hypercholes- increased perspiration were not stimulated, leading
(expressed as terolemia and bradycardia. Large scientists to consider Black Cohosh for
26-deoxyactein) doses may induce studies as a substitute for hormone
miscarraige replacement therapy

Cat’s Claw Uncaria Several alkaloids Inflammation, as Use cautiously in Studies have verified some anticancer
tormentosa including: an astringent, cardiac disorders as claims, as well as some
rhynchophylline, gastric ulcer, hirsutine, an indole immunostimulant properties. The
mytraphylline, rheumatism, alkaloid, has been major effective ingredient,
gambirine, and contraception, and shown to exhibit rhynchophylline may decrease blood
hirsutine; also six cancer antiarrhythmic activity pressure to the point of being
quinovic acid hypotensive at certain doses
glycosides

Chamomile Matricaria Bisabolol and Inflammation, GI Persons allergic to the Anti-inflammatory and antipyretic
recutita flavonoids spasms, and as a Compositae family claims are supported in animal
sedative may experience models. Its main active ingredient,
anything from contact rhynchophylline, has also been shown
dermatitis to to decrease blood pressure to the
anaphylaxis point of being hypotensive at certain
doses

Chaste Tree Vitex Monoterpene Menstrual GI symptoms, rash, Progesterone/estrogen balance was
agnuscastus derivatives irregularities, itching, headaches, improved in studies. Its inhibition of
(limonene, hormone and menstrual prolactin release has also been
1,8-cineol, bornyl imbalance, breast abnormalities can supported; this can aid in the
acetate, α- and β- pain, uterine pain, occur correction of luteal phase defects
pinene, sabinene), and decreased sex
flavonoids drive in males
(castican, orientin,
isovitexin), and
iridoid glycosides
(agnuside,
aucubin)

Cranberry Vaccinium Hippuric acid, Treatment, or GI symptoms, such as Significant decrease in urinary pH has
macrocar- phenolic acids, prevention of diarrhea, can occur at been observed in studies. However,
pon flavonol glycosides urinary tract very high doses treatment is still unproven as bacterial
infections susceptibility and minimum effective
dose were unclear

(continued overleaf)
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Pharmaceutical Chemistry | 103

Table 5.19 (continued)

Herbal Source Active Common uses Common side effects Supporting evidence
product ingredient(S)

Echinacea Echinacea Isobutylamides To decrease the Those allergic to the Some evidence points toward a
augustifolia length of cold or daisy family should shortening of duration for the
(common); prevent its avoid due to immune common cold; however, prevention
E. purpurea contraction response symptoms has been shown to be doubtful at best
(commerce)

Evening Oenothera Gamma-linolenic Breast disorders, None known Cholesterol-studies have shown that
Primrose biennis acid (GLA) PMS, breast pain, the active ingredient is successful in
cardiovascular significantly lowering blood
disease, cholesterol; however, in the
rheumatoid concentration found in primrose oil,
arthritis, multiple such a decrease is substantially less, if
sclerosis, atopic any. Breast cancer-studies have
eczema, and other indicated only a slight decrease in
dermatologic recurrence in those patients who have
disorders recovered from breast cancer.
Premenstrual syndrome-studies have
indicated a decrease in symptoms
associated with primrose oil

Feverfew Tanacetum Parthenolide Fever, migraine Abrupt discontinuation Severity and incidence of migraine
parthenium prophylaxis, can result in a headaches has shown to be
arthritis, menstrual withdrawal syndrome; decreased in those taking feverfew
pain, asthma, and increased heart rate
dermatitis has also been reported.
Should not be used in
children < 2 years old,
or in pregnant or
lactating women

Garlic Allium Alliin[(+)-S-allyl-L- High blood sugar, None known Garlic has been shown clinically to
sativum cysteine hypercholes- increase HDL, decrease LDL and total
sulfoxide] terolemia, and cholesterol. It has also been shown to
hyperlipidemia have antioxidant properties and to
decrease platelet aggregation

Ginger Zingiber Gingerols; shogaol Prevent motion In large amounts, CNS Ginger has been shown to
officinale sickness, for depression may occur. dramatically increase the amount of
cough, stomach May affect cardiac time needed to reach a state of
ache, and function and motion sickness. It also decreases
gallbladder anticoagulant activity cardiac workload by increasing
disease vasodilation. It has a strong
antimicrobial effect

Ginkgo Ginkgo Flavonol and Raynaud’s disease, Rare, but may include Ginkgo has been shown to increase
biloba flavone glycosides stress, tinnitis, heart palpitations, cerebral blood flow and decrease
(e.g., quescetin dementia, cerebral dizziness, headache cerebral deficiency. It has also been
and kaempferol); insufficiency, and dermatological shown to decrease inflammatory
rutin anxiety, asthma, reactions response in lungs reducing severity of
and circulation asthma attacks. It also increases
problems microcirculation and improvement in
pathologic blood flow disease has
been observed

(continued overleaf)
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104 | An Introduction to Pharmacy

Table 5.19 (continued)

Herbal Source Active Common uses Common side effects Supporting evidence
product ingredient(S)

Ginseng Panax quin- Ginsenosides Decreased energy, Nervousness is the An increase in CNS stimulatory and
quefolius (triterpenoid cancer, immune most common side inhibitory effects has been observed
saponins support, and effect; also some breast in patients taking ginseng. An increase
glycosides) cardiovascular nodulation and vaginal in overall cognitive function has been
problems bleeding have been established as well. However, no
reported studies to date have linked ginseng
and improved physical performance

Goldenseal Hydrastis Isoquinolone Topical infections Side effects are rare, Clinically, it has been shown to have
canadensis alkaloids and as an but contraindicated in modest antimicrobial activity, most
(hydrastine, anticatarrhal patients with effective topically
canadine, and hypertension or
berberine) pregnancy. In very
high doses, can cause
nausea, anxiety and
seizures

Grape seed Vitus vinifera Proanthocyanidins, Antioxidant, Hepatotoxicity in Clinically, it has been shown to have
polyphenols venous animal studies anti-enzyme properties resulting in a
insufficiency, decrease in breakdown of compounds
edema important for tissue structure such as
collagen, elastin, and hyaluronic acid

Green Tea Camellia Catechins and Cancer, Caffeine in green tea Clinically it has been shown to
sinensis polyphenol hyperlipidemia, may cause decrease total cholesterol; however,
components prevention of nervousness and triglycerides and HDL were
dental carries, as increased heart rate, unchanged. Also, antimicrobial
an antimicrobial, and should be avoided activity has been shown especially
antimutagenic, during pregnancy against mouth flora. It also has been
and an antioxidant shown to inhibit GI pathogens,
although the dose was 9 cups per day

Hawthorn Crataegus Oligomeric Hypertension, Hypotension and Studies have shown that hawthorn
laevigata procyanidins abnormal heart sedation can be increases vasodilation and coronary
(epicatechin and rate, experienced at high artery flow, as well as stabilize heart
flavonoids) artherosclerosis, doses. May interfere rate. It has also been shown to
angina pectoris, with digoxin blood decrease lipid levels
and as an levels
antispasmodic and
a sedative

Horse Aesculus hip- Aesculin Edema, Use should be avoided Increased vascular resistance and
chestnut pocastanum inflammation, and due to classification as tone has been indicated. A decrease
venous an unsafe herb by the in complaints and edema measures
insufficiency FDA because of was shown in patients with peripheral
toxicity. Topical edema. Anti-inflammatory properties
products containing have also been supported
this herb may also be
carcinogenic

(continued overleaf)
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Table 5.19 (continued)

Herbal Source Active Common uses Common side effects Supporting evidence
product ingredient(S)

Kava Kava Piper Kava lactones Mild to moderate Should not be used Studies have supported kava’s
methysticum anxiety and as a during pregnancy or positive effect on patients with mild
sedative by patients with to moderate anxiety. It has also been
depression. Use should demonstrated as an effective
be limited to 3 months anticonvulsant. In addition, kava has
to avoid habit-forming an antithrombotic effect on platelet
tendencies. Also, aggregation
problems with vision
and a condition similar
to pellagra have been
reported

Licorice Glycyrrhiza Carbenoxalone GI complaints Lethargy and Licorice has been shown to increase
uralensis quadriplegia may the lifespan of gastric epithelia cells. It
result from long-term has been demonstrated to be less
daily consumption effective than Cimetidine at treating
gastric and duodenal ulcers

Milk Thistle Silybum Silymarins Liver damage Mild allergic reactions Milk thistle has been shown to
marianum (flavano- prophylaxis, and mild GI symptoms normalize liver enzymes; however,
lignanssilybin, antitoxin improvement in the evolution and
isosilybin, mortality of cirrhosis is not supported
dehydrosilybin,
silydianin, and
silychristin)

Saw Serenoa Probable active Symptoms Should be avoided Clinically, several symptoms
Palmetto repens compounds are: associated with during pregnancy, but associated with benign prostatic
phytosterols, fatty benign prostatic no other side effects hyperplasia have been shown to
acids and their hyperplasia aside from mild GI decrease in those taking saw
ethyl esters, and symptoms palmetto. It has not been shown to
monoacylglyc- have any effect on prostate size or
erides presence of prostate specific antigen
in the blood

St John’s Hypericum Hypericin, Depression and Rare, but may include Clinical trials have shown that
Wort perforatum hyperforin, and viral infection constipation, other GI patients taking St. John’s Wort have a
related napthodi- symptoms, dry mouth, significant decrease in serotonin
anthrones dizziness and reuptake as well as an increased
photosensitivity. Mania dopamine function. Also, several
and sexual disturbance viruses (influenza, herpes simplex 1
occur even more rarely and 2 and some retroviruses) have
susceptibility to this compound. St.
John’s Wort has also demonstrated
potent antimicrobial activity

Valerian Valeriana Valepotriates, Restlessness and Few to none Valerian has been demonstrated to
officinalis valerenic acid, and sleep disorders improve sleep disorders very
valeranone effectively. Also, antianxiety studies
have indicated efficacy in treating
those symptoms

Data from DerMarderosian A, et al. Guide to Popular Natural Products, 2nd ed. St. Louis, MO: Facts and Comparisions, 2001; and United States
Pharmacopeia and National Formulary (USP 27-NF 22). Rockville, MD: The United States Pharmacopeial Convention, Inc., 2003.
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106 | An Introduction to Pharmacy

compounds present in very low concentrations. the biochemistry of disease states and the design of
However, this has been made easier by continued drugs for the prevention of diseases. An important
advances in extraction, concentration, and identifica- aspect of medicinal chemistry has been to establish
tion techniques. Bioassay guided fractionation, high a relationship between chemical structure and bio-
throughput screening and availability of cell-based logical activity. An increased consideration in recent
or enzyme assays have further simplified the process years has been to correlate chemical structure with
of analyzing and studying natural products. Since chemical reactivity or physical properties, and these
natural products already have a function in nature, correlations can, in turn, be related to their therapeu-
and therefore, typically already display pharmaco- tic actions.
logical activity, they are seen as improving the odds Although there has been a great deal of success
of synthesizing a good drug compared to starting in understanding the relationship between chemical
with a completely new structure. Such compounds structure and biological activity in a number of areas
are proving to be very useful as starting points for (e.g., for antibacterial drugs), there are still many
combinatorial chemistry and the synthesis of lead human afflictions that require new and improved
drug compounds. Natural products are complex drugs. Cancer, viral infections, and cardiovascular
organic molecules and their synthesis usually involves and mental diseases need new agents and approaches
multiple steps with low yields. However, recent for treating and preventing these maladies. One thing
advances such as small-molecule organic catalysis has become clear – many disease states (such as can-
and cascade reactions performed in a single step cer) involve a disruption in the normal regulatory
may be valuable in achieving total synthesis of machinery of the cell, and present the daunting
several complex natural molecules. Despite the prospect of addressing multiple potential molecular
difficulties, the renewed interest in natural source of targets that may be implicated in the development of
new chemical entities has resulted in approval of a the illness. This has only intensified our motivation
number of natural products and their analogs as new to achieve a better understanding of the relation-
drugs (Table 5.20). ship between the structure, activity, and specificity
of drug molecules acting on cellular targets, so that
the effects of small molecules on the web of interac-
Structure–activity relationships tions that support the life of a cell can be more fully
understood.
and drug design In developing drugs with specific activities, several
approaches are used. Often, bioactive compounds are
Introduction
first identified by using a high-throughput screen,21 an
For centuries, humans have observed that natural sub- assay in which typically thousands to millions22,23 of
stances not only can be used for their nutritional value small molecules (sometimes taken from proprietary
and for treatment of diseases, but also may bring libraries) are presented to a target of interest, and
about toxic or lethal effects. The Chinese Emperor assessed using a fast biological assay implemented
Sheng Nang in 2735 BC compiled a book of herbs in a compact format (e.g., 96-well plates). Once
and employed ‘‘Chang Shan’’ in the treatment of active library compounds are identified, the medicinal
malaria. Although the majority of the drugs used chemist and pharmacologist work together to improve
from antiquity to the nineteenth century came from the activity of these ‘‘lead molecules.’’ This will usu-
natural sources, in the twentieth century a new era ally involve the development of a structure–activity
arose when it became possible to treat diseases with model derived from the initial data, which will sug-
synthetic drugs. In addition, the modification of nat- gest modifications to the lead compound that are
ural products through various synthetic processes has predicted to increase activity. This initiates a cycle
provided a range of useful semi-synthetic drugs. of synthesis–biological test–synthesis–biological test,
The field of medicinal chemistry has evolved from which is iterated until a drug with the desired activity
an emphasis on the synthesis, isolation, and char- is obtained. Our enhanced understanding of receptor
acterization of drugs to an increased awareness of structure (at least for enzymes and other cytosolic
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Pharmaceutical Chemistry | 107

Table 5.20 Recent natural product analog drug approvals

Year Drug name Indication Natural Product (NP) NP originally derived from
template

2010 Cabazitaxel (Jevtana) Cancer Paclitaxel (Taxol) Taxus brevifolia

2010 Eribulin mesylate (Halaven) Cancer Helichondrin B Halichondria okadai

2010 Rifaximin (Xifaxan) Antimicrobial Rifamycin Streptomyces mediterranei

2009 Artemether (Coartem) Antimalarial Artemisinin Artemisia annua

2009 Capsaicin (Qutenza Neuropathic pain Capsaicin Capsicum sp.

transdermal patch)

2009 Colchicine (Colcrys) Gout / Mediterranean fever Colchicine Colchicum autumnale

2009 Everolimus (Afinitor, Cancer / Rapamycin Streptomyces hygroscopicus

Zortress) Immunosuppressant
(approved in 2004)

2009 Telavancin (Vibativ) Antibacterial Teicoplanin Actinoplanes teichomyceticus

2007 Ixabepilone (Ixempra) Cancer Epothilone Sorangium cellulosum

2007 Retapamulin (Altabax) Impetigo Pleuromutilin Pleurotus mutilus

2007 Temsirolimus (Torisel) Cancer Rapamycin Streptomyces hygroscopicus

2007 Trabectedin (Yondelis) Cancer Ecteinascidin Ecteinascidia turbinata

2006 Anidulafungin (Eraxis) Antifungal Echinocandin Aspergillus nidulans

2005 Exenatide (Byetta) Type 2 Diabetes Exendins Heloderma suspectum

2005 Micafungin (Mycamine) Antifungal Echinocandin Aspergillus nidulans

2005 Tigecycline (Tygacil) Antibacterial Tetracycline Streptomyces sp.

2004 Telithromycin (Ketek) Antibiotic Erythromycin Saccharopolyspora erythraea

2003 Daptomycin (Cubicin) Antibacterial Lipopeptide Streptomyces roseosporus

2002 Pimecrolimus (Elidel) Immunosuppressant Rapamycin Streptomyces hygroscopicus

2001 Acemannan (Carrington Wound healing Polysaccharide Aloe vera

patch)

2001 Caspofungin acetate Antifungal Echinocandin Aspergillus nidulans

(Cancidas)

Data from: Beutler JA. Natural products as a foundation for drug discovery. Curr Protoc Pharmacol. 2009; 46: 9.11.1–9.11.21.
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108 | An Introduction to Pharmacy

proteins or protein domains) also leads to the pos- set of organic functional classes with a specific rela-
sibility of virtual screening,24 where the interactions tive arrangement in space. An implicit assumption is
of a small molecule and a protein receptor are pre- that these groups must be positioned in this way to
dicted solely on the basis of structure and energetic interact with complementary features of the receptor;
models. While experiment remains the ‘‘final word’’ for example, a hydrogen-bond donor in the pharma-
as to the activity of a molecule, computational mod- cophore is presumed to interact with a hydrogen-bond
els have advanced to the point where virtual screens acceptor in the receptor, a bulky alkyl group with a
are routinely used to select compounds for initial hydrophobic pocket in the target active site, and so on.
testing, and to refine structure–activity relationships. The potency of a compound can often be correlated
Computational modeling has become a routine ele- with the number of features it shares in common with
ment of the drug discovery process, and a design the hypothetical pharmacophore, and this can repre-
team often will include a dedicated computational sent a rough but useful structure–activity relationship.
specialist. Figure 5.3 illustrates several pharmacophore models25
which abstract the features of compounds that exhibit
selective agonism toward estrogen receptor subtypes
Analog approach α and β, along with some active molecules which fit
Ligand-based design the pharmacophores. The spheres in the models repre-
sent spatial tolerances for declaring a match between
In drug design, we recognize two broad approaches:
a candidate molecule and the pharmacophore. For a
receptor-based design and ligand-based design.
molecule to fully match a pharmacophore, it must be
Receptor-based design starts with the assumption
possible to flex and position it so that all of the phar-
that we have an atomic-resolution model of a
macophore sites enclose a requisite chemical feature of
receptor (found most often by x-ray crystallography
the compound; for example, a sphere labeled ‘‘HD’’
or nuclear magnetic resonance (NMR)), usually a
must enclose a hydrogen-bond donating functional
protein molecule that includes an active site at which
group to contribute to a match.
small molecule ligands can bind. High-resolution
Since drug activity is directly determined by the
models can often be determined for soluble proteins
shape and electrostatic field of a molecule, a useful
or protein domains, including many interesting
targets such as enzymes, transcription factors, and approach is to modulate these properties by obtain-
cytoskeletal proteins. In receptor-based strategies, ing or synthesizing analogs of a molecule known
the goal is to identify molecules that are strongly to be active. Often a series of substitutions can be
complementary to the receptor, in both shape and effected to a parent compound by changing reagents
electrostatics (especially positions of hydrogen-bond used at various steps of the synthesis. By introduc-
acceptors and donors). In contrast, in ligand-based ing independent substitutions at several sites on the
design it is assumed that no initial information as to parent compound, a large number of analogs can
the structure of the receptor is available; instead, we be constructed, and coupling this with an assay
begin with activity information for a panel of known of biological activity provides a powerful mecha-
bioactive compounds, and assume that molecules nism to probe the structure–activity relationship. At
similar in shape and electrostatic properties to one the same time, structure–activity relationship stud-
of our known actives will likewise interact with the ies often provide the raw data needed to infer the
same target receptor. pharmacophore (using either computational tools or
Recognizing that similarity in shape and electro- chemical intuition) and thus to obtain drugs with
static profile implies similar biological activity, it is increased potency. After a collection of compounds
natural for us to abstract those features of a panel of with adequate potency has been obtained, additional
active compounds that are most important for elicit- properties can be measured, including selectivity,
ing a response. The pharmacophore is the chemical duration of action, toxicity, and metabolic stabil-
segment of a molecule that is responsible for biolog- ity, and these can serve as additional criteria when
ical action. Usually a pharmacophore will feature a selecting a drug candidate.
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Pharmaceutical Chemistry | 109

A1 A2 A3
HY
HY

6.55 10.36 HY

HA HY HY HY
10.54 HD HA
2.62 HD HA HD
8.46 6.38
HY HY
HY

B1 B2 B3
HY
HD
6.94 HD HD
2.29 HY
3.46 RA HY
6.05 4.75 RA RA
HY HY HY

Figure 5.3 Pharmacophore models for selective ERα and ERβ ligands. (A1) ERαmodel with distance constraints (Å); (A2) ERα
model mapped with the most active ligand 1 (RBA = 140, K 1 = 0.14 nM); (A3) ERα model mapped with selective ERα test set
ligands 4 , 6 , 10 , 43 ; (B1) ERβ model with distance constraints (Å); (B2) ERβ model mapped with the most active ligand 24 (RBA =
144, K 1 = 0.35 nM); (B3) ERβ model mapped with selective ERβ test set ligands 5 , 16 , 32 , 40 . (Reproduced from Fang J et al.
Computational insights into ligand selectivity of estrogen receptors from pharmacophore modeling. Mol Inform 2011; 30:
539–549.)

Homologs OH

One approach to systematic modification is to adjust HO (CH2)nCH3

the size of a selected portion of the molecule in con-
trolled steps. A homologous series refers to a series Hexylresorcinol (n = 5)

of analogs that differ in structure by a simple incre- with six carbon atoms (n = 5) in the side-chain. If the
ment in the molecular formula. For example, these alkyl chain is lengthened or decreased, a decrease in
may be produced by sequential chemical change that activity is observed relative to hexylresorcinol.
There are times when changing the number of
includes increasing or decreasing the length of an
methylene groups may lead to a change in the type
akyl carbon chain. A series of homologs of this type
of biological activity rather than its intensity. For
is used to provide insight into the relationship of example, it is known that alkyltrimethylammonium
biological activity and chemical changes that involve analogs
only the number of methylene groups attached at a CH3
single site. This type of variation directly modulates CH3 +
N (CH2)nCH3CI–
the hydrophobic/hydrophilic partition coefficient, and
CH3
consequently the biological action. Often, the com- Alkyltrimethylammonium
pounds with short alkyl chains are low in activity; as possess different types of activity depending on the
the chain length is increased, the biological activity length of the alkyl group. If the alkyl group is up to
increases to an optimum point, and as more methy- six carbons (n = 5), the compounds are muscarinic
lene groups are added, activity decreases. A classic agonists. Thus, these compounds have activity similar
example of this phenomenon is the activity of the to acetylcholine.
O
n-alkylresorcinols in which the optimum biological
CH3CO(CH2)2N+(CH3)3CI–
activity, as measured by phenol coefficients against
Bacillus typhosus, is hexylresorcinol. Acetylcholine chloride
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110 | An Introduction to Pharmacy

on muscarinic receptors. With seven carbons (n = An even more compelling classical example
6) to eight carbons (n = 7), these compounds are of improved ligand efficiency is provided by the
partial agonists; when the length is greater than nine anti-hemorrhagic menadione.
carbons (n = 8), these compounds are muscarinic O
antagonists.
CH3

Fragment-based approaches
A very different tack is not to build molecules up, but O
rather tear them down, thus determining the func- Menadione
tional groups responsible for activity. In recent years,
fragment-based approaches26 have enjoyed increasing Menadione (vitamin K3 ) is a precursor to the natu-
popularity. This is in part motivated by the recogni- ral product vitamin K1 , which has similar action in
tion that naturally occurring active molecules may reducing hemorrhage, but is a much larger molecule:
include large components that are not required for O
activity. A classic example is cocaine, an alkaloid CH3

obtained from Erythroxylon coca, which has served CH2 CH3

as the prototype molecule for the development of a O C C CH3 CH3
H CH2CH2CH2 C (CH2)3 C (CH2)3CH(CH3)2
series of potent local anesthetics, produced by succes-
H H
sive simplification of the starting structure: Vitamin K1

CH3
N H
COOCH3 CH3
H N
H
C OC
CH3 O C NH2 COOCH2CH2N(C2H5)2 NH2 COOC2H5
H O CH3
H
Cocaine β-eucaine Prococaine Benzocaine

In this series, the carbomethoxy group of cocaine is Menadione retains only the naphthoquinone ring of
first removed to produce tropacocaine, the tropane vitamin K1 , while maintaining the essential biological
ring is next simplified to produce β-eucaine, and activity.
the six-member ring of β-eucaine can be broken to Modern fragment-based approaches26,28 focus
produce procaine without loss of activity (although less on natural products or the deconstruction of
procaine does introduce an additional amine group). known actives, and rely more on large chemical
It was demonstrated that the critical part of procaine libraries as rich sources of structural diversity. While
required for activity was the hydrophilic amine seg- our emphasis here is on ligand-based approaches, we
ment attached to an intermediate chain, which in turn would be remiss not to mention some very productive
was attached to a lipophilic ester function. The key experimental and computational strategies that
idea is that while the totality of a molecule may be utilize detailed knowledge of receptor structures.
involved in determining its overall biological profile, One approach to de novo design of new drugs is to
including bioavailability and metabolism, the portion first identify those sites on a target protein that will
actually responsible for target activity may be of lim- bind small molecules. The goal is not to immediately
ited extent, and point to lead compounds that are find lead compounds with drug-like properties, but
easier to synthesize. Moreover, smaller active com- rather to identify collections of fragment molecules
pounds present superior ligand efficiency,27 defined (e.g., single rings with varying substituents, small
as the ratio of the free energy of binding to the num- acyclic molecules with one or two functional groups)
ber of heavy atoms in the compound, and this has which bind tightly enough to form one or more ad
become widely recognized as an important metric for hoc scaffolds to develop larger molecules which will
evaluating drug molecules; smaller molecules are not serve as leads. While fragments may only bind with
only more economical to synthesize, they are demon- millimolar affinity, it may still be possible to detect
strated to have higher rates of success in surviving the binding, and even to localize the bound fragment in
clinical trial phase and eventually reaching the market. the receptor.
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Pharmaceutical Chemistry | 111

Experimental techniques that support fragment- construct larger molecules. While it is generally rec-
based drug discovery include x-ray crystallography ognized that such theoretical calculations are far less
and NMR. Crystallographic studies can be carried reliable than experiment, the accuracy of the predic-
out after co-crystallization of the target protein struc- tions made by such tools is steadily improving as the
ture with one or more fragment compounds. The underlying algorithms are refined. It should also be
electron-density map is studied for the presence of noted that experimental screening of large numbers of
fragment occupancy in the vicinity of the active site, fragments is expensive and sometimes difficult to carry
and it may be possible to resolve multiple fragments out for specific targets; thus theoretical computations
that bind close together with a mutual orientation are increasingly seen as an attractive alternative.
that is consistent with a larger structure that links
the two together:29 alternatively, libraries of larger Quantitative structure–activity
compounds involving two or more fragments may be relationships
employed at the outset.30 In principle, it should be
possible to develop a novel compound with binding A long-standing goal of workers in the area of quan-
affinity that reflects the sum of the binding energies titative structure–activity relationships (QSAR) has
of the individual fragments, and in fact this has been been the development of quantitative methods of
a useful strategy against several molecular targets. determining the activities of a series of compounds.
One of the earliest hypotheses that attempted to
(There is evidence, however, that this process is not
relate activity to a physicochemical parameter was
invertible, in the sense that a known binder compris-
the Meyer–Overton narcosis theory.33 In 1901, both
ing several fragments may not be ‘‘explained’’ on the
men working independently observed that, for gen-
basis of its component parts, which may prefer alter-
eral anesthetics, activity was related to the lipid/water
native binding sites when presented individually.31 )
partition coefficient; for example, cyclopropane with
NMR provides another route to detecting the
a value of 65 was far more effective than nitrous oxide
binding of small fragments and to localizing them
with a coefficient of 2.2.
in the receptor. Chemical shifts in the receptor are
In the field of theoretical chemistry, Hammett34
very sensitive to the binding of small molecules, and
was the first to demonstrate that the pKa values of
moreover NMR structure-determination methods can
substituted benzoic acids could be predicted as a
be applied to determine a three-dimensional structure
function of the various substituents attached to the
for the bound ligand in favorable circumstances, even
ring and their abilities to either donate or withdraw
in situations where fragments may overlap. Again, in
electrons from the carboxyl group. These results then
favorable circumstances it may be possible to identify
were extended to other reactions and other series
synthetic strategies that effect a merger of neighboring
of compounds using the same substituent constants
compounds, creating a larger molecule with higher
derived from the benzoic acid series. In the Hammet
potency that may serve as a novel lead.
equation,
Yet another approach to fragment-based design
is to dispense with experiments for initial screening, k
log = ρσ (5.43)
and instead rely on computational tools to predict, k0
solely on the basis of structure, the most likely binding where k is the rate constant for the reaction of a
sites for small fragments, and moreover to automat- substituted aromatic compound, k0 is the rate con-
ically assemble these to form larger compounds that stant for the unsubstituted aromatic compound, ρ
might serve as useful lead molecules. A wide variety is the reaction constant, and ρσ is the substituent
of such de novo drug design strategies32 are available. constant. Later work led to substituent constants in
While the approaches are diverse, all typically rely which the electronic effect is separated into inductive
on libraries of chemical fragments to serve as raw and resonance terms; in the Taft equation, a term Es
material, a method to identify likely binding sites, is defined as a measure of the steric requirements of a
a stochastic approach to explore possible positions substituent.
and orientations of fragments, a scoring function to Contemporary QSAR approaches, despite their
assess and rank the binding positions of the fragments, great diversity, share some broad features in common:
and finally some mechanism to merge fragments to the use of numerical descriptors to characterize the
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112 | An Introduction to Pharmacy

molecules in a collection under study, and the devel- (bonds). With this perspective in place, many graph-
opment of a functional model between the descriptors theoretic concepts are available to inspire new descrip-
and the measured bioactivity of the molecules in the tors, such as the classical Randic index:
set. This functional model is then used to predict the
 1
activities of molecules that lie outside the training set r=  (5.45)
used to construct it. b∈B db(i) db(j)

Here the sum ranges over all bonds b (each bond con-
Descriptors
necting atoms b(i) and b(j)), and dk is the degree
A wide array of measures have been adopted to char- of atom k, equal to the number of connections
acterize the molecules in a series. The most familiar of (bonds) including that atom. (We note that in all
these are the physicochemical descriptors, including computations of 2D descriptors, it is customary to
molecular weight, dipole moment, and perhaps most ignore hydrogens.) Graph-theoretic descriptors are
importantly log P, the logarithm of the octanol–water fast to compute, capture structural information in
partition coefficient: non-obvious ways, and have been shown to strongly
correlate with selected molecular properties. Taking
[Soct ] a further step, we can use the graph depiction to con-
log P = log10 (5.44)
[Saq ] struct a matrix representation of the molecule, where
each off-diagonal position (row i, column j) signi-
where [Soct ] and [Saq ] are the equilibrium concentra- fies presence or absence of a bond between atoms i
tions of the compound in the low-polarity octanol and j; an off-diagonal element that contains a non-
phase and aqueous medium, respectively. Log P is a zero value indicates a connection between the atoms,
measure similar to the lipid–water partition coeffi- and perhaps also the order of the bond. Diagonal
cient of Meyer–Overton theory, and this and other elements may hold a selected property of the atom
measures of hydrophobicity remain among the most corresponding to that row/column. By construction,
important molecular descriptors, as they are indica- these matrices will be symmetrical (swapping rows
tive not only of the likelihood of binding to particular and columns leaves the matrix unchanged). The eigen-
receptor sites, but also of transport across membranes values36,37 of an n × n matrix are found by treating
(i.e., bioavailability) and other features of storage and it as an operator in n-dimensional space and iden-
disposition. tifying ‘‘special’’ directions it leaves unchanged. In
Other descriptors seek to capture more details of physical calculations, these often have special signifi-
chemical structure. Two-dimensional (2D) descrip- cance (e.g., vibrational frequencies); in QSAR they are
tors depend on chemical connectivity alone; the simply numbers that have been shown to sometimes
simplest of these are counts of various functional correlate strongly with bioactivity, and thus are use-
groups, including hydrogen-bond donors and accep- ful as descriptors. While the connection between the
tors. These and other numerical counts may correlate eigenvalues of a molecular structure matrix and the
with bioactivity. The approach may be extended to molecule’s properties may be opaque, the practical
its logical limit to construct a molecular hologram, a utility of these numbers as descriptors is undisputed.
histogram in which chemical fragments map to bin Whereas 2D descriptors are completely defined
positions, and the histogram counts the number of by the elements in a compound and their pattern of
occurrences of fragments that map to the same bin.35 bonding, three-dimensional (3D) descriptors require
By decomposing an input molecule into all fragments that all the atoms have assigned x–y–z coordinates.
within a range of sizes, and mapping these to a Computing atomic coordinates is not a trivial task;
histogram of fixed length, a small descriptor is created modeling packages such as Schrödinger and MOE
which encapsulates much chemical information. include methods for coordinate generation, and there
Other 2D descriptors are defined by treating the are specialized tools like CORINA38 dedicated to
molecule as a mathematical graph, a tree structure this purpose. Coordinates may be stored with the
consisting of vertices (atoms) connected by edges compounds in a chemical library, depending on its
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Pharmaceutical Chemistry | 113

format and intended purpose, or we may choose to In more recent studies, a variety of novel meth-
compute them as needed. ods have been used to construct predictive models,
Three-dimensional QSAR descriptors include often borrowed from the world of data mining. These
those involving surface area, since this geometrical include k nearest neighbor (kNN) and ‘‘lazy learn-
measure is a function of the specific conformation of ing’’ approaches39 where the activity of a compound
a molecule. Surface descriptors include total polar is predicted on the basis of the training compounds it
and nonpolar surface areas, where each portion of the is closest to (as measured in the space of descriptors),
surface is assigned to one or the other category based and neural networks have also been applied to con-
upon the chemical types of the atoms underlying struct predictive models (these have the advantage of
the surface, and can be extended to a histogram readily modeling nonlinear relationships). Methods
approach where surface contributions are tallied over have been developed that use data-mining techniques
a range of a selected hydrophobicity index (such as in conjunction with traditional PLS, for example using
atomic contributions to the log P). a genetic algorithm to select the best set of descriptors
The 3D descriptors with the greatest potential for building a predictive model.40 For some series of
explanatory power are grid-based descriptors, which active compounds, such hybrid methods may succeed
are generated by enclosing a molecule, or a set of where traditional PLS fails. Indeed, the ways in which
molecules, in a rectangular lattice of points. Each different methodologies from different fields can be
grid point can sample the steric volume presented by mixed and recombined provides a fertile ground for
each molecule, as well as its electrostatic potential experimentation and development, and ensures that
or other properties. It is important to stress that QSAR will continue to be an important and evolving
every grid point is an individual descriptor, and a area of work.
QSAR study involving a grid may imply the presence An important concern with any predictive method
of hundreds or even thousands of descriptors, with is that when the number of descriptors is much greater
important implications for the reliability of predictive than the training set of active compounds (a common
models. scenario in 3D QSAR), the algorithm may automati-
cally pick out a subset of descriptors whose variation
correlates with activity purely by chance, and produce
Models
what appears to be a valuable predictive model. This
The universal concern of QSAR studies is to construct model will only work on the original set of train-
a function that will predict the bioactivity of molecules ing molecules, and will likely fail miserably when
against a given target, or other measurable proper- validated on another set of compounds. To guard
ties of interest (such as bioavailability). The classical against this, it is important to always employ a cross-
approach is to build a linear regression model, a linear validation technique. This may mean dividing a set
function that maps a collection of descriptor values of compounds of known activity into distinct train-
(potentially large in number) to a single real number, ing and validation sets, with the training compounds
the predicted activity/property (e.g., the log of the used to construct the model, which is then verified
IC50 ). The output of the model is called the response. by using it to predict the activities of the validation
There are a number of mathematical approaches to molecules. A widely used and simple alternative to this
construct this function, and all recognize some typical is called leave-one-out (LOO). In LOO, each active
difficulties that arise when there are a large number compound is selected in turn to be removed from
of input variables to a predictive function, and where the training set; the remaining compounds are used
many of these may be poorly correlated with variation to construct the predictive model, which is then used
in the response. All of the approaches, which include to compute the activity of the compound removed.
principal components analysis (PCA) and partial least The residuals for the compounds (differences between
squares (PLS), seek to collapse together those vari- measured and predicted activities) are collected and
ables whose variation is strongly correlated, so as to used to compute the correlation coefficient, which in
reduce the effective number of inputs to the regression this context is termed the cross-validated r2 , or q2 .
model and increase its robustness. A widely used rule-of-thumb is to consider a q2 value
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114 | An Introduction to Pharmacy

of 0.5 or greater as indicative of a useful model (the molecule has a measured activity against the target
non-cross-validated r2 for such a model might actu- of interest. It can be seen that each grid point thus
ally be close to unity, and is not a good measure of serves as a separate descriptor, analogous to log P or
the model’s utility). In the end, a non-cross-validated molecular weight in ‘‘classical’’ QSAR. The difference
model is constructed using all the compounds in the of course is that while a traditional QSAR study may
training set. entail dozens of descriptors, a grid with a fine spacing
can easily lead to thousands of descriptors. Fortu-
Applications nately, fast computers coupled with an appropriate
Many successful applications of QSAR to the design implementation of the PLS regression method51 can
of bioactive molecules are available in literature. produce a useful model in this situation, one which
They range from ‘‘classical’’ studies that employ automatically de-emphasizes unimportant descriptors
physicochemical and 2D descriptors, to more current (e.g., grid points at which activity does not correlate
3D QSAR methods, usually involving a grid-based with measured field values).
approach. An illustrative example of classical QSAR In CoMFA, the structures of the training set need
model development is given by the rational design to be correctly superimposed in a consistent manner.
of a series of 1-(X-phenyl)-3,3-dialkyl triazenes as Alignments can be realized by reference to crystallo-
antitumor agents.41 While these compounds were graphic data for a series of actives in complex with a
extensively investigated because of their potent anti- common receptor or by using molecular docking.
tumorigenic effects, they also exhibited significant When no receptor-based information is available,
mutagenicity.42 QSAR studies were successfully con- structural alignments are often built according to
ducted on a congeneric series of triazene derivatives a pharmacophore hypothesis, or by relying on a
to identify structural modifications that reduced the shared scaffold if the active molecules form a con-
mutagenic properties of these compounds, while leav- generic series (often the case). Interactions between
ing unaffected their desirable antitumor activities. the aligned molecules and the probe atom presume
Also, QSAR studies have been extensively applied existing steric and electrostatic force-field parameters.
to the rational design of anti-HIV inhibitors active An important advantage of CoMFA is that the sig-
against HIV-related biological targets.43 – 45 Other nificant grid points (those where variations in steric
pertinent examples include the implementation and/or electrostatic fields correlate well with activ-
of QSAR models to design novel zinc-containing ity) are identified immediately by the PLS procedure,
inhibitors of matrix metalloproteinases46 as well as and moreover the kind of variation associated with
to the use of sulfonamide derivatives as potential increased activity (e.g., increasing steric bulk or nega-
inhibitors of carbonic anhydrase.47 tive electrostatic potential) is also known. This allows
In the course of the 1980s the computing power the grid to be ‘‘color coded’’ by the strength of cor-
available to researchers engaged in drug discovery relation (intensity) and the kind of variation (color),
increased by orders of magnitude, greatly expanding leading to isocontour maps that inform the medicinal
the number of descriptors that could be considered chemist as to where the addition or removal of steric
in a QSAR analysis. This enabled the introduction of bulk, or the modulation of electric charge, is likely to
powerful methodologies such as comparative molecu- lead to increased activity.
lar field analysis (CoMFA),48 a 3D QSAR approach49 The first implementation of CoMFA refers to a
developed by Tripos50 in 1988. CoMFA measures the series of steroid molecules binding to two different
electrostatic and steric (van der Waals) interactions globulin targets.48 Since then, significant progress
between a series of aligned molecules (the training has been made in the application of CoMFA, and
set) and a probe atom, which is placed at all the several noteworthy examples are available, includ-
vertices of a regular grid of points that enclosed the ing the CoMFA analysis for the design of p38 MAP
aligned molecules. In this way, the electrostatic and kinase inhibitors52,53 and the synthesis and character-
steric properties of the set are sampled throughout ization of novel cyclic sulfamide inhibitors of HIV-1
the enclosing volume. Each point records individual protease.54 CoMFA remains one of the most powerful
field values for all the molecules, and each training and popular QSAR methods ever devised.
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Pharmaceutical Chemistry | 115

Although not a QSAR method per se, another estimated (and cross-validated) and a selection of the
important 3D tool is GRID,55 a structure-based lig- meaningful variables, which significantly explain the
and design tool that involves the prediction of binding predictive power of the model, is finally performed.
pockets on protein surfaces by calculating interaction Over the past few years, several applications of the
energies, using a set of empirical energy functions. GRID/GOLPE combination have been implemented
Similar to CoMFA, GRID relies on the use of a reg- to successfully guide the design of new bioactive
ular lattice of points which, in this case, is overlaid molecules against a number of targets, including
against the binding pocket. Again, a selection of chem- inhibitors of glycogen phosphorylase b,60 histone
ical probes is distributed throughout the grid volume, deacetylase inhibitors,61 and the design of novel
while empirical scoring functions are used to calcu- putative inhibitors of the tyrosine kinase Abl.62
late specific interaction energies between each probe
and the receptor atoms. Lastly, a 3D map is obtained
where molecular interaction fields (MIF) are visual-
Pharmaceutical profiling
ized and used to locate favorable interaction regions
and protein-binding sites. One of the most successful
Introduction
applications of GRID in the field of structure-based
drug design is its role in the discovery of the drug According to Mosby’s Medical Dictionary, 8th edn,63
Relenza56 (GlaxoSmithKline), a potent inhibitor of a drug profile is an outline or summary of the charac-
the influenza virus replication. The natural evolution teristics of a drug or drug family, listing dosage types,
of the GRID maps led to their use as descriptors pregnancy category, prescription or over-the-counter
in CoMFA analyses for the successful development forms, generics (if available), contraindications, and
of QSAR and 3D QSAR approaches. More recent classification if covered by controlled-substance laws.
applications have been reported in the field of ADME Therefore, pharmaceutical profiling may be simply
and metabolism, in particular through the software defined as pharmaceutical and biomedical research
tool VolSurf.57,58 activities undertaken in order to identify and/or pre-
As already noted, in typical CoMFA and dict a drug profile in the early drug discovery and
CoMFA/GRID analyses, a very large number of development phase to ensure future clinical suc-
variable descriptors can be easily computed for each cess in terms of patient outcomes (e.g., efficacy and
compound. However, many of these variables are safety). This topic is becoming increasingly important
likely to be uninformative as to activity or binding, as underscored in a recent series of comprehensive
and many will be tightly correlated (e.g., two manuscripts following the Pharmaceutical Research
neighboring grid points may sample nearly identical and Manufacturers of America (PhRMA)’s initiative
field values). Indeed, any structural variation in on predictive models of efficacy, safety, and com-
the compounds generally affects only a subset of pound properties.64 – 68 Traditionally, the process of
related variables; thus a selection procedure is drug discovery has been directed by target generation
needed to enhance the overall quality of the PLS from observation of the biological activity of a natu-
model by neglecting redundant and uninformative ral or synthetic chemical entity on a physiological or
descriptors. GOLPE59 (generating optimal linear pathological process.69 This ‘‘one molecule at a time’’
PLS estimations) is a powerful tool introduced in approach which is based on trial and error, serendip-
1993 that achieves this goal, and which has been ity, scientific intuition, genius, and luck, has achieved
widely applied in combination with other tools. several noteworthy therapeutic successes. The avail-
GOLPE implements a procedure of preselection ability of new molecular approaches to the selection of
of nonredundant variables with high degree of drug therapy is an emerging need and the traditional
orthogonality in the multidimensional space defined approach based on the evaluation of patient charac-
by the descriptors. A fractional factorial design teristics is clearly far from optimal. In many cases the
(FFD) approach is then used to choose different majority of treated patients do not have significant
subsets of descriptors used to generate PLS models. benefits from treatment and they often experience
Lastly, the predictive abilities of these models are moderate to severe toxicities.70
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116 | An Introduction to Pharmacy

Paul Ehrlich’s pioneering experiments with cells ‘‘me-too’’ philosophy, or a mixture of all three. High-
and body tissue revealed the fundamental principles throughput screening (HTS), robotics, and automa-
of the immune system and established the legiti- tion now allow assays to be performed using very
macy of chemotherapy – the use of chemicals to treat small volumes with novel liquid-handling technolo-
disease. Moreover, recent advances in genomics, pro- gies. These technologies had little, if any, impact on
teomics and informatics, and analytical techniques facilitating the discovery of new clinically successful
have allowed the development of pharmaceutical pro- drugs. To this end, HTS and computational tech-
filing. For example, as we better understand how bio- nologies can be easily combined to improve chances
logical processes unfold in real time through advances of hit discovery and lead selection.77 These include
in chronobiology and related fields, we are able to cre- docking (e.g., DOCK programs such as AutoDock
ate safer, more effective drugs, drug delivery systems, and Glide, a crude combination of computational
and disease monitoring and prevention systems.71,72 chemistry and parallel synthesis), similarity search
Tests that predict clinical outcome for patients (e.g., (e.g., Network Conceptor, Inc.’s COMPARE algo-
cancer therapy) on the basis of the genes expressed by rithm to identify molecules with similar effect), phar-
their tumors are likely to increasingly affect patient
macophores (3D arrangement of molecular features
management, heralding a new era of personalized
necessary for bioactivity using the Catalyst program),
medicine.73
quantitative structure–activity relationship (QSAR),
The use of direct-to-consumer genome-wide pro-
and de novo design which is based on crystal structure
filing to assess disease risk is controversial, and little
of the molecular target.
is known about the effect of this technology on
Docking has gained great importance for rational
consumers. In a selected sample of subjects who com-
drug design. This approach is relevant in drug dis-
pleted follow-up after undergoing consumer genome-
covery where the drug function is computationally
wide testing, such testing did not result in any measur-
assessed by protein–drug interaction. The results of
able short-term changes in psychological health, diet
docking can be used to find inhibitors for specific tar-
or exercise behavior, or use of screening tests. Poten-
get proteins and thus to design new drugs. In addition
tial effects of this type of genetic testing on the popu-
lation at large are not known.74 Advances in analysis to molecular docking,78 two of the most successful
techniques, such as mass spectrometry (MS), high- methods described in the literature for computational
resolution liquid phase separations, and informat- drug design are in silico screening (e.g., inhibitor
ics/bioinformatics for large-scale data analysis have discovery79,80 ) and molecular dynamics simulations
enabled pharmaceutical profiling at different levels. (e.g., for dynamic models of protein–ligand interac-
To complete the already long list of issues facing tions to aid in lead optimization81,82 ).
the pharmaceutical industry, we should also note that There are several comprehensive review
unused pharmaceuticals are posing unknown risks for papers83 – 88 and books76,89 on these topics. Ligand
the environment and take a toll on human health.75 similarity-based lead identification is a technique that
In an effort to elucidate and predict pharmaceuti- follows the principle of similarity. It does not require
cal profile, the in silico, in vitro, and in vivo tools information about the 3D structure of the target
for prediction, measurement, and application of com- protein. It is assumed that molecules with similar
pound properties to select and improve potential drug structures will have similar chemical properties.
candidates have been reported elsewhere.76 Hence, the information provided by a compound,
or set of compounds, known to bind to the desired
target is used to identify new compounds from the
Pharmaceutical profiling in drug
external databases of chemical compounds using
discovery
virtual screening approaches. The most commonly
Computational methods for the prediction used methodologies for ligand similarity-based lead
of ‘‘drug-likeness’’ identification are shown in Table 5.21.
Early drug discovery efforts relied on the screen- The QSAR process quantitatively correlates struc-
ing of natural product extracts, pure serendipity, the tural molecular properties (descriptors) with functions
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Pharmaceutical Chemistry | 117

Table 5.21 Selected softwares in QSAR analysis

Software/webserver name Description

ACD/Log P Freeware Fragment-based algorithm for log P prediction

Carcinogenic Potency Unique and widely used international resource of the results of 6540 chronic,
Database (CPDB) long-term animal cancer tests on 1547 chemicals

COMPARE HP NonStop NSK-only utility program that identifies the differences between files
or segments of files. It can be used to compare text files, entry-sequenced files,
object or unstructured files. The product has two different modes of comparison:
uses extensive correlation technology to reduce false matches and miscompares
that tend to ‘‘confuse’’ other similar utilities. NCI’s COMPARE can identify additions,
deletions and modifications

DALTON Program for ab initio calculation of molecular properties

DSSTox Distributed Structure-Searchable Toxicity (DSSTox) Public Database

MoKa In silico computation of pK a values

Molinspiration Calculation of Molecular Properties and Drug-likeness

PK Tutor Free Excel Tools for PK and ADME Research and Education

PreADMET ADMET Predict permeability for Caco-2 cell, MDCK cell and BBB (blood–brain barrier), HIA
Prediction (human intestinal absorption), skin permeability and plasma protein binding

PreADMET Toxicity Predict toxicological properties from chemical structures, such as mutagenicity
Prediction and carcinogenicity

RCDK Allows the user to load molecules, evaluate fingerprints, calculate molecular
descriptors and view structures in 2D

Steric A program to calculate molecular steric effects

Adapted from Computational Resources for Drug Discovery website (http://crdd.osdd.net/qsar.php).

(e.g., physicochemical properties, biological activities, are defined as hydrogen-bond acceptors, and N–H
toxicity) for a set of similar compounds. The main or O–H groups are considered as hydrogen-bond
objectives of QSAR models are to allow the prediction donors. Log P refers to the octanol–water partition
of biological activities of untested or novel compounds coefficient of a compound and is used as a measure of
to provide insight into relevant and consistent chem- lipophilicity. Other important drug properties include
ical properties or descriptors (2D/3D) that define the molecular weight, pKa , permeability, and species of
biological activity. Once a series of predicted models the drug molecules (acids, bases, zwitterions, and neu-
is collected, these can be used for database mining trals), plasma protein binding, volume of distribution,
for the identification of novel chemical compounds; intravenous or oral clearance, half-life, and preclini-
particularly for those having drug-like properties cal bioavailability. These properties for the 108 drug
following Lipinski’s ‘‘Rule of Five’’90 along with suit- dataset have been extensively analyzed using predic-
able pharmacokinetic properties. The Rule of Five tive methods such as those of Mahmood,91 Obach et
states that any oxygen (O) and nitrogen (N) atoms al.,92 Hosea et al.,93 and PhRMA.64
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118 | An Introduction to Pharmacy

Energy minimization is very widely used in molec- Although many successful QSAR and quantita-
ular modeling and is an integral part of techniques tive structure–property relationship (QSPR) models
such as conformational search procedures. It is also are available, these models have inherent disadvan-
used to prepare a system for other types of calcula- tages. By their very nature, they tend to find the most
tions. For example, it may be used prior to a molecular generalized relationships that smooth over interest-
dynamics or Monte Carlo simulation in order to ing substructural effects and tend to be limited in
relieve any unfavorable interactions in the initial the precision of prediction. Such generalizations in
configuration of the system. This is especially recom- the prediction of primary potency, and other prop-
mended for simulations of complex systems such as erties, are often insufficient for guiding design in a
macromolecules or large molecular assemblies.94 The lead optimization phase. Precision and accuracy are
molecular mechanics or quantum mechanics energy further limited by the quality of descriptors used in
at an energy minimum corresponds to a hypothetical, the model. Although many thousands of descriptors
motionless state at 0 K. Experimental measurements can be generated, the value of each is not always
are made on molecules at a finite temperature when clear and can lead to misleading relationships and
the molecules undergo translational, rotational, and chance correlations depending on the data and mod-
vibrational motion. To compare the theoretical and eling technique used. Descriptors frequently describe
experimental results, it is necessary to make appro- chemical structure incompletely, and so information
priate corrections to allow for these motions. These about the structure–activity relationship is lost. To
corrections are calculated using a standard molecular solve this problem, recently matched molecular pairs
mechanics formula. The internal energy U(T) at a analysis (MMPA) has been proposed.97 For example,
temperature T is given by: MMPA was used for the optimization of pharmaceu-
tical properties such as a drug’s aqueous solubility
U (T) = U trans (T) + Urot (T) + Uvib (T) + Uvib (0) and plasma protein binding.98
(5.46)

If all translational and rotational modes are fully New methods of synthesis, screening small and
accessible in accordance with the equipartition large molecules, and drug reprofiling
theorem, then Utrans (T) and Urot (T) are both equal Over the past 10 years, a handful of academic and
to 3.2 kB T per molecule (except that Urot (T) equals industrial research groups have developed strategies
kB T for a linear molecule) where kB is Boltzmann’s for the synthesis of DNA-encoded small-molecule
constant.94 Aqueous solubility is a critical physic- libraries. The DNA-encoded library field holds the
ochemical property and must be addressed early potential to address the general problem of biolog-
during drug discovery research. Due to the difficulty ical ligand discovery, including pharmaceutical lead
in accurately predicting aqueous solubility in silico, generation.99
high-throughput experimental determination of Many processes in the human body have evolved
aqueous solubility is in great demand. Chen et al.95 to regulate the transport of various molecules, cells, or
evaluated a method using a multi-wavelength UV particles across epithelial barriers. To take advantage
plate reader and disposable 96-well UV plates for of this biology, total gene expression analysis (TOGA)
fast solubility determination. In addition to excellent gene expression profiling, a systematic multistep pro-
sensitivity and reproducibility, a UV plate reader cess, was used to identify receptor or transporter
method also offers the flexibility of being able to molecules to target delivery vehicles for transport
determine thermodynamic solubility in the presence across an epithelial barrier.100 Discoveries made by
or absence of dimethyl sulfoxide, a solvent widely this process will provide targets for development of
used for combinatorial compounds during HTS.95 new vaccines and new insights into the biology of
According to the previous analysis, the solubility transepithelial transport.
(Sw ), melting point (mp), and permeability are related The number of diabetic patients has recently been
using equation (5.5)96 increasing worldwide. In many cases, diabetes is
asymptomatic for a long period and the patient is
log Sw ≈ − log P − 0.01 mp + 1.05
(5.47) not aware of the disease. Therefore, the potential
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Pharmaceutical Chemistry | 119

biomarker(s) leading to the early detection and/or The focus on drug reprofiling as a new strategy
prevention of diabetes mellitus should be identified. for drug discovery and development is a way to iden-
The biomarker candidates related to diabetes mellitus tify new treatments for diseases.105 In this strategy,
were recently extracted from a multivariate statistical the actions of existing medicines, whose safety and
analysis (orthogonal partial least squares discriminant pharmacokinetic effects in humans have already been
analysis) followed by a database search. N-Acetyl-l- confirmed clinically and approved for use, are exam-
leucine is an endogenous compound found in all ined comprehensively at the molecular level and the
biological specimens (plasma, hair, liver, and kidney) results used for the development of new medicines.
and appears to be a potential biomarker candidate This strategy is based on the fact that we still do
related to diabetes.101 Several drugs have been with- not understand the underlying mechanisms of action
drawn from the market or received black box labeling of many existing medicines, and as such the cellu-
following clinical cases of QT interval prolongation, lar responses that give rise to their main effects and
ventricular arrhythmias, and sudden death. Other side-effects are yet to be elucidated. To this extent,
drugs have been denied regulatory approval because identification of the mechanisms underlying the side-
of their potential for QT interval prolongation. Since effects of medicines offers a means for us to develop
clinical arrhythmia risk is a major cause for com- safer drugs. The results can also be used for developing
pound termination, preclinical profiling for off-target existing drugs for use as medicines for the treatment
cardiac ion channel interactions early in the drug dis- of other diseases. Promoting this research strategy
covery process has become common practice in the could provide breakthroughs in drug discovery and
pharmaceutical industry. An assay development for development.106
three cardiac ion channels was demonstrated as a
reliable pharmacological profiling tool for cardiac ion Drug formulation screening
channel inhibition to assess compounds for cardiac One of the major changes in the pharmaceutical indus-
liability during drug discovery.102 try has been the integration of development activities
Combinatorial, automated HTS of small into the early phases of drug discovery. The goal of
molecules has revolutionized modern drug dis- this paradigm shift is the prompt identification and
covery.103 By using these methods, a library of 2350 elimination of candidate molecules that are unlikely
structurally unique, degradable, cationic polymers to survive later stages of discovery and development.
has been synthesized. High-throughput cell-based The growing role of computational methods in this fil-
screening identified 46 new polymers that transfected tering process has been reported.107 In the context of
with a higher efficiency than conventional nonviral preformulation and formulation, predictive analyses
delivery systems, such as poly(ethyleneimine).103 are related to the physical chemical characterization
Each branch in complex macromolecules, such as of the preferred solid states of the active pharmaceu-
low-density polyethylene (LDPE), can have a wide tical ingredient (API), optimal formulation variables,
range of molecular weights and can be positioned and process parameters. To genuinely enhance the
arbitrarily along other branches, so the number of API’s physicochemical properties for targeted formu-
distinct species within an LDPE melt is extremely lation, a good knowledge of all possible salt forms
large. If the molecular species in such a melt cannot and polymorphs is required.
even be fully inventoried, how can one hope to The physicochemical characterization of the solid
model its flow properties (rheology), which depend state of new drug substances in development requires
on how these branches tangle? As a step in solving the isolation of all forms to be considered first. The
such limitations, prediction of the real flow of a most important task is the selection of the best sol-
polymer by making simplifying assumptions about vent for the salt generation48 and early recognition of
the distribution of branches and how they transfer the thermodynamically stable form.49 For example,
force through the molecule have been reported.104 it has been reported that an organic solvent may
These ongoing efforts may lead to better profiling adversely influence the ionization of drug due to a
of pharmaceutical inactive ingredients functionalities decrease in dielectric constant as compared to water.
based on physicochemical properties. While assessing the influence of organic solvents on
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120 | An Introduction to Pharmacy

salt formation of drugs, one should consider their polyethylene glycol (PEG) is used to reduce pro-
effects on the ionization of counterion species used. tein solubility in a quantitatively definable manner.
For example, in forming salt of a basic drug with Utilizing an automated, high-throughput system, an
a carboxylic acid, the organic solvent may not only immunoglobulin in a variety of buffer conditions was
decrease the pKa of the base, it may also increase the exposed to increasing concentrations of PEG and the
pKa of the conjugate acid compared with its value amount of protein remaining in solution was deter-
in water. This will have a negative impact on salt mined. Based on these comparisons, it was concluded
formation.108 The selection of this thermodynami- that rapid, high-throughput determinations of relative
cally stable form is generally preferred since it allows a protein solubility profiles can be used as a practical,
robust manufacturing process and delivers a constant experimental tool to compare monoclonal antibody
quality for the manufacturing of the drug product. preparations and to rank order buffer and pH condi-
However, the stabilization of metastable forms, and tions during formulation development.115
especially the amorphous state, increases the challeng- To accelerate the choice of appropriate excipients
ing task of development. The solid properties of the in drug microencapsulation process, coarse-grained
salt forms and polymorphs have to be studied in a computer simulations of polymer–drug interactions
thermodynamic and kinetic context. Highly sophis- to study the encapsulation of hydrophobic drugs (e.g.,
prednisolone, paracetamol) and hydrophilic drug (iso-
ticated automated combined analysis techniques and
niazid) have been performed. The comparison of these
modeling tools are required to achieve this goal.109
simulations with experimental data showed good
To increase the success rate of the drug product
correlation with these data for hydrophobic encapsu-
on the market, it is preferable to examine experimen-
lation within polylactide microspheres and predicted
tally the contribution of salt/crystal screening and
the experimental data within certain concentration
formulation study as early as possible in the drug
limits (e.g., paracetamol levels exceeding 5 mg/mL).
discovery/development process. High-throughput
However, the mesoscale technique was unable to
formulation screening (HTFS) methods can enable
model the hydrophilic drug encapsulation.116
this,110,111 and have been recently reported in the
Molecular dynamics simulation was recently
literature.112,113 For example, the formulation of
combined with docking calculations to model and
protein drugs is a difficult and time-consuming
predict polymer–drug interactions in self-assembled
process, mainly due to the complexity of protein
nanoparticles consisting of ABA-type triblock copoly-
structure and the very specific physical and chemical mers, where A-blocks are PEG units and B-blocks are
properties involved. Understanding protein degra- low-molecular-weight tyrosine-derived polyarylates.
dation pathways and the factors affecting solubility The model compounds tested were nutraceutical
is essential for the success of a biopharmaceutical curcumin, the anticancer drug paclitaxel, and
drug. Basically, the HTFS platform consists of prehormone vitamin D3. The study suggests that
two parts: (1) an automated sample preparation computational calculations of polymer–drug pairs
systems for dispensing the drug and the formulation can potentially be a powerful prescreening tool in
ingredients in both liquid and powder form; and (2) drug development and optimization of new drug
sample analysis using specific methods developed for delivery systems, therefore reducing both the time
each protein to investigate physical and chemical and the cost of the process.117
properties of the formulations in microplates.114
In the biotechnology industry it is well known Degradant profiling in active pharmaceutical
that protein solubility is a critical attribute in mon- ingredients and drug products
oclonal antibody formulation development, as insol- The roles of degradant profiling in active pharma-
ubility issues can negatively impact drug stability, ceutical ingredients (API) and drug products have
activity, bioavailability, and immunogenicity. A high- been extensively reviewed118 to fulfill development
throughput adaptation of an experimental method and regulatory needs. Alsante et al.118 provided a
previously established in the literature to determine roadmap for when and how to perform studies, help-
apparent protein solubility has been described, where ful tools in designing rugged scientific studies, and
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Pharmaceutical Chemistry | 121

guidance on how to record and communicate results. With regard to quality, one should not assume
Forced degradation studies are used to facilitate the that moderate- to high-throughput assays produce
development of analytical methodology, to gain a bet- poor-quality data. One should continue to strive for
ter understanding of API and drug product stability, precise and accurate data and to implement methods
and to provide information about degradation path- that correlate well to critical drug success param-
ways and resulting products.118 Degradant profiling eters such as half-life and stability during storage.
is now possible due to advances in analytic tech- Quantity and speed continue to improve with innova-
niques such as thin-layer chromatography (TLC) and tion in parallel and integrated analytical technologies
spectroscopy. Recently, impurity profiling of phar- (e.g., liquid chromatography mass spectrometry [LC-
maceuticals by TLC has been reviewed as well.119 MS]) and should be supported. Effective decision-
Despite the current tendency in different pharma- making benefits from (1) data that provide insights
copeias for high-performance liquid chromatography for important questions (e.g., kinetics, mechanisms),
(HPLC) to be favored, TLC remains a very popu- (2) effective communication of this information, (3)
lar analytical method in the pharmaceutical industry. application of the information by integration of profil-
The possibilities of TLC in the different areas of phar- ing scientists into discovery teams, and (4) knowledge
maceutical analysis, such as process and intermediate by medicinal chemists and biologists about com-
control, illustrated by impurity testing of API and pound properties and their effects. A discovery pro-
final products have been highlighted.119 cess that effectively integrates properties (property-
Fourier transform infrared–attenuated total based design with activity–structure-based design)
reflection (FTIR-ATR) is a well-established stan- to select and optimize compounds is an ongoing
dard method used to study in vitro drug release goal.122
in semisolid formulations, drug penetration, and
influence of penetration modifiers. It is also capable
of characterizing drug effects in in vivo studies. Conclusions and perspectives
Photoacoustic spectroscopy (PAS) has been applied
to measure drug content in semisolid and solid In recent news on the jobs market,123 the indus-
formulations to determine drug penetration into try journalist Ed Silverman said that, ‘‘It’s a whole
artificial and biological membranes. The big advan- big mess the pharmaceutical industry is in, . . . It’s an
tage of this technique is the possibility of spectral unfortunate set of circumstances . The companies have
depth profiling. However, FTIR-PAS is so far limited had fewer new drugs in their product pipelines and . . .
to in vitro investigations. Raman spectroscopy can at the same time they’re facing expiring patents on the
be used to characterize the structure of colloidal biggest sellers.’’ In fact, the pharmaceutical industry
drug carrier systems. It is readily applicable to in relies mainly on long-established products for rev-
vivo studies, but such investigations must fulfill the enues; just 5% of the US$856 billion in 2010 drug
relevant laser safety guidelines. With recent technical sales was attributable to products launched within the
improvement in vibrational microspectroscopy, previous 5 years. Most importantly, the industry is
FTIR imaging shows great promise in its ability approaching what many people call ‘‘the big patent
to visualize the drug and excipient distribution in cliff’’ – the imminent expiration of a large number of
pharmaceutical formulations, such as tablets and patents, which will allow generic drug manufacturers
therapeutic transdermal systems, as well as to reveal to produce cheaper versions of blockbuster drugs. In
the mechanism of drug release. For example, macro- the US alone, the patent exclusivity of more than 110
ATR-IR images of a pharmaceutical tablet showing products is set to expire between 2012 and 2014,
the distribution of sugar, starch, and magnesium among them 14 blockbuster drugs.
stearate have been reported.120 Furthermore, this The world’s leading pharmaceutical companies
unique technique offers completely new possibilities face considerable risk to their revenue streams in the
to study the lateral diffusion of drugs.121 The topic of next 3 years. The global economic crisis that started
accelerated stability profiling in drug discovery has in late 2007 and pressure from governments and con-
been extensively reviewed elsewhere.122 sumers to lower drug prices will worsen the crisis.123
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122 | An Introduction to Pharmacy

In the same news article,123 it was also stated that Prodrugs

‘‘The era of people working for a large company for
20 to 30 years is over.’’ Some analysts viewed the The term ‘‘prodrug,’’ or ‘‘proagent,’’ was first used
research and development employees of the future by Albert124 to indicate pharmacologically inactive
working for a series of smaller research-intensive compounds that could be used to modify the physic-
innovator companies. It is also recognized that the ochemical properties of drugs to increase their use-
demand for new drugs remains, with many important fulness and/or decrease associated toxicity.125 Albert
unanswered scientific questions. This crisis warrants mentioned that the substance can be only a pro-
a new rethinking of the research and development drug if it is broken down in vivo to give the active
process in the industry. drug. Examples of this theory were phenacetin, chlo-
It was reasonably speculated that pharmaceutical ral hydrate, pamaquin, and proguanil (Fig. 5.4). This
profiling will continue to be a critical topic in this concept has been used by medicinal chemists as a tool
new era for a better and continuous integration of to solve issues with problematic drugs. Prodrugs must
genomics, proteomics, and disease dynamics taking undergo a chemical or enzymatic transformation to
circadian rhythm into consideration in cases such as the active forms and promoieties within the body to
cancer and hypertension71 to enhance drug safety and exert desired pharmacological actions (Fig. 5.5).126
efficacy and the prevention of disease. Profiling will The promoiety is not necessary for pharmacologic
contribute to the better use of available and limited activity but is carefully selected to pass on a desirable
resources with better control over production cost property to the drug, resulting in prodrug with desired
physicochemical properties. The promoiety should be
to maximize drug success rate on the market. Since
safe and rapidly excreted from the body.127
a successful profiling process requires professionals
Prodrugs can exist naturally, such as many phy-
from many disciplines (e.g., medicinal chemist,
tochemicals/botanical constituents and endogenous
formulation scientist, market analyst, clinicians,
substances, or they can be produced by synthetic or
regulators), all healthcare professionals (academics,
semisynthetic processes either intentionally as part
basic scientists, educators, or industrialists) should
of a rational drug design or unintentionally during
identify effective means to collaborate toward this
drug development.128 Release of the active drug is
common goal.
controlled and can occur before, during, or after
The regulatory systems and requirements need
absorption, or at the specific site of action within the
to be better harmonized and reinforced across the
body, depending on the purpose for which prodrug is
world by agencies such as the International Confer-
designed.129,130
ence on Harmonization, or novel global regulatory Almost all drugs have some undesirable physico-
models. To solve some of these crises of the pharma- chemical and biological properties. Their therapeutic
ceutical industry, it is reasonable to envision a new efficacy can be improved by eliminating the unde-
model of pharmaceutical companies and/or ecology- sirable properties, while retaining the desirable ones.
friendly services (for drug recycling or reprofiling) to This can be achieved through biological, physical, or
better make use of unused or old pharmaceuticals chemical means.131 The major goal in prodrug design
for new uses either to treat unmet medical needs or is to overcome the various physicochemical, phar-
for developing countries, thereby generating afford- maceutical, biopharmaceutical, and pharmacokinetic
able medications for all on global scale with a better limitations of the parent drug, which otherwise could
impact on global health and the environment. It is also hinder its clinical use.132 – 136 For example, prodrugs
anticipated the combination of vigorous and genuine provide possibilities for overcoming drug delivery
implementation of emerging concepts such as pharma- challenges, such as poor aqueous solubility, formula-
ceutical profiling, quality by design, and innovative tion, insufficient oral absorption, chemical instability,
approach to clinical trials will dramatically help to inadequate brain penetration, toxicity, and local irri-
reduce failure rates in the future. tation. Prodrugs can also improve drug targeting, and
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Pharmaceutical Chemistry | 123

(a) (b)

NH2
HN

H
N CH3 N

O
H3C O O

(c) (d)
OH
H H H
N N N CH3
Cl

OH
Cl NH NH CH3
Cl Cl

Figure 5.4 Structures of A) phenacetin, B) pamaquin, C) chloral hydrate, and D) proguanil.

in vivo
+

Prodrug
Drug Promoiety

Figure 5.5 Illustration of prodrug concept.

the development of a prodrug of an existing drug form formaldehyde. Aspirin (acetyl salicylic acid) is a
with improved properties may represent a life-cycle common non-steroidal anti-inflammatory drug used
management opportunity.137 for treatment of pain and arthritis; a less irritating
The prodrug concept has found a number of useful form of sodium salicylate.131,139 In the body, aspirin
applications in drug research and development. There is rapidly deacetylated to form salicylic acid and acetic
are a number of subcategories of prodrugs. The most acid. Aspirin and salicylic acid have been proposed as
common category is one in which additional chemi- anti-inflammatory agents.140 Acetic acid can be acted
cal substituents have been attached covalently to the on rapidly by metabolic enzymes, thus, is basically
drug molecule. Release of the free drug is then accom- a non-toxic by-product.141 Prontosil is an example
plished either enzymatically or chemically.137 Earlier of an accidental prodrug. It is the first commercially
examples of prodrugs include methanamide (hexam- available antibacterial antibiotic and a prodrug of
ine), aspirin, and prontosil (Fig. 5.6).138 Methanamide sulfanilamide. Prontosil is inactive as an antibacte-
was used in 1899 as a urinary tract prodrug that rial, but it is turned in vivo to pharmacologically
delivers the antibacterial formaldehyde. It is a stable, active sulfanilamide by the enzyme azo reductase.
inactive compound at pH greater than 5. However, These studies led to discovery of the sulfonamides as
in acidic environment, the compound disintegrates to antibacterial agents.127
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124 | An Introduction to Pharmacy

aqueous solubility and stability, adequate lipophilic-

(a)
N ity, sufficient safety, and reasonable conversion to
H+, urine the parent drug in vivo. Unmet needs that require
N N 4NH3 + 6CHOH
N Formaldehyde addressing remain, for example, with respect to pro-
tein and macromolecular drug delivery. Wide-ranging
Methanamide
research in this field and a growing knowledge of
(b)
Prontosil
drug delivery should generate more new marketable
prodrugs in the future.
H2N N N SO2NH2

NH2 Azo reductase Fundamentals of medical

radionuclides
H2N NH2 + H2N SO2NH2
Applications of radionuclides in medicine
NH2
Sulfanilamide and pharmacy
(c)
Radium has the distinction of being the first radionu-
COOH COOH
O Esterases clide used in medicine, employed as early as 1901.
+ CH3COOH
This nuclide was the most important medical radionu-
O CH3 OH

Salicylic acid Acetic acid clide in use until approximately 1946, when artificially
Acetyl salicylic acid
produced radionuclides became available in quantity.
Figure 5.6 In vivo conversion of A) methanamide, B) Since that date, growth in the medical applications
prontosil, and acetyl salicylic acid to their active compounds. of radionuclides has been very rapid, as their useful-
ness has become more and more apparent in medical
diagnosis, therapy, and research and as greater num-
There are currently a number of prodrugs in bers of physicians and other scientific personnel have
clinical trials. Classification can be based on the ther- been trained in their use. Current medical procedures
apeutic categories; for example, anticancer, antiviral, employ more than 50 radionuclides in a wide variety
antibacterial, non-steroidal anti-inflammatory, car- of chemical and physical forms.
diovascular, etc., or based on the categories of moiety Other than for basic research, radionuclides are
that attach to the active drug; for example, esters, used in medicine and pharmacy in two different ways:
carbonates and carbamates, amides, and oximes as (1) sealed radiation sources or (2) radiopharma-
prodrugs;142 – 144 or based on the delivery method; ceuticals.
for example, oral, topical, or parenteral delivery. As sealed radiation sources, their principal roles
There are a number of ways that drugs can be are in (1) therapy and (2) calibration of radiation
modified. What is necessary is that the parent drug has detection instrumentation. For therapy, the choice of
a functionality that is amenable to modification. Func- the radionuclide for a given application is governed
tional groups that are amenable to prodrug design largely by the properties of the radiation required for
include carboxylic, hydroxyl, amine, phosphate, and treatment; the type and energy of the radiation and
carbonyl groups. Modifications of these groups can range in tissues are prime considerations. For ther-
lead to esters, carbonates, carbamates, amides, phos- apeutic applications, the radiation sources are either
phates, and oximes. This creates the prodrugs that (1) externally beamed into cancerous tissue (telether-
can provide drug release triggered by esterases, phos- apy) or (2) implanted in the form of seeds, wires,
phatases, proteases, hypoxia, pH changes, reducing, or ribbons (or other physical forms) within, or in
oxidizing, and light conditions.137 proximity to, cancerous tissue for specified periods of
Prodrugs are usually used with the aim of increas- time (brachytherapy). For these purposes, the chem-
ing drug permeation by enhancing lipophilicity or ical properties or chemical form of the radionuclide
water solubility. The prodrug must display enough are relatively unimportant. Likewise, for calibration
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Pharmaceutical Chemistry | 125

purposes, the nature of the radiation emitted is usually Fision by-products

pertinent, whereas the chemical properties are not. Fission is a radioactive process in which a relatively
A radiopharmaceutical is a preparation, intended heavy nucleus is divided into two new nuclei of nearly
for in vivo use that contains a radionuclide in the equal size with the simultaneous emission of two or
form of a simple salt or a complex. It may exist as three neutrons. Fission may be spontaneous, but the
a solid, liquid, gas, or pseudogas. The chemical and reaction is normally induced by bombardment of the
physical identity and form of a radiopharmaceuti- parent nucleus with a neutron:
cal are very important, because, in each case, once
235 1
administered, the radiopharmaceutical is intended to 92 U + 0n → X + Y + 2.5 10 n,
target certain tissues, binding sites and/or biochemical
pathways. Depending on its specific physicochemical where X and Y are fission products (new nuclei)
and radiation properties, a radiopharmaceutical can with a Z value between 30 and 65 and a sum of
be used for either diagnostic or therapeutic purposes, 92. Fission reactions may be self-sustaining. For each
and, in a few cases, both. For diagnostic applications, neutron consumed, an average of 2.5 new neutrons
a radiopharmaceutical should not be pharmacologi- are produced that may initiate the fission of other
cally active, in that it should not produce a physiologic nuclei. Such a reaction is called a chain reaction. If
effect. It is administered in extremely small (tracer) at least one of the 2.5 neutrons produced is used to
quantities, so it does not alter the physiologic or sustain the reaction, the reaction is said to be critical.
pathophysiologic process being measured. The nature The following illustrates one of many combina-
of the radiation emitted by a diagnostic radiopharma- tions of fission reactions that are possible:
ceutical is important, primarily for its ease of detection 238
92 U +10 n →131 106 1 1
50 Sn + 42 Mo +0 n +0 n.
(i.e., to obtain an image or other diagnostic data).
Conversely, for a therapeutic radiopharmaceutical, The 131 Sn and the 106 Mo are very radioactive and
the type and energy of the radiation, as well as its have very short half-lives. They immediately decay by
range in tissues, are very important considerations, as a series of beta decay processes:
was the case with sealed sources used for therapy. A
131 131 131 131
radiopharmaceutical preparation designed for thera- 50 Sn → 51Sb → 52Te → 53I
106 106 106 106
46 Mo → 43Tc → 44Ru → 45Rh.
peutic purposes must contain enough radioactivity to
produce the intended tissue effects.
The development, evaluation, preparation, test- Both 131 I and 106 Ru are available commercially as
ing, and clinical use of radiopharmaceuticals have led fission-produced radionuclides, although 106 Ru is not
to the introduction of the specialty disciplines, known routinely used for medical applications.
as nuclear medicine and nuclear pharmacy. In the Before use, the desired nuclide must be chemically
United States alone, practitioners in these specialties separated from a large number of other fission-
are responsible for the care of approximately 40,000 produced radionuclides. For many of the radionu-
to 50,000 patients each day, on average. clides produced by fission, separation of the desired
nuclide from the mixture of fission products is too
difficult or costly.

Production of radionuclides Neutron reactions

Most, if not all, radionuclides used in medicine and Many radioactive nuclides used in radiopharmaceu-
pharmacy are produced artificially. Table 5.22 is a ticals are prepared by neutron activation (n, λ) or
compilation of medical radionuclides along with their transmutation (n, p) reactions, by placing a suit-
physical properties. These radionuclides are produced able target material in a nuclear reactor, where it
by three general methods: (1) as a fission by-product is bombarded by neutrons. By means of (n, λ) and
in a nuclear reactor; (2) as the product of a neutron (n, p) reactions, reactors produce radionuclides hav-
reaction – either by activation or transmutation; and ing a high neutron-to-proton ratio that typically decay
(3) by use of a particle accelerator, such as a cyclotron. by emission of a negatron. For example, radioactive
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126 | An Introduction to Pharmacy

Table 5.22 Physical characteristics of radionuclides commonly used in medicine

Nuclide Common Half-life Decay mode Principle emissions Gamma ray

production (MeV) constant
(R/mCi hour at 1 cm)

11 C 14 N(p, α )11 C 20.4 minutes β+ 0.97 β + (100%) 5.9

0.511 γ (200%)

13 N 16 O(p, α )13 N 10.0 minutes β+ 1.2 β + (100%) 5.9

0.511 γ (200%)

14 C 14 N(n, p)14 C 5730 years β− 0.156 β − (100%)

15 O 14 N(d, n)15 O 2.05 minutes β+ 1.74 β + (100%) 5.9

0.511 γ (200%)

18 F 18 O(p, n)18 F 110 minutes β + , ECa 0.635 β + (97%) 5.7

0.511 γ (194%)

32 P 31 S(n, p)32 P 14.3 days β− 1.71 β − (100%)

51 Cr 50 Cr(n, γ )51 Cr 27.8 days EC 0.320 γ (9%) 0.18

57 Co 56 Fe(p, γ )57 Co 271 days EC 0.014 γ (9%) 0.57

0.122 γ (86%)

0.136 γ (10%)

60 Co 59 Co(n, γ )60 Co 5.27 years β− 0.31 β − (99%) 13.2

1.173 γ (100%)

1.332 γ (100%)

67 Ga 68 Zn(p, 2n)67 Ga 78.3 hours EC 0.093 γ (38%) 1.6

0.184 γ (20%)

0.300 γ (16%)

0.394 γ (5%)

68 Ga 68 Ge daughter 68.3 minutes β + , EC 1.9 β + (88%) 5.4

0.511 γ (176%)

81m Kr 81 Rb daughter 13 seconds ITa 0.191 γ (66%) 1.6

(continued overleaf)
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Pharmaceutical Chemistry | 127

Table 5.22 (continued)

Nuclide Common Half-life Decay mode Principle emissions Gamma ray

production (MeV) constant
(R/mCi hour at 1 cm)

82 Rb 82 Sr daughter 75 seconds β + , EC 3.15 β + (96%) 6.1

0.511 γ (192%)

89 Sr 88 Sr(n, γ )89 Sr 50.5 days β− 1.46 β − (100%)

90 Y 90 Sr daughter 64 hours β− 2.27 β − (100%)

99 Mo fission 2.75 days β− 0.45 β − (18%)

1.23 β − (82%) 1.8

0.181 γ (6%)

0.74 γ (13%)

0.778 γ (5%)

99m Tc 99 Mo daughter 6.02 hours IT 0.140 γ (89%) 0.7

111 In 112 Cd(p, 2n)111 In 67.3 hours EC 0.171 γ (90%) 3.2

0.246 γ (94%)

123 I 127 I(p, 5n)123 Xe 13.2 hours EC 0.159 γ (83%) 1.6

daughter

0.127 x (71%)

125 I 124 Xe(n, γ )125 Xe 60.2 days EC 0.036 γ (7%) 1.4

daughter

0.027 x (110%)

131 I fission 8.04 days β− 0.61 β − (90%) 2.2

0.284 γ (6%)

0.364 γ (82%)

0.637 γ (7%)

133 Xe fission 5.25 days β− 0.35 β − (100%) 0.5

0.081 γ (36%)

0.031 x (39%)

(continued overleaf)
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128 | An Introduction to Pharmacy

Table 5.22 (continued)

Nuclide Common Half-life Decay mode Principle emissions Gamma ray

production (MeV) constant
(R/mCi hour at 1 cm)

137 Cs fission 30 years β− 0.51 β − (94%) 3.3

1.18 β − (6%)

0.662 γ (84%)

153 Sm 152 Sm(n, γ )153 Sm 46.3 hours β− 0.640 β − (30%) 0.9

0.71 β − (50%)

0.81 β − (20%)

0.103 γ (29%)

186 Re 185 Re(n, γ )186 Re 3.72 days β − , EC 1.07 β − (77%) 0.08

0.93 β − (23%)

0.137 γ (9%)

201 Tl 203 Tl(p, 3n)201 Pb 73 hours EC 0.135 γ (3%) 0.47

daughter

0.167 γ (10%)

0.07 × (94%)

0.08 × (20%)

a EC, electron capture; IT, isomeric transition.

phosphorus (32 P) can be prepared from stable phos- In this case, the radioactive phosphorus can be sep-
phorus (31 P) by neutron capture: arated from the unreacted sulfur by chemical proce-
dures. Where 32 P is made from 31 P, such chemical
31
+ 1
→ 32
+ γ. separations are not practical.
15 P 0n 15 P
Transmutation is useful for the preparation of
The disadvantage of this method is that the radioac- many radioactive nuclides, especially those of low
tive phosphorus (32 P) is highly diluted with stable 31 P. atomic number. As the atomic number increases,
Phosphorus-32 of low specific activity can be used for (n, γ ) reactions are favored over (n, p) reactions.
certain purposes, such as the investigation of phos- For example, cobalt-60 is produced by the reac-
phate fertilizers, but would be less useful for many tion 59 Co(n,γ )60 Co, because the reaction 60 Ni(n,
biological and medical applications. p)60 Co does not occur with sufficient frequency to
Radioactive phosphorus can be made by transmu- make the process commercially feasible. 125 I(t1/2 =
tation, if high specific activities are required: 60 d) is produced from 124 Xe,

124
32
+ 1
→ 32
+ 1 Xe(n, γ )125 Xe EC → 125
I.
16 S 0n 15 P 1 p.
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Pharmaceutical Chemistry | 129

Secondary neutron capture results in the side reaction 16

125 O(p, pn)15 O
I(n,γ )126 I. Because 126 I(t1/2 314 d) is an undesirable
impurity in 125 I, it is removed through its own decay. 18
O(p, n)18 F
Cyclotron-produced radionuclides 20
Ne(d, α)18 F
Certain radionuclides are cyclotron-produced. The
cyclotron and similar particle accelerators can be used 70
Zn(p, α)67 Cu
only with charged particles, such as electrons, protons,
alpha particles, or deuterons, because the operation of 66
Zn(d, n)67 Ga
such machines depends on the interaction of magnetic
and/or electrostatic fields with the charge (either + 68
Zn(p, 2n)67 Ga
or −) of the particle undergoing acceleration. When
the particles have been accelerated to a high velocity, 69
Ga(p, 2n)68 Ge
even approaching the velocity of light and repre-
senting enormous energies, they are caused to strike 82
Kr(p, 2n)81 Rb →81m Kr
a target containing the atoms to be bombarded.
Sodium-22 is prepared this way, by the interaction of 111
Cd(p, n)111 ln
high-velocity deuterons with magnesium. The nuclear
equation is 112
Cd(p, 2n)111 ln
24
Mg(d,α)22 Na. 203
Tl(p, 3n)201 Pb→201 Tl
Cyclotrons produce neutron-deficient isotopes;
Usually, a nuclide can be made by more than one
that is, the neutron-to-proton ratio is low. These
reaction. For example, 123 I can be prepared either
nuclides decay by positron emission or electron cap-
directly or indirectly. Direct reactions include the
ture. Cyclotron-produced radionuclides are carrier-
following:
free, because they are normally produced by
transmutation. 123
Te(p, n)123 I
The following reactions are typical for the
121
cyclotron production of some medically useful Sb(4 He, 2n)123 I
nuclides:
122
Te(d, n)123 I
10
B(d, n)11 C
124
Te(p, 2n)123 I.
11
B(p, n)11 C
Indirectly, the intermediate 123 Xe (or 123 Cs, which
14
N(p, α)11 C decays to 123 Xe) is prepared, which then decays to
123
I:
14
N(p, α)11 C
122
Te(3 He,2n)123 Xe → 123
I
10 13
B(α, n) N
122
Te(3 He,2n)123 Xe → 123
I
12 13
C(d, n) N
123
Te(3 He,3n)123 Xe→123 I
16 13
O(p, α) N
127
I(p,5n)123 Xe → 123
I
14 15
N(d, n) O
124
Xe(p,2n)123 Cs → 123
Xe →123 I.
15 15
N(p, n) O
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130 | An Introduction to Pharmacy

Radionuclide generators parent nuclide. Radioactive decay of the long-lived

When clinical procedures require that a radionu- parent results in the production of a short-lived
radioactive daughter nuclide that is eluted or milked
clide be administered internally, it is advantageous
from the generator, by means of an appropriate elu-
to use a nuclide with a short half-life, to minimize the
ant. Characteristics of a number of parent–daughter
radiation dose received by the patient. It is evident,
systems used in radionuclide generators are found in
however, that the shorter the half-life, the greater the Table 5.23.
problem of supply. One answer to this problem is the The molybdenum-99/technetium-99m generator
radionuclide generator, which uses the phenomenon (Fig. 5.7) consists of an alumina (Al2 O3 ) column
of sequential decay. A radionuclide generator pro- on which molybdenum-99 is adsorbed as ammo-
vides a mechanism for separating a clinically useful, nium molybdate. Radioactive decay of 99 Mo produces
99m
short half-life daughter nuclide from a long-lived Tc, which is eluted from the column with 0.9%

Table 5.23 Selected radionuclide generators

Parent isotope Half-life Daughter isotope Half-life Mode of decay

68 Ge 271 d 68 Ga 68 minutes β+

81 Rb 4.7 h 81m Kr 13 seconds ITa

82 Sr 25 d 82 Rb 1.3 minutes β+

87 Y 80 h 87m Sr 2.8 hours IT

90 Sr 28 y 90 Y 64 hours β

99 Mo 67 h 99m Tc 6.0 hours IT

109 Cd 453 d 109m Ag 39.2 seconds IT

113 Sn 118 d 113m In 1.7 hours IT

115 Cd 53.4 h 115m In 4.5 hours IT

122 Xe 20 h 122 I 3.6 minutes β+

132 Te 3.2 d 132 I 2.3 hours β−

137 Cs 30 y 137m Ba 2.6 minutes IT

144 Ce 285 d 144 Pr 17.3 minutes β−

178 W 21.5 d 178 Ta 9.4 minutes β+

191 Os 16 d 191m Ir 4.9 seconds IT

195m Hg 41 h 195m Au 30.6 seconds IT

225 Ac 10 d 213 Bi 45.6 minutes α, γ , β −

a IT, isomeric transition.

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Pharmaceutical Chemistry | 131

1.0
99
.8 Mo
Sterile
saline solution
.6

Lead .4
shield

.2

Fraction of ingrowth
99m
Tc
Lead Alumina .1
shield column .08
99
Mo
.06

.04
Frit

.02

Sterilizing
.01
filter 0 10 20 30 40 50 60 70
Time (hours)

99m
Tc
In eluate
Figure 5.8 Elution curve. The lower solid lines show the
theoretical activity of 99m Tc in the generator as a result of
Figure 5.7 Schematic diagram of a radionuclide generator in-growth followed by elution of 99m Tc at 24-hour intervals. If
for the production ob technetium-99m by elution from the generator were not eluted, in-growth would follow the
molybdenum-99 absorbed on an alumina column. broken line and a transient equilibrium would be established.
The upper solid line represents decrease in activity of 99 Mo,
the parent nuclide, due to radioactive decay.

Sodium Chloride USP. Upon elution, the 99m Tc is

in the form of sodium pertechnetate (Na99m TcO4 ). more important than in medicine and pharmacy. Drug
Elution, repeated every 24 hours, provides a sat- nomenclature, particularly, would become confusing,
isfactory balance between concentration and quan- meaningless, and incomprehensible without a well-
tity of eluted 99m Tc. If a high activity of 99m Tc is developed system of rules.
not required, the generator can be eluted more fre- It is not unusual for each drug entity to be known
quently. Figure 5.8 shows a typical elution curve by several chemical names, more than one code num-
for a 99 Mo/99m Tc generator. The generator must be ber, several trivial designations, a formally selected
replaced about once per week, due to the decay of nonproprietary name, and one or more trademarks.
99
Mo. Therefore, it is essential that a logical, well-defined
nonproprietary nomenclature system is available to
facilitate the exchange of drug information.
Drug nomenclature This section describes the mechanisms for creating
nonproprietary drug names that are used in the
Advances in the scientific disciplines continue to occur United States. It includes history, scope, function,
at such an accelerated rate that the processing of infor- and operation of the nomenclature system devised by
mation has become a separate and distinct discipline the United States Adopted Names (USAN) Council.
in its own right. Precise and current terminology A brief introduction of the liaison relationship
is an important tool of science, and nowhere is it between the USAN Council and the US Food and
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132 | An Introduction to Pharmacy

Drug Administration (FDA) and policies of the name; the numbers are assigned by the firm in an
World Health Organization (WHO) International arbitrary manner or following some internally cre-
Nonproprietary Name (INN) program are also ated convention. Codes may be acronyms or letter
included. The majority of the information in this combinations derived from portions of the chemical
section has been obtained with permission directly or common name (e.g., AZT for azidothymidine or
from the USAN Council website maintained by the TPA for tissue plasminogen activator).
American Medical Association (AMA) at http://www. Code designations usually are considered as con-
ama-assn.org/ama/pub/physician-resources/medical- venient ‘‘shop labels’’ and are meant to be discarded
science/united-states-adopted-names-council.page. when a more appropriate name is selected. However,
The authors of the current edition of this scetion many of these codes appear in early scientific literature
have edited the information provided by the authors dealing with investigative work prior to the selection
of previous editions for clarity, have provided of a nonproprietary name. Frequently they are used
updated information as necessary, and have added in clinical studies in the absence of a nonproprietary
information useful for this topic. name to identify the chemical entity. Code designa-
tions, therefore, must be considered a part of drug
Drug name types nomenclature, but they are not acceptable for general
use. In themselves, these codes give no information
The term drug nomenclature implies that drugs may about the compounds they represent.
have several types of names, each having its own func- The use of acronyms instead of the proper non-
tion, and indeed this is the case. Although some names
proprietary names may also be dangerous because
are scientifically precise, others may be ambiguous or
many contractions are extremely similar, such as
misleading.
DDI (didanosine) and DDC (zalcitabine). Similarly,
The first type of name, usually applied to com-
AZT is commonly used for the antiviral zidovudine
pounds of known composition, is the chemical name.
(derived from azidothymidine, its shortened chemical
Among the several conventions that exist for creat-
name). However, AZT can just as readily represent the
ing chemical names, the most widely established is
immunosuppressant azathioprine. Medication errors
the American Chemical Society’s Chemical Abstracts
due to use of acronyms have been reported both by
Services (CAS) Index naming system. Use of this sys-
the Institute for Safe Medication Practices and the
tem results in the creation of systematic (CAS Index)
USP Medication Errors Reporting Program.
names for chemical entities that serve as a key to the
Trivial names occasionally are assigned to a new
chemical literature of the world. The CAS system is
compound, usually by researchers working on it.
used by the USAN program.
For substances of plant or animal origin that Nomenclature agencies strongly discourage the use
cannot be classified as pure chemical compounds, of trivial names as generally they are coined hap-
scientific identification is given in terms of precise hazardly and are usually not suited for adoption as
biochemical, botanical, or zoological names. Such official nonproprietary names. Too frequently, trivial
designations are also scientifically exact, but like names are similar to existing names, which may lead
their chemical counterparts, they tend to be complex, to confusing them with established nonproprietary
unwieldy, and generally not useful to the physician, names.
pharmacist, or other users of drug nomenclature. When a new drug has successfully survived the
Most drugs acquire a code designation as a conve- successive research stages and testing to the point
nient means of referring to the compound before it has where it appears it may become a marketable prod-
been assigned either a nonproprietary name or a trade- uct, a trademark is developed by the manufacturer.
mark. Such codes are generally a letter and number Properly registered trademarks become the legal prop-
combination, such as SC-40230 (bidisomide, Searle), erty of their owners and cannot be used freely in the
Ro 4–3780 (isotretinoin, Roche), or RP 56976 (doc- public domain. Selected for their brevity and ease of
etaxel, Rhone-Poulenc Rorer). The letter(s) generally recall, trademarks usually give little or no scientific
represent an abbreviation of the research laboratory information about the drug.
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Pharmaceutical Chemistry | 133

Each type of name described thus far aims to serve CPC initiated a nomenclature program to provide
its specific purpose; however, none fulfills the need for nonproprietary names for individual drugs available
a single, simple, informative designation available for commercially under more than one trademark. This
unrestricted public use. The nonproprietary name is activity continued until the early 1940s when the
the only name intended to function in this capacity. Council on Drugs began to require a nonproprietary
The nonproprietary name often is referred to as the name for every active compound listed in all AMA
generic name, but this practice is inaccurate, as each publications.
nonproprietary name is specific for a given compound, The 1938 Food, Drug and Cosmetic (FDandC)
even though it may possess a stem that is common to Act stipulated that the common or usual name should
a related group of drugs. be used as part of drug labeling to identify the drug
Throughout this section, the term nonproprietary entity. In the absence of such a name (or until a
name applies to those names that have been selected name attained such status), a chemical name was to
by the formal process of negotiation between the drug be used.
manufacturer and the USAN Council. The Drug Amendments of 1962 replaced the
‘‘common or usual’’ terminology with the more mean-
ingful requirement that nonproprietary names must
History be ‘‘simple and useful.’’ Also, for the first time, the
Commissioner of the FDA was given the authority to
The United States Pharmacopeia (USP) has been designate the official name if he determined that such
supplying standards for pharmaceutical preparations action was necessary or desirable.
since the first edition appeared in 1820. Because there Despite the nomenclature activities of the AMA,
was a need for titles for monographs included in the USP, and APhA, large numbers of drug products did
USP that described the drugs for which standards not become the subject of either the NF, the USP, or
were being prepared, the USP was one of the first the Council on Drugs monographs and continued to
publications to recognize the necessity for a standard- be identified by their chemical names, trivial names,
ized system of drug nomenclature and the first to take or trademarks selected by the manufacturers. As
action to establish such a system. medicine and pharmacy advanced and drugs became
The American Pharmacists Association (APhA) more specific in their actions and structurally more
began publication of a second compendium, the complex, other nomenclature-related needs were rec-
National Formulary (NF) in 1888 and established ognized that made it apparent that each new drug
quality standards for drugs included in the NF. The needed a nonproprietary name selected early in its
editor of the NF quickly became involved with pro- development. A systematic approach to assure drug
viding nonproprietary names for the monographs name appropriateness and acceptability to AMA,
published in the NF. USP, NF, and the drug manufacturer now became
In 1906, the US government legally recognized more obvious. Each new drug also needed a global
the significance of the work being done by the USP name – one name used and accepted worldwide.
and the NF by declaring both publications official A significant step toward supplying this need was
compendia. Since that time, monograph titles have taken in June 1961, with the formation of the AMA-
had the status of official nonproprietary names. USP Nomenclature Committee. The names adopted
As new pharmaceutical products increased in by this committee were deemed acceptable as poten-
number, other organizations recognized the need for tial compendia monograph titles, and the acronym
formally approved names while the drug entity was USAN (United States Adopted Name) was coined to
still in its investigational stages. The AMA Council designate names formally processed and approved by
on Pharmacy and Chemistry (CPC), later known as the Committee. The APhA participated in the pro-
the Council on Drugs, was created in 1905 as an gram from its inception but did not become a full and
advisory body to the Board of Trustees to encour- official sponsor until January 1964, at which time the
age rational drug use by physicians. In conjunction name of the committee was changed to the USAN
with screening and evaluating new remedies, the Council.
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134 | An Introduction to Pharmacy

The USAN council The USAN Review Board Secretariat is supported

by the USP. At the time of any appeal to the Board,
The agency responsible for the selection of nonpropri-
representatives of the drug firm involved in the spe-
etary names for single-entity drugs marketed in the US cific case can participate in the deliberations, but they
is the United States Adopted Names (USAN) Coun- have no voting privileges. The USAN Council Secre-
cil. This expert committee on drug nomenclature is tariat becomes the spokesperson for the Council. The
jointly sponsored by the AMA, the USP, and APhA. determination of the USAN Review Board is final and
All three agencies were involved in the selection of not subject to appeal.
drug names for many years prior to the establish- The USAN Council Secretariat is located at the
ment of the USAN Council in the 1960s. The aim of AMA headquarters in Chicago, Illinois. The agency
USAN is the global standardization and unification works closely with the WHO INN Committee, and
of drug nomenclature and related rules to ensure that various national nomenclature groups. In addition,
drug information is communicated accurately and the USAN program has liaison organizations all over
unambiguously. The Council conducts its negotiation the world. These organizations include the following:
activity by correspondence. Twice a year, the Coun-
cil convenes to discuss nomenclature policy, liaison
activity, and new nomenclature strategies. Chemical abstracts service
Today, the USAN Council comprises of five mem- 2540 Olentangy River Road, P.O. Box 3012, Colum-
bers: one member is appointed by each of the three bus, OH 43210
sponsoring organizations, one is a liaison member
from the FDA, and one is a member-at-large who must
be approved by the three sponsoring organizations. WHO INN program manager
Council members are nominated by their sponsoring
World Health Organization, Avenue Appia 20, 1211
organizations annually. Every year their nominations
Geneva 27, Switzerland
must be approved by the boards of trustees of the
other sponsoring organizations, who also approve
the nominees for the FDA liaison and the member-at- Belgium
large positions. Council members may serve for up to
10 consecutive years. L’Inspecteur en chef-Directeur, Ministère de la Santé
At an early stage in the development of the Publique et de l’Environement, Inspection générale de
USAN Council, it was anticipated that occasional la Pharmacie, Cité administrative de l’Etat, Quartier
disagreements might arise between the Council and Vésale 333 B1010, Bruxelles Belgium
a manufacturer over the selection of a particular
nonproprietary name. In the majority of such cases,
China
the Council and the firm can, in time, work out an
acceptable compromise. However, in rare instances, The Deputy Chief, Drug Standard Division II, The
an impasse may develop that needs adjudication by Chinese Pharmacopeia Commission, Ministry of
someone not directly involved with the USAN Council Health, Temple of Heaven, Beijing 100050, People’s
or the drug manufacturer. The USAN Review Board Republic of China
was established as the final arbitrator of nomencla-
ture disputes when normal procedures have failed.
Each sponsoring organization nominates two mem- France
bers to the Review Board annually; nominations must DCF – Dénominations Communes Françaises,
be approved annually by the Boards of Trustees of Agence du Médicament, Direction des Laboratoires
the other sponsoring organizations. No term limits et des Controles, Unité Pharmacopée, 145–147
have been placed on member’s participation on the boulevard Anatole France, F-93285 Saint-Denis
Review Board. Cedex, France
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Pharmaceutical Chemistry | 135

Hungary Human Services published in the Federal Register an

amendment to the FDandC Act that stated in part
Director-General, National Institute of Pharmacy,
that ‘‘ . . . the Food and Drug Administration agrees
P.O. Box 450, 1372 Budapest 5, Hungary
with ‘‘Guiding Principles for Coining US Adopted
Names for Drugs,’’ published in USAN and the USP
Italy Dictionary of Drug Names . . . ‘‘and that . . . the
established name . . . will ordinarily be either the
DCIt – Commission – Denominazione Communi
compendia name of the drug or, if there is no com-
Italiane, Director-General, Pharmaceutical Division,
pendia name, the common or usual name of the drug.
Ministero della Sanità, Viale della Civiltà Romana 7,
Interested persons, in the absence of the designation
I-00144 Roma, Italy
of an official name, may rely on the USAN listed in
USAN and the USP Dictionary of Drug Names as
Japan being the established name in accordance with the
JAN –Japanese Accepted Names, Japanese Ministry Federal Food, Drug, and Cosmetic Act.’’
of Health and Welfare, New Drugs Division, Phar- The FDA also plays a role when a manufacturer
maceuticals Affairs Bureau, 1-2-2, Kasumigaseki, seeks to register a trademark (proprietary name) for
Chiyoda-ku, Tokyo 100, Japan a drug entity that has been assigned a USAN. Within
the Center for Drug Evaluation and Research (CDER)
of the FDA, the Office of Surveillance and Epidemi-
United Kingdom ology (OSE) within the Division of Medication Error
BAN – British Approved Names, The Secretary, Prevention and Analysis (DMEPA) reviews proposed
British Pharmacopoeia Commission, Market Tow- proprietary names. DMEPA consults with the Divi-
ers, 1 Nine Elms Lane, London SW8 5NQ, United sion of Drug Marketing, Advertising, and Communi-
Kingdom cations (DDMAC) and receives input from pertinent
disciplines involved with the review of the appli-
cation and determines the acceptability of proposed
USAN council and FDA Liaison proprietary names. In reviewing proposed proprietary
The USAN Council and the FDA conducted an unof- names, both promotional and safety aspects of a name
ficial liaison until early 1967 when it was determined are considered.
that a formal cooperative effort in the development
of nonproprietary names would be more beneficial to
WHO and international nonproprietary
both. In June 1967, an official agreement was signed
names
between the sponsors of the USAN Council and the
FDA to appoint annually one voting member to the The USAN Council functions primarily to serve the
Council. This contract stipulated that the FDA would health professions in the United States. However, at a
accept as the ‘‘official or established’’ name any drug time when drug manufacturers market their products
name the USAN Council adopted. In this agreement, in many countries and medical and pharmaceutical lit-
the Commissioner of the FDA reserved the right to erature is widely translated around the world, the need
select the official name in those instances in which the for cooperation in nomenclature activities among the
USAN Council could not reach consensus. It should major drug-producing countries clearly is evident.
be noted that the designation of a name as an ‘‘offi- To prevent the confusion that arises when sev-
cial or established’’ name by the FDA did not follow eral nonproprietary names are used for a single drug,
automatically but was accomplished by publication, either in the same country or in different countries, the
subject to public comment, in the Federal Register. WHO has assumed the responsibility for coordinating
All parties upheld this agreement until it was modified drug nomenclature at the international level. In 1915
17 years later. the International Pharmaceutical Federation estab-
On November 26, 1984, the Commissioner of lished a Committee on International Nomenclature
Food and Drugs and the Secretary of Health and and assigned it the responsibility for identifying each
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136 | An Introduction to Pharmacy

pharmaceutical substance by a globally available and proposal. An objection generally reflects a belief that
unique nonproprietary name. The WHO Constitution the proposal is confusingly close to (i.e., conflicts with)
in 1946 relegated the duty of drug nomenclature to the a name already in use. If no objection is received, the
WHO. By 1953, the WHO initiated the selection and proposed INN will attain the status of recommended
publication of INNs for pharmaceutical substances. INN. Subsequently, WHO will publish the name as a
The present INN Program is administered by ‘‘recommended International Nonproprietary Name
the INN Program Manager in Geneva, Switzerland. (rINN).’’ The WHO publishes lists of rINN on a bian-
Nonproprietary names are selected biannually by nual basis. Many member states then recognize the
members of the WHO Expert Advisory Panel on rINN as the sole or preferred nonproprietary name
the International Pharmacopoeia and Pharmaceuti- for use in their respective countries.
cal Preparations. This advisory panel is composed of A cumulative list of INNs and the guidelines
representatives from national nomenclature groups. for coining an INN (INN for Pharmaceutical
Through its Committee on Nonproprietary Substances) can be obtained from the WHO
Names, whose members are drawn from repre- in Geneva, Switzerland or on their website at
sentatives of the national nomenclature agencies, www.who.int/medicines/services/inn/en/. The INN
WHO has developed procedures and formulated Cumulative List now contains more than 7000 names
guiding principles for the selection of INNs. National for drug entities. The INN Committee adds 120 to
nomenclature agencies usually act as agents for the 150 new designations each year.
drug manufacturers by referring mutually selected Guidelines on the Use of International Non-
designations (usually prior to national adoption) to proprietary Names (INNs) for Pharmaceutical
the WHO with a request that these names be selected Substances is available online at: http://whqlibdoc.
as an INN. who.int/hq/1997/WHO_PHARM_S_NOM_
A drug manufacturer located in a country with- 1570.pdf.
out a nomenclature agency is permitted to make a
direct submission for a nonproprietary name to the
Procedure for obtaining a USAN
INN Committee or, alternatively, to an established
nomenclature agency in another country, preferably The criteria set by the USAN Council for initiating
a country in which the pharmaceutical preparation is the process for selection of a USAN states that if a
likely to be marketed. substance is regarded as an Investigational New Drug
INNs are selected for substances that can be (IND) within the terms of the federal Food, Drug and
characterized unequivocally by a chemical name or Cosmetic Act, selection of a USAN should begin dur-
formula, and exceptions to this rule are rare. The ing clinical trials, so that the USAN will be adopted
INN is designated for the active part of the molecule before the relevant New Drug Application (NDA)
only. The INN Program does not select names for is filed. USAN application forms may be obtained
mixtures or herbal substances. online at www.ama-assn.org/ama/pub/physician-
The process of INN selection is similar to that resources/medical-science/united-states-adopted-
utilized to select a USAN. After the manufacturer names-council.page or by writing to the USAN
submits an application, review and objections periods Secretariat at AMA Headquarters, 515 N State
are followed by selection of the INN. Details of the Street, Chicago, IL 60654.
process are explained below. In practice, firms usually apply for a USAN when
Under its charter, the WHO is empowered simply the investigational therapy is in Phase I or Phase II
to recommend specific actions or procedures to its clinical trials. By then the sponsor’s patents or intel-
Members States. The WHO INN Committee initially lectual property covering the substance are in place,
publishes in WHO Drug Information the selected and it is early enough in clinical trials that the risk of
names as ‘‘proposed International Nonproprietary not having a name for the NDA is low. The earliest
Names (pINN).’’ From the date of publication, four time that US firms may request a USAN is during
months are allowed for member states or other inter- Phase I clinical studies. The typical time for US firms
ested parties to submit comments or objections to any to apply for a USAN is during Phase II clinical studies.
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Pharmaceutical Chemistry | 137

Before most USANs are adopted, three parties stem assignment requested by the applicant are per-
(i.e., the sponsor, the USAN Council and the INN formed. A ballot is prepared with the firm’s proposed
Expert Group) must accept the name. This process names and alternative suggestions, if any, and any
is facilitated by the USAN Program staff. All negoti- conflicts with nonproprietary or proprietary names
ations are conducted throughout the year by USAN are noted for the USAN Council.
Council member correspondence and electronic bal- Next, the USAN Council reviews the names.
loting or at either of the biannual USAN meetings, Review criteria include absence of conflicts with non-
typically occurring in January/February and July. The proprietary or proprietary names, appropriate use
purpose of these meetings is to review and set pol- of the nomenclature scheme, and usefulness of the
icy, review the INN Expert Group decisions, discuss proposed names to the healthcare providers. Names
multiple-round negotiations and address negotiations too similar to existing nonproprietary or propri-
where a consensus has not yet been reached. New etary names are rejected. The FDA’s opinion on the
negotiations are accepted on a space-available basis. proposed name(s) is sought through the FDA rep-
When considering an acceptable name the follow- resentative on the USAN Council. When consensus
ing criteria are constantly kept in mind by the USAN is reached, USAN Program staff forwards the name
Council: usefulness to healthcare providers, patient selected to the firm.
safety, adherence to the nomenclature rules, absence After the USAN Council completes deliberation
and recommends a name, it is sent to the sponsor
of conflicts with existing names, suitability for use
for acceptance or rejection. Once the USAN Coun-
internationally, ease of pronunciation, and other fac-
cil recommendation letter is sent to the applicant,
tors. The USAN Council does not choose names based
the name under consideration is published online on
on specific marketing considerations.
the USAN website for public comment. If the firm
Immediately after receiving a submission, the
accepts the name, it proceeds through international
USAN Program Secretariat verifies that the applica-
review before adoption as a USAN. When accepting a
tion is complete (payment must be received) and that
name, the applicant will need to notify their assigned
the substance meets all prerequisites to apply. Two
negotiator and, depending upon the type of submis-
important requirements are that the substance has
sion, include a check made out to WHO for their
entered clinical trials and has an IND number. If the
application fee and to process the submission through
requirements are met the submission is considered a
the WHO-INN Expert Group to ultimately receive a
complete application.
recommended INN (rINN).
Each complete application is assigned a file num-
When rejecting a name, the notification must
ber and a USAN Program staff member as the ‘‘nego- include new name suggestions for the USAN Council
tiator.’’ The negotiator serves as the manufacturer’s and explain the reasons for rejection. Rejection leads
contact for all questions and correspondence. Fol- to another round of review by the negotiator and
lowing assignment of these, the applicant receives the USAN Council and can add about six months
an acknowledgment letter, which confirms receipt of to the timeline. The applicant should carefully weigh
the submission and application fee, and includes the whether to reject the name and subsequently delay
USAN file number and the name of the assigned adoption. The negotiator will review potential alter-
negotiator. native suggestions before they are submitted to the
Before submitting an application to the USAN USAN Council, as this will expedite further ballot-
Council, the negotiator verifies the chemical informa- ing. When an alternative is finalized, the negotiator
tion listed on the application and searches databases prepares a new ballot accompanied by the sponsor’s
for drug information. The negotiator determines how letter describing reasons for rejecting the names and
the drug may be classified using the nomenclature any new supporting information. If the USAN Council
scheme and whether the proposed names appropri- deems a proposed name unacceptable due to con-
ately reflect its action. A detailed check to verify that flicts or patient safety concerns, the name will not be
the submitted names are free of conflicts with nonpro- reconsidered. If a new stem is deemed unacceptable,
prietary or proprietary names and an analysis of the additional, new data and information are required
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138 | An Introduction to Pharmacy

to support the case for a new stem. New stems are of each month. A letter and adoption statement for-
assigned only when no existing stem is appropriate. mally notify the applicant that the negotiation has
Additional rounds of USAN Council balloting are been completed and a USAN assigned. A firm may
conducted as many times as necessary to reach an begin using a USAN when it receives an adoption
acceptable name. There is no charge for additional statement. There is no need to wait until publication,
rounds of balloting. which would normally occur 60 days later. Upon
At the completion of the USAN Council review publication the adoption statement is published on
and after a name is accepted, the USAN Program staff the USAN website and forwarded to both USP for
request an INN on behalf of the sponsor (depending inclusion in the USP Dictionary of USAN and Inter-
on the type of submission). The INN Expert Group, national Drug Names and CAS for inclusion in their
which is composed of scientists and regulatory experts databases. Internationally, names are published twice,
from around the world, reviews and accepts the pro- as proposed INN and recommended INN, in the jour-
posed name, or suggests an alternative. INN review nal WHO Drug Information. A firm may request a
criteria include conflicts with non-US nonproprietary publication deferral for up to six months.
names or trademarks, connotations in languages other
than English, and conformity to international nomen-
clature schemes. Many firms seeking a USAN are References
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real polymers. Science 2011; 333: 1834–1835. formulations. Anal Chem 2003; 75: 2140–2146.
105. Clark DE. Outsourcing lead optimization: constant 121. Wartewig S, Neubert RH. Pharmaceutical applications
change is here to stay. Drug Discov Today 2007; 12: of mid-IR and Raman spectroscopy. Adv Drug Deliv
62–70. Rev 2005; 57: 1144–1170.
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122. Kerns EH, Di L. Accelerated stability profiling in drug 134. Stella V. Prodrug strategies for improving drug-like
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125. Han H-K, Amidon GL. Targeted prodrug design to Prodrugs: Challenges and Rewards. Vol. 1. New York:
optimize drug delivery. AAPS Pharmsci 2000; 2(1): AAPS Press/Springer, 2007: 3–33.
48–58. 139. Long CH. Urinary tract infection. The Blong Kong
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ican Society of Health-System Pharmacists, 2007. 141. Fuchs T. Case study: Cefuroxime Axetil: an oral pro-
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6
Pharmaceutical analysis and quality
control

Analysis of medicinals 143 Spectroscopic methods of analysis 172

Biological testing 146 Mass spectroscopic methods of analysis 175

Clinical analysis 148 Dissolution 177

Quality assurance and control 149 Appendix A: Example specifications 180

Stability of pharmaceutical products 151 Appendix B: 21 CFR food and drugs 182
Bioavailability and bioequivalence testing 166 References 185

Chromatographic methods of analysis 169

Analysis of medicinals for hypothetical drug products are provided in

Appendix A.
Specifications can be categorized in a couple of
Specifications
manners. One way is by the intended use of the prod-
The pharmaceutical manufacturer is responsible for uct. For example, is the medicinal an investigational
ensuring the quality, purity, identity, and strength product intended for use in a clinical study, or is it
of each lot of drug product manufactured. One a commercial product that will be marketed? Let’s
mandatory control strategy is to ensure that the lot consider the evolution of a hypothetical oral drug
‘‘conforms to specification,’’ which means that the product as it enters the clinic for single- and multiple-
drug product (formulated preparation), when tested ascending dose safety studies during Phase I clinical
to the listed analytical procedures, will meet the listed studies, then multiple-ascending dose efficacy studies
acceptance criteria.1 Specifications are critical quality in Phase IIa, and confirmatory efficacy studies in Phase
standards. IIb and Phase III. In order to enter the clinic rapidly, a
A specification is a document that is defined as a simple drug product called a drug-in-capsule was cho-
list of tests, references to analytical procedures, and sen for Phase I. This dosage form consists of neat drug
appropriate acceptance criteria (numerical range or (no excipients) that has been accurately weighed into
limit).1 The pharmaceutical manufacturer justifies the gelatin capsules. The manufacturing process meets the
information on the specification, which is approved volume demand for Phase I, but the dosage form must
by regulatory authorities. Examples of specifications be changed prior to scaling-up to Phase II. Hence,
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144 | An Introduction to Pharmacy

the drug-in-capsule is a ‘‘lame duck’’ dosage form. the cream must have a viscosity of 10,000 mPa·s at the
Specifications for investigational products tend to time of release. Therefore, the acceptance criteria for
have acceptance criteria that reflect the early life of the the release and stability specifications would be not
product. Here, the acceptance criteria for dissolution less than (NLT) 10,000 mPa·s and NLT 2000 mPa·s,
of our drug-in-capsule may be ‘‘record result.’’ respectively, in order to ensure a quality product for
Now let’s say that our drug-in-capsule drug prod- its entire shelf life.
uct will be replaced with a dosage form that is
manufactured using a scalable manufacturing pro-
cess – a tablet for Phase II. The tablet will first be
Compendia
used in Phase II ascending-dose clinical studies, so All drug products, whether commercial or inves-
several dose strengths will need to be manufactured. tigational, must meet standards that have been
Let’s say that these dose strengths are 10, 25, and established by Pharmacopeial Conventions or Reg-
100 mg. The acceptance criterion for the dissolution ulatory Agencies. The United States Pharmacopeial
test may remain as ‘‘record result’’ because the dosage (USP) Convention is a scientific nonprofit organi-
form is new, or the criterion may be a ‘‘disaster check’’ zation that sets standards for the quality, purity,
criterion. Although the analytical chemist may not be identity, and strengths of medicines, food ingredients,
able to assign a strict acceptance criterion because and dietary supplements manufactured, distributed,
of the limited data, a slow-dissolving drug from an and consumed worldwide.2 – 4 USP drug standards
immediate-release tablet may jeopardize the interpre- are enforceable in the United States by the Food and
tation of the clinical results. So a criterion like 70 Drug Administration (FDA), and these standards
percent of the drug dissolved after 60 minutes may are developed and relied upon in more than 130
be appropriate for the 100-mg tablet. The lower dose countries.2,4
strengths are usually assigned the same acceptance The European Directorate for Quality of
criterion. Medicines and Healthcare (EDQM), which publishes
Finally, the tablet has entered late development the European Pharmacopoeia, establishes official
and will be used for confirmatory studies. The dose standards that provide a legal and scientific basis for
ranging Phase IIa studies determined that the effica- quality control during the development, production,
cious dose was 60 mg, so a new 60-mg tablet was and marketing of medicines in all signatory states of
developed for use in the Phase III studies. During the European Union Convention on the Elaboration
Phase III, a robust manufacturing process has been of a European Pharmacopoeia (i.e., 37 member
developed at suitable scale, a robust dissolution test states and the European Union).5,6 In addition to
also has been developed and validated, and many the signatory states, seven European countries, 16
lots of tablets have been manufactured and analyzed. non-European countries (including Australia, Brazil,
Now, a suitable acceptance criterion at the time of Canada, China, the Russian Federation, and the
New Drug Application (NDA) or Medicare Modern- United States) and the World Health Organization
ization Act (MAA) submission may be 70% of the are listed as observers. Consequently, the standards
drug dissolved after 30 minutes. developed by Ph. Eur. have an impact on the quality
Another common categorization involves using of medicines across the globe.5,6
different acceptance criteria for release testing and The USP and Ph. Eur. publish books of pharma-
stability testing in order to account for changes that copeial standards. The thirty-fifth revision of the USP
may occur during the shelf life. For example, a top- and the thirtieth edition of the National Formulary,
ical cream may become less viscous upon storage USP 35/NF 29, became official on May 1, 2012. The
at 25◦ C to 30◦ C for two years. The cream may be USP-NF is continuously revised. Standard revisions
too fluid to apply when its viscosity is less than are found in supplements to the USP-NF that are
1000 mPa·s. A suitable acceptance criterion for a sta- published twice yearly. Accelerated revisions are
bility specification may be 2000 mPa·s. Let’s say that published in Pharmacopeial Forum (PF) and on the
the development data indicate that in order to ensure USP website, http://www.usp.org. A new edition
a viscosity of 2000 mPa·s at the end of the shelf life, of USP/NF becomes official each year on May 1.
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Pharmaceutical analysis and quality control | 145

Chapters <1> through <999> are enforceable The monograph gives manufacturers, govern-
chapters, while Chapters <1000> through <1999> ments, and scientists a public standard by which
are informational chapters.3 to judge an article’s quality. Monographs play an
The seventh edition of the European Pharma- important role in meeting the USP’s mission by
copoeia (Ph. Eur 7.0) became official on January 1, providing standards for substances consumed in a
2011. This edition will be augmented with eight sup- global marketplace – standards that help maintain
plements over a three-year period.5 The eighth edition public health. The USP-NF comprises more than
of Ph. Eur. will become official on January 1, 2014. 4000 monographs.12 The USP contains monographs
The European Pharmacopoeia is published in English for drug substances and preparations (drug products);
and French. excipient monographs are in the NF.
The British Pharmacopoeia (BP) is the official The European Pharmacopoeia contains more
collection of standards for UK medicinal products than 2000 general and specific monographs, including
and pharmaceutical substances.7 The standards are chemical substances, antibiotics, vaccines, dosage
established by the British Pharmacopeia Commission. forms, herbal drugs, and homeopathic preparations.5
Canada and Australia also use the BP is as their official One major difference between the Ph. Eur. and USP is
standards. The BP is recognized in over 100 countries illustrated by this example: the USP has monographs
as an internationally acceptable standard and remains for tablets of a specific drug (e.g., amoxine), whereas
an essential reference for all individuals and orga- Ph. Eur. will have only a general monograph for
nizations working within pharmaceutical research, tablets. The BP and JP also contain monographs
development, manufacture, and testing across the of drug substances and drug products. The BP,
globe.8 A new edition of the BP becomes official which contains over 3000 monographs, incorporates
each year on January 1. monographs of the European Pharmacopoeia.13
Japan’s Ministry of Health, Labor, and Welfare
(MHLW) publishes the Japanese Pharmacopoeia (JP),
which provides an official standard to ensure the
Release and stability testing
quality of medicines in Japan.9 – 11 The Japanese Release and stability testing can be classified in a
Pharmacopoeia, 16th edition (JP 16) became offi- couple of practical ways. One is by the nature of the
cial on April 1, 2011. JP 16 is printed in Japanese testing performed: chemical, physical, and microbial.
only at the time of publication of this chapter. For example, the assay for the amount of active
JP 15, however, is available in English. Both edi- ingredient in a gel would be a chemical test, the
tions can be found on the Japanese Pharmacopoeia viscosity measurement and the in vitro release test
website (http://jpdb.nihs.go.jp/jp16e/) and are free of would be physical tests, and the microbial limits test
charge. would be a microbiological test. This classification
system is often used in analytical laboratories that are
specialized by the type of test being performed. The
Monographs
chapters in pharmacopoeias are also organized by the
A monograph is written after a drug product has nature of the test.3,5,9,10
been registered and established in the marketplace Another classification system that is used is based
and usually before its patent expires. The USP defines on the attribute that is being tested. For example, the
a monograph as a written standard that describes an International Conference on Harmonization (ICH)
article (e.g., drug substance, drug product, excipient, Guidances and the USP provide two categories for
compounded preparation).12 A monograph published the system: analytical tests and acceptance criteria
in any USP compendium provides the name of a for assessing (1) general quality attributes and (2)
substance; its definition; package, storage, and label- product performance.1 , 14 – 17 Using the previous gel
ing requirement; and information on tests needed to example, the assay, viscosity, and microbial limits
ensure the substance is of the appropriate identity, tests would be examples of tests that assess general
strength, quality, and purity.3 The later part of a quality attributes. while the in vitro release test would
monograph is similar in scope to a specification. assess product performance.
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146 | An Introduction to Pharmacy

Universal tests excipient. The most common type of impurities that

are measured is related substances, which are process
There are four tests that are generally applicable to all
impurities from the new drug substance synthesis,
drug products: description, identification, assay, and
degradation products of the API, or both. The test for
impurities.
related substances is often referred to as a purity test
Description and must be stability-indicating. The method can be
the same as that used for assay, or it can be a different
This test is often called ‘‘appearance’’ on a specifi-
method that has been developed for measuring low-
cation and is a qualitative description of the dosage
level impurities. An additional method to measure
form. For example, the description of a tablet on
chiral purity may be used to quantify enantiomeric
a specification may read: white, round, biconvex,
impurities in the drug product. In cases in which an
film-coated tablet, imprinted with ‘‘400’’ on one side.
organic solvent is used during the manufacture of
Identification the drug product, a method for measuring residual
solvents is also used.
The purpose of an identification or identity test is to
verify the identity of the active pharmaceutical ingre-
dient(s) (API) in the dosage form. This test should be Future direction
able to discriminate between compounds of closely
The biggest change in the analysis of medical products
related structure that are likely to be present. Infrared
in the coming years will likely be in the implemen-
and Raman spectroscopy are commonly used tech-
tation of the Quality by Design (QbD) paradigm
niques. A more practical technique, however, is high-
and corresponding ICH Guidelines into everyday
performance liquid chromatography (HPLC) because
pharmaceutical development. The information and
the identity and assay can be determined using the
knowledge gained from pharmaceutical development
same analytical method. The ICH Q6A Guidance,1
studies and manufacturing experience provide scien-
however, does not regard identification solely by a sin-
tific understanding to support the establishment of
gle chromatographic retention time as being specific,
the design space, specifications, and manufacturing
the definition of which is the ability of the method
controls. The use of meaningful analytical methods
to assess unequivocally the analyte in the presence of
and specifications will be an integral part of QbD
the sample matrix (excipients, impurities, and degra-
because quality is expected to be built into the design
dation products). Thus, some laboratories will couple
of the product. Analytical tests, especially those that
a diode array or mass spectrometric (MS) detector to
test product performance, will be expected to be dis-
the HPLC system. The diode array detector provides
criminating. For example, dissolution tests will be
a UV spectrum of the drug; the MS detector gives the
expected to tell when a manufacturing or formulation
nominal mass of the drug.
change will affect the product performance.
Assay
This test determines the strength or content of the API
Biological testing
in the dosage form and is sometimes called a content
test. The method should be stability-indicating, which
Introduction
means that the method is quantitative and specific and
can detect chemical changes with respect to time, so Biological testing includes the quantitative assay of
that the quantity of the active ingredient(s) can be drugs by biological methods as well as the application
accurately and precisely measured in the presence of qualitative biological tests. Such testing uses intact
of the sample matrix. HPLC is the most common animals, animal preparations, isolated living tissues
technique used for stability-indicating methods. and cells, or microorganisms. In addition to drugs,
biological tests are a requirement for plastics to be
Impurities used as containers or closures for ophthalmic and
ICH Guidance Q6A1 defines an impurity in a drug parenteral preparations or to be used as implants,
product as any component that is not the API or an devices, or other related systems.
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Pharmaceutical analysis and quality control | 147

The practices of the USP are a good index of use of a biological rather than a chemical assay
the state of biological testing. The USP/NF18 is a procedure.
combination of chapters describing current assays or A chemical assay quantitatively determines the
procedures using USP reference standards, as well as amount of a specific compound or structural moiety
monographs of drug substances. The monographs are present in a given sample. Once the concentration
developed by researchers and contain the name of has been established, an assumption is made rel-
the drug or preparation; the definition; packaging, ative to the biological activity of the sample. In
storage, and labeling requirements; and the series of contrast, a biological assay measures the actual bio-
tests, procedures for the tests, and acceptance criteria logical activity of a given sample, which may represent
for the drug.19 Currently there is a trend to use fewer the algebraic sum of the interaction of a number of
animals in research and biological testing and to use chemical and physical-chemical factors. For example,
alternatives such as cells and microorganisms in cul- the data obtained from a chemical assay will not
ture. This decrease in animal use can be observed in provide information concerning the contribution to
the decreased requirement for animal testing by the the net biological activity of trace amounts of sub-
USP as documented in their monographs. Wherever stances that do not influence the chemical analysis.
possible, in vitro procedures should be used to com- Such substances may produce qualitative variations in
plement or replace in vivo tests for evaluating the biological activity that may be responsible for unex-
suitability of plastics. pected side effects or toxic reactions. Furthermore, the
The majority of currently available therapeutic enhancing or inhibiting influences of variations in the
agents are substances of known chemical composition physical state of the active principle are not reflected
that can be assayed by quantitative chemical or phys- in the results of a chemical assay. The safety, efficacy,
ical analyses. However, there are a limited number and dependability of dosage of drugs are contingent
of useful drugs that cannot be assayed satisfactorily upon standardization, and biological assays must be
by chemical or physical means. Such drugs, which employed in some instances even though the chemical
are primarily of natural origin, are assayed by biolog- identities of the active principles in the preparation
ical methods. Biological standardization procedures may be known.
are generally less precise, more time consuming, and
more expensive to conduct than are chemical assays;
therefore, they generally are reserved for use: Animal testing
As animals are an important unknown factor in most
1. If the chemical identity of the active principle has
biological assays, the need for their proper selection
not been elucidated fully.
and adequate care is self-evident. Most laboratories
2. If no adequate chemical assay has been devised for
seek a reliable source of animals that can supply their
the active principle, although its chemical struc-
needs from colonies maintained for this purpose. In
ture has been established (e.g., insulin).
3. If the drug is composed of a complex mixture of any one test it is desirable to use animals of only one
substances of varying structure and activity (e.g., strain. Usually bioassayists adopt a specified strain
extracts of digitalis leaf, posterior pituitary gland). for all work of a particular type. This enables the
4. If purification of the crude drug, sufficient for the bioassayist to gain experience concerning the expected
performance of a chemical assay, is not possible normal variation. For some assays a specific sex must
or practical (e.g., the separation of vitamin D from be employed (e.g., estrogenic tests); in other assays
certain irradiated oils). either sex may be used, but the effect that sex may
5. If the chemical assay is not a valid indication of play in the response should not be overlooked. The
biological activity, due, for example, to lack of male rat, for instance, has a faster growth rate than
differenti- the female; therefore, indiscriminate use of both males
ation between active and inactive isomers. and females in a rat growth test should be avoided.
Differences in the response of the sexes may extend
There are several situations in which factors such into other categories, such as response toward toxic
as specificity, sensitivity, or practicality dictate the materials. Animals used in these biological assays
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148 | An Introduction to Pharmacy

should always be handled according to the National requirements specified by the USP 35/NF 30;18 hence,
Institutes of Health guidelines.20 there is a considerable subjective element present.
Furthermore, the effect measured in the test ani-
mals often is not that which the drug is intended to
Bioassay procedures
produce in treating patients. The importance of this
Bioassays are conducted by determining the amount discrepancy was minimized formerly, but recent stud-
of a preparation of unknown potency required to ies have shown that when several active principles are
produce a definite effect on suitable test animals or present in a crude drug, those producing the maximal
organs under standard conditions. therapeutic effect are not necessarily the ones chiefly
responsible for the action measured in the assay. As
Reference standards a result, samples found to be of equal strength by
To minimize the source of error resulting from ani- assay may show different potencies when employed
mal variation, standard reference preparations are clinically. An example of this situation is found in the
used in certain bioassay procedures. The principle discussion on digitalis.
of the using a reference standard consists of succes-
sively testing the unknown and standard preparations Classification of bioassay procedures
on two groups of similar animals, or, in some cases Bioassays are classified in three groups according to
(e.g., epinephrine, posterior pituitary) on the same whether the effect produced is all or none (as death),
animal or organ. The amount of the unknown prepa- graded (as rise in blood pressure), or is characterized
ration required to produce an effect equal to that by developing in a measured period of time (as the
produced by a defined amount of the standard will be curative response to thiamine). It should be noted that
inversely proportional to their relative potencies. The in all three types, with few exceptions, the calculations
potency of the unknown therefore can be expressed of potency are based on the sizes of doses necessary to
as a percentage of that of the reference standard. produce approximately equal effects and not on the
In some assays it is necessary to adopt precise magnitude of the responses. Furthermore, the results
methods of calculating potency based on observa- derived from all are quantitative in that the potency
tions of relative, but not necessarily equal, effects. of the unknown is expressed in terms of the standard.
Likewise, methods of computation have been devised
to determine the statistical reliability of the results.
The chapters on Biological Tests and Assays in the Clinical analysis
USP 35/NF 3021 also present a detailed considera-
tion of factors germane to the chapter on Design and The characterization and quantitation of the various
Analysis of Biological Assays.22 components of blood, urine, and other body fluids
When reference standards are required for use in are the primary functions of the clinical laboratory.
assays, they are available as a service from USPNF The major divisions of clinical analysis are clinical
Reference Standards, 12601 Twinbrook Parkway, biochemistry, hematology, blood-bank technology,
Rockville, MD 20852. These references are standard- histopathology, immunology, and microbiology. The
ized in terms of the appropriate existing international accurate diagnosis of disease and determination of a
standards. potential therapeutic regimen frequently are based on
the laboratory analysis of blood, urine, feces, gastric
Disadvantages of bioassays secretions, or cerebrospinal fluid. Modern medical
Biological assays leave much to be desired in sev- practice is tending toward greater reliance on labora-
eral respects. Although some are extremely sensitive tory results as definitive measures of pathological or
in detecting small differences in concentration, their normal states.
quantitative accuracy usually falls considerably below Pharmacists should familiarize themselves with
that obtainable with most chemical analyses. The the basic principles involved in sample collection,
techniques and interpretations involved often can analysis, and diagnostic significance of the various
vary with different operators, in spite of the rigid clinical parameters. Their role in community health
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Pharmaceutical analysis and quality control | 149

necessitates comprehension of the methodology and Emphasis is being placed on the inspection of quality
diagnostic value of clinical laboratory procedures. systems as part of the regulatory pre-approval pro-
The influence of various drugs and drug interactions gram when reviewing NDAs and Biological License
on these parameters must be considered in both the Applications (BLAs).
clinical and drug-abuse situation.

QA and QC: organization/responsibilities

Quality assurance and control Industry, to ensure compliance with these government
regulations and with their own internal policies and
The pharmaceutical industry, as a vital segment procedures, has developed very sophisticated qual-
of the healthcare system, conducts research and ity organizations with well-defined responsibilities. It
manufactures and markets pharmaceutical and has been accepted that QA and QC have different
biological products and medical devices used for the functions within an organization; although both are
acute/chronic treatment and diagnosis of disease. considered part of the Quality Unit as identified in
Recent advances in drug discovery, primarily in the the Code of Federal Regulations Title 21 (CFR) (see
field of biotechnology and in the required controls Appendix B). QC most commonly functions to test
over manufacturing processes, are presenting new and measure material and product. QA establishes
challenges to the control of quality and to the systems systems for ensuring the quality of the product. Firms
that operate internally in the industry. The external must decide upon the exact roles they wish QC and
regulations established by the federal FDA and other QA to perform in operations and put these definitions
regulatory bodies also add to these challenges. The in writing.
evolving role of the industrial quality professional
requires more extensive education including food QA functions and responsibilities
and drug law, business, as well as the traditional The QA department within any organization, because
science/technology coursework. of its responsibilities, normally will report to a rel-
The pursuit of quality is being approached atively high-level administrator within a company,
through the application of quality systems including depending on its size. In smaller companies they may
risk-based assessment and continuous improvement, report to the chief executive officer or the president.
whereby management and labor join forces to build In larger corporations, they will sometimes report to
quality into products while helping to ensure the the president or executive vice-president or chief of
company’s financial success. This changed emphasis operations. In any case, however, responsibility for
is directed toward defect prevention (proactive) quality, as currently dictated by the FDA, ultimately
rather than defect detection (after the fact). resides with top management which has responsibility
Quality assurance (QA) and quality control (QC) for ensuring that appropriate resources are provided
departments develop and follow standard internal to meet all quality and compliance requirements. In
operating procedures directed toward assuring the all cases, the QA department will be independent of
quality, safety, purity, and effectiveness of drug prod- the economic issues associated with manufacturing
ucts. The FDA has issued a primary regulation to the and distribution of the product.
industry entitled Current Good Manufacturing Prac- The QA department is responsible for ensuring
tice for Finished Pharmaceuticals (commonly referred that the quality policies adopted by a company are
to as the cGMPs or GMPs) (see Appendix B). Numer- followed. In some organizations, QA serves as the pri-
ous guidelines have been issued relative to specific mary contact with regulatory agencies and is the final
dosage forms and operations such as aseptic manu- authority for product acceptance (release) or rejection.
facturing, validation and stability testing, etc., which It is customary for QA to play a major role in the
impose significant compliance requirements. These identification and preparation of the necessary policies
guidelines also serve as the basis for compliance inves- and standard operating procedures (SOPs) relative to
tigations conducted by the FDA and are used in regu- the control of quality. Where QA has responsibility
latory agency inspections of facilities and operations. for final product release, it must determine that the
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150 | An Introduction to Pharmacy

product meets all the applicable specifications and management, but with QC being independent of
that it was manufactured according to internal stan- production. This higher-level management may be
dards and cGMPs. QA departments now tend to work the same or different individuals, but it allows
as a team member with the other functional groups independent operation of both functions without
within the firm rather than simply to serve a police direct conflict arising when reaching a final decision
function, a largely outdated role of QA. on the acceptability of final products.
A second major responsibility of the QA depart- The analytical control laboratory must be staffed
ment is the quality monitoring or audit function. with persons who are trained academically and are,
Through this activity, it is able to determine if oper- through experience, capable of performing the often
ations have adequate systems, facilities, and written complex analyses used to evaluate the acceptability
procedures to control the quality of products pro- of the materials tested. The equipment and instru-
duced. Thus, the QA function not only determines mentation in the laboratory must be suitable for
that the procedures are current and correct, but that performing the testing in an accurate and efficient
properly trained operators are following them. Com- manner. Detailed specifications must be available, as
bining this review of SOPs with an audit of facilities well as validated test methods against which products
and operations, including those of contract manufac- and raw materials will be evaluated. The specifica-
turing and testing subcontractors, will give company tions detail the limits for acceptance of the article,
management an inside report on its level of com- based on identified critical parameters.
pliance and will allow the necessary changes and/or The testing and acceptance of only high-quality
corrections to be made prior to a product failure raw materials is essential for the production of uni-
or being reported as a deficiency during an inspec- formly acceptable products. QC plays a major role
tion by an FDA investigator. This is consistent with in the selection and qualification of vendors from
the top-level management review component of the whom these materials are purchased. Testing of rep-
quality systems approach currently emphasized by resentative samples is required, and in many cases,
FDA during inspections. Senior management of a an audit of the vendor’s operation is necessary to
company looks to the QA function to assess oper- determine their suitability and degree of compliance
ations continually and to advise and guide them with GMPs and other relevant standards prior to their
toward full compliance with all applicable internal being approved. The vendor audit frequently is orga-
and external regulations. Organizationally, the Qual- nized by QA, with technical support from research,
ity department(s) should report, as directed by the QC, and manufacturing.
GMPs, to someone other than the person responsible At various critical in-process steps in production,
for production. it may be necessary to sample and test product against
criteria previously established. Often, in-process alert
QC functions and responsibilities or action levels will be identified for the critical in-
QC is responsible for the day-to-day control of qual- process parameters as a means of process control.
ity within a company. This department is staffed with These alert or action levels are normally set such that
scientists and technicians responsible for the sampling they are more restrictive than the final acceptance
and analytical testing of incoming raw materials and limits, but serve as an in-process control by providing
inspection of packaging components, including label- early warnings of conditions that could lead to an
ing. QC conducts in-process testing when required, out-of-control situation and thus will allow timely
performs environmental monitoring, inspects oper- corrective action before such conditions occur. The
ations for compliance, and conducts the required acceptance criteria for such testing are established
release tests on finished dosage form. Finally, QC using QbD approaches which identify the Design
is responsible for monitoring product quality through Space within which the process will perform satis-
distribution, including testing of product complaint factorily. Trending of analytical data is also useful
samples, evaluating product stability, and so on. in providing early warning signals that the process is
Many companies have the heads of QC and moving out of control. It should be noted, however,
production report to a common higher level of that materials, which have reached the alert or action
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Pharmaceutical analysis and quality control | 151

level criteria, are still acceptable for use in manufac- be taken to bring them within acceptable limits so as
turing, since they have not exceeded an out-of-limit not to compromise the quality of the product. This
rejection level. monitoring and control of the environment will fur-
QC is responsible, as part of its testing and inspec- ther ensure the quality and stability of the product
tion functions, for monitoring the environmental by preventing the products from being exposed to a
conditions under which products are manufactured hostile environment.
and/or held. Different levels of control are established Control of packaging components, especially
depending on the intended use of the dosage form. those that come into direct contact with a product,
Parenteral and ophthalmic products must be produced is required. These materials must be inspected
in a controlled environment that is designed to ensure and tested against rigid specifications to ensure
their sterility. Monitoring of air and water systems is that they meet predetermined functional standards.
critical in confirming that they are being controlled This includes evaluation of compatibility of the
and that the levels of particulates, microbial matter, product with the packaging materials. Labeling is
and other contaminants are within pre-established understandably a critical component, not just in
limits. The USP contains monographs and specifica- its original design and acceptance, but also with
tions on Water Used for Pharmaceutical Purposes. regard to secure storage and issuance to ensure
Formerly, the Federal Government Standard 209E, accountability. Furthermore, final product labeling
Airborne Particulate Cleanliness Classes in Clean- must be 100% inspected to ensure that it is correct.
rooms and Clean Zones, established acceptable limits Often automated imaging methods are employed to
for particulates in a controlled environment, but it is conduct these inspections.
no longer considered applicable to the pharmaceutical
industry, having been replaced by international stan-
Stability of pharmaceutical
dards. Federal standards are currently not enforced
for environmental quality, but guidance is available products
in the FDA Concept Paper, Sterile Drug Products Pro-
duced by Aseptic Processing, published in September Introduction
2004.23 In addition, reference is made to the Base- Stability of a pharmaceutical product may be defined
line Pharmaceutical Engineering Guide, Vol. 3, Sterile as the capability of a particular formulation, in a
Manufacturing Facilities, published by the Interna- specific container/closure system, to remain within
tional Society of Pharmaceutical Engineering (ISPE) its physical, chemical, microbiological, therapeutic,
in partnership with the FDA, in June 2000.24 Gener- and toxicological specifications at a defined storage
ally, conditions listed as Class ISO 5 (formerly Class condition. Pharmaceutical products are expected to
100) (or equivalent) are maintained in areas where meet their specifications for identity, purity, quality,
parenteral products are filled into clean, sterile con- and strength throughout their defined storage period
tainers. The ISO 5 classification is defined as an area at specific storage conditions. Assurances that the
that can be controlled to contain fewer than 100 par- packaged product will be stable for its anticipated
ticles, 0.5 microns and larger, per cubic foot of air. In shelf life must come from an accumulation of valid
addition, manufacturers must establish limits for the data on the drug in its commercial package. These
presence of viable microorganisms in the environment stability data include selected parameters that, taken
and appropriately monitor the air quality in the filling together, form the stability profile.
area. The stability of a pharmaceutical product is inves-
Another major element of control is the environ- tigated throughout the various stages of the devel-
mental monitoring of the areas in which nonsterile opment process. The stability of a drug substance
products are manufactured, such as liquids, tablets, is first assessed in the preformulation stage. At this
and capsules. The objective here is first to determine stage, pharmaceutical scientists determine the drug
an acceptable level of particulates and microbial con- substance and its related salts stability/compatibility
taminates and then to control them to this level. If with various solvents, buffered solutions and excipi-
particulate levels are found to be excessive, steps must ents considered for formulation development. Suitable
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152 | An Introduction to Pharmacy

analytical methods must be employed in order to by the pharmacy to the patient. Dispensing of the drug
ensure the likelihood that this assessment will be product may be at a hospital, a clinic, and a traditional
successful. Optimization of a stable formulation of ‘‘brick and mortar’’ pharmacy or from a mail-order
a pharmaceutical product is built (using statistical pharmacy. Therefore, the stability typically must also
design) upon the information obtained from the assess the robustness of the drug product through
preformulation stage and continues during the for- its supply chain. It is not unusual for temperature
mulation development stages. excursions to occur during these transfers of control.
Typically, the first formulation development stage Inventory control, or holding, of each drug is
may be for preclinical studies or as late as the prepara- important for a wholesaler or pharmacy. A drug must
tion of a ‘‘first in human’’ formulation which is often be within its expiration dating throughout its use by
a non-elegant formulation optimized for short-term the patient. Solid oral dosages may be dispensed in the
dose-ranging clinical studies. The second major for- commercial packaging or in a pharmacy supplied con-
mulation development stage occurs to support Phase tainer closure system. Most prescriptions are supplied
II clinical studies (proof of concept phase). The phar- to patients for up to 30 or 90 days by traditional and
maceutical product developed at this stage is usually mail-order pharmacies, respectively. Inventory con-
the prototype for the commercial product. There- trol of product by wholesalers and pharmacies must
fore, the pharmaceutical product will be formulated assess how much dating must remain on a product for
based in part on the stability information obtained it to be useful for its customer. This causes the actual
from the previous formulations and must meet sta- holding of a product to be shorter than the expiration
bility requirements for longer-term clinical studies. In date. Under normal circumstances it is unusual for
the final formulation development state for Phase III a pharmacy to accept any product with less than 6
clinical studies, the formulation must be truly rep- month dating remaining on a product.
resentative of what the commercial pharmaceutical Much has been written about the development
product will be in order to avoid delays in approval. of a stable pharmaceutical product. Comprehensive
In addition to building on the clinical requirements treatments of all aspects of pharmaceutical product
of the drug, the commercial pharmaceutical product stability have been published by Connors et al.25 ,
must also incorporate the commercial or the final Carstensen26 and more recently by Allen.27 This
market image of the product, which includes the con- will cover the applicable topics from preformulation
tainer closure system. The stability of this product to drug approval to assure that the pharmaceuti-
must be demonstrated to the appropriate regulatory cal product developed is stable. Requirements for
agencies in order to assign an expiration period and compounded products will also be discussed.
date for the product. This expiration period allows The USP General Chapter <1191>4 defines the
for the assignment of an expiration date based on the stability of a pharmaceutical product as ‘‘extent to
manufacture date of each lot of drug product. which a product retains, within specified limits, and
Once a pharmaceutical product has gained reg- throughout its period of storage and use (i.e., its shelf
ulatory approval and is marketed, the pharmacist life), the same properties and characteristics that it
must understand the proper storage and handling of possessed at the time of its manufacture.’’ There are
the drug. In some cases, a pharmacist may need to five types of stability that must be considered for each
prepare stable compounded preparations from this drug (Table 6.1).
product. The use of kinetic and predictive studies for estab-
Most drug products are not shipped directly from lishing credible expiration dating for pharmaceutical
the manufacturer to a pharmacy. Typically, a drug products is now accepted worldwide. Scientifically
product is shipped from a manufacturer to a distri- designed studies using reliable, meaningful, and spe-
bution center. From the distribution center the drug cific stability-indicating assays, appropriate statistical
product is then shipped to a wholesaler. From the concepts, and a computer to analyze the resulting data
wholesaler, the drug product may be shipped to the are used to determine an accurate and realistic shelf
distribution center for a pharmacy chain or directly to life. In this way the maximum amount of valid infor-
the pharmacy. Finally, the drug product is dispensed mation is obtained to establish a reliable, defendable
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Pharmaceutical analysis and quality control | 153

shall appear on the immediate container and the outer

Table 6.1 Types of stability
retail package. However, when single-dose contain-
Type of stability Conditions maintained throughout ers are packaged in individual cartons, the expiration
the shelf life of the drug product date may be placed on the individual carton instead of
the immediate product container. If a dry product is to
Chemical Each active ingredient retains its
be reconstituted at the time of dispensing, expiration
chemical integrity and labeled potency,
dates are assigned to both the dry mixture and the
within the specified limits.
reconstituted product. Tamper-resistant packaging is
Physical The original physical properties, to be used where applicable.
including appearance, palatability,
uniformity, dissolution, and
suspendability are retained. Product stability
Microbiological Sterility or resistance to microbial growth Many factors affect the stability of a pharmaceutical
is retained according to the specified product including the intrinsic stability of the active
requirements. Antimicrobial agents that ingredient(s), the potential interaction between active
are present retain effectiveness within and inactive ingredients, the manufacturing process,
the specified limits.
the dosage form, the container-liner-closure system
Therapeutic The therapeutic effect remains and the environmental conditions encountered during
unchanged. shipment, storage and handling, and length of time
between manufacture and usage.
Toxicological No significant increase in toxicity occurs. Classically, pharmaceutical product stability eval-
uations have been separated into studies of chemi-
cal (including biochemical) and physical stability of
formulations. Realistically, there is no absolute divi-
expiration date for each formulation. The assigned sion between these two arbitrary divisions. Physical
expiration date is a direct application and interpre- factors – such as heat, light, and moisture – may ini-
tation of the knowledge gained from the stability tiate or accelerate chemical reactions, whereas every
study. time a measurement is made on a chemical compound,
Although there are exceptions, 90% of labeled physical dimensions are included in the study.
potency generally is recognized as the minimum One type of time-related chemical stability failure
acceptable potency level over the shelf life of a drug is a decrease in therapeutic activity of the preparation
product. Exceptions to this minimum potency include to below some arbitrary labeled content. A second
drugs with active pharmaceutical ingredients that type of chemical stability failure is the appearance
have a narrow therapeutic thresholds and biologics. of a toxic substance, formed as a degradation prod-
The stability of a commercial pharmaceutical uct upon storage of the formulation. The numbers of
product is expressed as an expiration date (expiry). published cases reflecting this second type are few.
Expiration dating is defined, therefore, as the time However, it is possible, though remote, for both types
in which a drug product in a specific packaging of stability failures to occur simultaneously within the
configuration will remain stable when stored under same pharmaceutical product. Thus, the use of stabil-
recommended conditions. This date is usually calcu- ity studies with the resulting application of expiration
lated by adding the established expiration period to dating to pharmaceuticals is an attempt to predict the
the date of manufacture. The date of manufacture is approximate time at which the probability of occur-
many times defined as the date in which the active rence of a stability failure may reach an intolerable
pharmaceutical ingredient is first combined with a level. This estimate is subject to the usual Type 1 or
drug product excipient. alpha error (setting the expiration too early so that
An expiration date, which is expressed tradition- the product will be destroyed or removed from the
ally in terms of month and year, denotes the last day market appreciably earlier than actually is necessary)
of the month. In the United States, the expiration date and the Type 2 or beta error (setting the date too
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154 | An Introduction to Pharmacy

late so that the failure occurs in an unacceptably of hydrogen peroxide and hypochlorites, and the for-
large proportion of cases). Thus, it is obligatory that mation of precipitates have been included.
the manufacturer clearly and succinctly defines the
method for determining the degree of change in a Pharmaceutical dosage forms
formulation and the statistical approach to be used As the various pharmaceutical dosage forms present
in making the shelf life prediction. An intrinsic part unique stability problems, they are discussed sepa-
of the statistical methodology must be the statements rately in the following section.
of value for the two types of error. For the safety of
the patient a Type 1 error can be accepted, but not a Tablets
Type 2 error. Stable tablets retain their original size, shape, weight,
One type of time related physical stability failures and color under normal handling and storage condi-
may affect the availability or rate of drug release of tions throughout their shelf life. In addition, the in
a product. This type of physical stability failure may vitro availability of the active ingredients should not
cause the active ingredient not to be released or a change appreciably with time.
higher rate of drug release (dose dumping). Another Excessive powder or solid particles at the bottom
type of time related physical stability failures are of the container, cracks or chips on the face of a
appearance related. These may just cause the drug tablet, or appearance of crystals on the surface of
product not to appear pharmaceutically elegant or tablets or on container walls are indications of phys-
may be an artifact of another physical or chemical ical instability of uncoated tablets. Hence, the effect
stability failure. of mild, uniform, and reproducible shaking and tum-
In this treatment, physical and chemical stability bling of tablets should be studied. The recommended
are discussed along with those dosage form properties test for such studies is the determination of tablet
that can be measured and are useful in predicting friability as described in the USP. Tablet Friability
shelf life. The effect of various physical and chemical USP <1216> describes the recommended apparatus
phenomena of pharmaceuticals also is treated. and the test procedure. After visual observation of the
Knowledge of the physical stability of a formu- tablets for chips, cracks, and splits, the intact tablets
lation is very important for three primary reasons. are sorted and weighed to determine the amount of
First, a pharmaceutical product must appear fresh, material worn away by abrasion. In general, a maxi-
elegant, and professional, for as long as it remains on mum weight loss of not more than 1% of the weight
the shelf. Any changes in physical appearance such of the tablets being tested is considered acceptable for
as color fading or haziness can cause the patient or most products. The results of these tests are compar-
consumer to lose confidence in the product. Second, ative rather than absolute and should be correlated
since some products are dispensed in multiple-dose with actual stress experience. Packaged tablets also
containers, potency of the active ingredient over time should be subjected to cross-country shipping tests as
must be ensured for each individual dose. A cloudy well as to various drop tests.
solution or a broken emulsion can lead to a non- Tablet hardness (or resistance to crushing or frac-
uniform dosage pattern. Third, the active ingredient turing) can be assessed by commercially available
must be bioavailable to the patient throughout the hardness testers. As results will vary with the specific
expected shelf life of the preparation. A breakdown make of the test apparatus used, direct comparison of
in the physical system can lead to non-availability or results obtained on different instruments may not nec-
‘‘dose dumping’’ of the medication to the patient. In essarily be made. Thus, the same instrument should
the case of metered-dose inhaler pulmonary aerosols, be used consistently throughout a particular study.
particle aggregation may result in inadequate lung Color stability of tablets can be followed by an
deposition of the medication. appropriate colorimeter or reflectometer with heat,
The chemical causes of drug deterioration have sunlight, and intense artificial light employed to accel-
been classified as incompatibility, oxidation, reduc- erate the color deterioration. It is still not unusual for
tion, hydrolysis, racemization, and other mechanisms. color assessment to be performed visually. Caution
In the latter category, decarboxylation, deterioration must be used in interpreting the elevated temperature
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Pharmaceutical analysis and quality control | 155

data, as the mechanism for degradation at that tem- an environment of extreme dryness, gelatin capsules
perature may differ from that at a lower temperature. may harden and crack under slight pressure. Gelatin
It is not always proper to assume that the same capsules should be protected from sources of micro-
changes will occur at elevated temperatures as will bial contamination. Encapsulated products, like all
be evidenced later at room temperature. Cracks, mot- other dosage forms, must be packaged properly.
tling, or tackiness of the coating indicates evidence of Because moisture may be absorbed or released
instability of coated tablets. by gelatin capsules depending on the environmen-
Typically, dissolution is the in vitro test performed tal conditions, little physical protection is offered to
to estimate bioavailability for a tablet regardless of hygroscopic or deliquescent materials enclosed within
the solubility of the active ingredients. Disintegration a capsule when stored in an area of high humidity. It
has been relegated to an in-process test or used to is not uncommon to find capsules packaged in con-
help dissolution. Dissolution tests should be run in tainers along with a packet of desiccant material as a
an appropriate medium at 37◦ C. Actual dissolution precautionary measure.
conditions, including medium, are developed during Dissolution development and requirements for
the clinical development phase of a product. The capsules are similar to tablets. The capsule shell can
dissolution method developed has to demonstrate a affect dissolution test results but not be relevant to
correlation that is relevant to the bioavailability of bioavailability. Both hard and soft gelatin capsules
the dosage form. Dissolution profiles are examined exposed to excessive heat and moisture may exhibit
during development to provide sufficient information delayed or incomplete dissolution due to cross-linking
to define a single sample time point with a mini- of the gelatin in the capsule shell. The cross-linking
mum concentration for immediate release product. of gelatin capsules is an irreversible chemical reac-
Controlled release drug products require a dissolu- tion. Cross-linking may also occur in capsules that
tion profile with concentration ranges at set sampling are exposed to aldehydes and peroxides. Although
points for product assessment. When no significant cross-linked capsules may fail dissolution due to pel-
change (such as a change in the polymorphic form licle formation, digestive enzymes will dissolve the
of the crystal) has occurred, an unaltered dissolution- capsules. For hard or soft gelatin capsules that do
rate profile of a tablet formulation usually indicates not conform to the dissolution specification, the dis-
constant in vivo bioavailability. solution test may be repeated with the addition of
Uniformity of weight, odor, texture, drug and enzymes. Where water or a medium with a pH less
moisture contents, and humidity effect may also be than 6.8 is specified as the medium in the individual
studied during a tablet stability test. monograph, the same medium specified may be used
with the addition of purified pepsin that results in
Gelatin capsules an activity of 750,000 units or less per 1000 mL. For
Hard gelatin capsules are the type used by phar- media with a pH of 6.8 or greater, pancreatin can be
maceutical manufacturers in the production of the added to produce not more than 1750 USP units of
majority of their capsule products. The pharmacist protease activity per 1000 mL.
in the extemporaneous compounding of prescriptions
may also use hard gelatin capsules. Soft gelatin cap- Suspensions
sules are prepared from shells of gelatin to which A stable suspension can be redispersed homoge-
glycerin or a polyhydric alcohol such as sorbitol has neously with moderate shaking and can be poured
been added to render the gelatin elastic or plastic-like. easily throughout its shelf life, with neither the particle
Gelatin is stable in air when dry but is subject to size distribution, the crystal form, nor the physiolog-
microbial decomposition when it becomes moist or ical availability of the suspended active ingredient
when it is maintained in aqueous solution. Normally changing appreciably with time.
hard gelatin capsules contain between 13% and 16% Most stable pharmaceutical suspensions are floc-
moisture. If stored in a high humidity environment culated; that is, the suspended particles are bonded
capsule shells may soften, stick together or become together physically to form a loose, semi-rigid struc-
distorted and lose their shape. On the other hand, in ture. The particles are said to uphold each other while
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156 | An Introduction to Pharmacy

exerting no significant force on the liquid. Sedimented light should be projected through a diaphragm into
particles of a flocculated suspension can be redispersed the solution. Undissolved particles will scatter the
easily at any time with only moderate shaking. light, and the solution will appear hazy. Although
In non-flocculated suspensions, the particles the Coulter counter also can be used, light-scattering
remain as individuals unaffected by neighboring instruments are the most sensitive means of following
particles and are affected only by the suspension solution clarity.
vehicle. These particles, which are smaller and Solutions should remain clear over a relatively
lighter, settle slowly, Once they have settled, they wide temperature range such as 4 to 47◦ C. At the
often form a hard, difficult-to-disperse sediment. lower range an ingredient may precipitate due to
Non-flocculated suspensions can be made acceptable its lower solubility at that temperature, whereas at
by decreasing the particle size of the suspended the higher temperature the flaking of particles from
material or by increasing the density and viscosity of the glass containers or rubber closures may destroy
the vehicle, thus reducing the possibility of settling. homogeneity. Thus, solutions should be subjected to
When studying the stability of a suspension, a cycling temperature conditions.
differential manometer is used to determine if the sus- The stability program for solutions also should
pension is flocculated. If the suspension is flocculated, include a study of pH changes, especially when
the liquid will travel the same distance in the two side the active ingredients are soluble salts of insoluble
arms. With non-flocculated suspensions, the hydro- acids or bases. Among other tests are observations
static pressures in the two arms are unequal; hence, for changes in odor, appearance, color, taste, light-
the liquids will be at different levels. stability, pourability, viscosity, isotonicity, gas evo-
The history of settling of the particles of a sus- lution, microbial stability, specific gravity, surface
pension may be followed by a Brookfield viscometer tension, and pyrogen content, in the case of parenteral
fitted with a Helipath attachment. This instrument products.
consists of a rotating T-bar spindle that descends When solutions are filtered, the filter medium may
slowly into the suspension as it rotates. The dial read- absorb some of the ingredients from the solution.
ing on the viscometer is a measure of the resistance Thus, the same type of filter should be used for
that the spindle encounters at various levels of the preparing the stability samples as will be used to
sedimented suspension. This test must be run only on prepare the production-size batches.
fresh, undisturbed samples. For dry-packaged formulations reconstituted
An electronic particle counter and sizer, such as prior to use, the visual appearance should be
a Coulter counter, or a microscope may be used to observed on both the original dry material and on the
determine changes in particle size distribution. Crystal reconstituted preparation. The color and odor of the
form alterations may be detected by microscopic, cake, the color and odor of the solution, the moisture
near-IR or Raman examination and, when suspected, content of the cake, and the rate of reconstitution
must be confirmed by X-ray powder diffraction. should be followed as a part of its stability profile.
All suspensions should be subjected to cycling
temperature conditions to determine the tendency Emulsions
for crystal growth to occur within the suspension. A stable emulsion can be redispersed homogeneously
Shipping tests, namely transporting bottles across the to its original state with moderate shaking and can
country by rail or truck, are also used to study the be poured at any stage of its shelf life. Although most
stability of suspensions. of the important pharmaceutical emulsions are of the
oil in water (O/W) type, many stability test methods
Solutions can be applied to either an O/W or water in oil (W/O)
A stable solution retains its original clarity, color, emulsion.
and odor throughout its shelf life. Retention of clar- Two simple tests are used to screen emulsion for-
ity of a solution is a main concern of a physical mulations. First, heating to 50 to 70◦ C and observing
stability program. As visual observation alone under its gross physical stability either visually or by turbidi-
ordinary light is a poor test of clarity, a microscope metric measurements can determine the stability of an
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Pharmaceutical analysis and quality control | 157

emulsion. Usually the emulsion that is the most stable and apply. Hence, it is important to be able o define
to heat is the one most stable at room temperature. quantitatively the consistency of an ointment. This
However, this may not be true always, because an may be done with a penetrometer, an apparatus that
emulsion at 60◦ C may not be the same as it is at room allows a pointed weight to penetrate into the sample
temperature. Second, the stability of the emulsion can under a measurable force. The depth of the penetra-
be estimated by the coalescence time test. Although tion is a measure of the consistency of an ointment.
this is only a rough quantitative test, it is useful for Consistency also can be measured by the Helipath
detecting gross differences in emulsion stability at attachment to a high-viscosity viscometer or by a
room temperature. Burrell Severs rheometer. In the latter instrument the
Emulsions also should be subjected to refrig- ointment is loaded into a cylinder and extruded with
eration temperatures. An emulsion stable at room a measured force. The amount extruded is a measure
temperature has been found to be unstable at 4◦ C. of the consistency of the ointment.
It was reasoned that an oil-soluble emulsifier pre- Ointments have a considerable degree of structure
cipitated at the lower temperature and disrupted the that requires a minimum of 48 hours to develop after
system. An emulsion chilled to the extent that the preparation. As rheological data on a freshly made
aqueous base crystallizes is damaged irreversibly. ointment may be erroneous, such tests should be
The ultracentrifuge also is used to determine emul- performed only after the ointment has achieved equi-
sion stability. When the amount of separated oil is librium. Slight changes in temperature (1 or 2◦ C) can
plotted against the time of centrifugation, a plateau affect the consistency of an ointment greatly; hence,
curve is obtained. A linear graph results when the oil rheological studies on ointments must be performed
flotation (creaming) rate is plotted versus the square of only at constant and controlled temperatures.
the number of centrifuge revolutions per minute. The Among the other tests performed during the sta-
flotation rate is represented by the slope of the line bility study of an ointment are a check of visual
resulting when the log distance of emulsion–water appearance, color, odor, viscosity, softening range,
boundary from the rotor center is plotted against consistency, homogeneity, particle size distribution,
time for each revolution per minute. and sterility. Undissolved components of an oint-
For stability studies, two batches of an emulsion ment may change in crystal form or in size with
should be made at one time on two different sizes of time. Microscopic examination or an X-ray diffrac-
equipment. One should be a bench-size lot and the tion measurement may be used to monitor these
other a larger, preferably production-size, batch. Dif- parameters.
ferent types of homogenizers produce different results, In some instances it is necessary to use an ointment
and different sizes of the same kind of homogenizer base that is less than ideal, to achieve the required
can yield emulsions with different characteristics. stability. For example, drugs that hydrolyze rapidly
are more stable in a hydrocarbon base than in a base
Ointments containing water, even though they may be more
Ointments have been defined as high-viscosity suspen- effective in the latter.
sions of active ingredients in a non-reacting vehicle.
A stable ointment is one that retains its homogeneity Transdermal patches
throughout its shelf life period. The main stability A typical transdermal patches consist of a protective
problems observed in ointments are bleeding and backing, a matrix containing active drug, an adhesive
changes in consistency due to aging or changes in tem- that allows the patch to adhere to the skin and a
perature. When fluid components such as mineral oil release liner to protect the skin adhering adhesive.
separate at the top of an ointment, the phenomenon Therefore, the transdermal patch must deliver drug
is known as bleeding and can be observed visually. as labeled, adhere properly to both the backing and
Unfortunately, as there is no known way to accelerate to the patient’s skin. In addition, the transdermal
this event, the tendency to bleed cannot be predicted. patch must be pharmaceutically elegant through the
An ointment that is too soft is messy to use, shelf life of the product. For a transdermal patch, this
whereas one that is very stiff is difficult to extrude means that the release line peels easily with minimal
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158 | An Introduction to Pharmacy

transfer of adhesive onto the release liner and that too large will not be absorbed into nasal membrane
the adhesive does not ooze from the sides of the or run out of the nose and poor spray pattern will
patch. Therefore, the typical stability related tests for deposit the drug ineffectively in the nasal cavity.
transdermal patches are appearance, assay, impuri- The typical stability related tests for nasal inhala-
ties, drug release per USP<724>, and backing peel tion products include appearance, assay, impurities,
force. spray content uniformity, particle (droplet) size dis-
tribution of the emitted dose, spray pattern or/and
Metered-dose aerosols drug products plume geometry, leachables, weight loss and preser-
A metered dose inhalation product comprises an vative content. Sterility and microbial testing may be
aerosol can containing a propellant and drug, and required periodically for stability testing.
a mouthpiece used to present an aerosolized drug to
the patient. There are many drug contact components Incompatibility
in a metered-dose inhalation product. Therefore, the Typically, physicochemical stability is assessed at the
drug may be in contact with materials that could allow preformulation stage of development. A drug sub-
plasticizer leach into the propellant. The typical sta- stance candidate is treated with acid, base, heat,
bility related tests for metered-dose aerosols include light, and oxidative conditions to assess its inher-
appearance, assay, impurities, plume geometry, emit- ent chemical stability. Binary mixtures of the drug
ted dose, particle size distribution of the emitted dose, substance with individual excipients are also inves-
and number of doses per unit. In addition, stabil- tigated at the preformulation stage. These tests are
ity studies on leachables may be required. Shelf life performed to determine the drug substance sensitivity
of metered-dose aerosols drug products may also be to degradation or reactivity with common pharmaceu-
dependent on the orientation that the drug product tical excipients. The most common reactions observed
is stored. Typically most canister type products are for drug substances from these tests include: hydrol-
tested at least in the upright orientation. ysis, epimerization (racemization), decarboxylation,
dehydration, oxidation, polymerization, photochem-
Dry-powdered inhalation products ical decomposition and addition. All drug substances
A dry-powdered inhalation product consists of drug have the potential to degrade by at least one of
with excipients delivered in a dry powdered form. the reactions mentioned above. With an understand-
The delivery system for a dry-powdered inhalation ing of the stability/reactivity of a drug substance in
product may be a separate device or integrated with the preformulation stage, it is possible to formu-
the active. A dry-powdered dosage must reproducibly late the drug product to minimize drug decompo-
deliver a specific amount of drug at a particle size that sition. Numerous examples are described in other
can be deposited into the lungs. Particles too large sections of this book, and the literature is replete with
will get trapped in the throat and particles too small illustrations.
will just be carried out of the lungs on the next expira- Although undesirable reactions between two or
tion. The typical stability related tests for dry powder more drugs are said to result in a physical, chemical, or
inhalation products include appearance, assay, impu- therapeutic incompatibility, physical incompatibility
rities, emitted dose, particle size distribution of the is somewhat of a misnomer. It has been defined as a
emitted dose, and water content. physical or chemical interaction between two or more
ingredients that leads to a visibly recognizable change.
Nasal inhalation products The latter may be in the form of a gross precipitate,
A nasal inhalation product consists of drug with haze, or color change.
excipients delivered from a delivery system. The deliv- On the other hand, a chemical incompatibility is
ery system for a nasal inhalation product may be a classified as a reaction in which a visible change is
separate device or integrated with the active. A nasal not necessarily observed. Since there is no visible
inhalation product must reproducibly deliver a spe- evidence of deterioration, this type of incompati-
cific amount of drug at a particle size and plume that bility requires trained, knowledgeable personnel to
can be deposited into the nasal membrane. Particles recognize it.
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Pharmaceutical analysis and quality control | 159

A therapeutic incompatibility has been defined as The molecular structures most likely to oxidize
an undesirable pharmacological interaction between are those with a hydroxyl group directly bonded to
two or more ingredients that leads to: an aromatic ring (e.g., phenol derivatives such as cat-
echolamines and morphine), conjugated dienes (e.g.,
1. Potentiation of the therapeutic effects of the ingre- vitamin A and unsaturated free fatty acids), hetero-
dients. cyclic aromatic rings, nitroso and nitrite derivatives,
2. Destruction of the effectiveness of one or more of and aldehydes (e.g., flavorings). Products of oxidation
the ingredients. usually lack therapeutic activity. Visual identification
3. Occurrence of a toxic manifestation within the of oxidation, for example, the change from colorless
patient. epinephrine to its amber colored products, may not
be visible in some dilutions or to some eyes.
Oxidation is catalyzed by pH values that are
Chemical reactions
higher than optimum, polyvalent heavy metal ions
The most frequently encountered chemical reactions, (e.g., copper and iron), and exposure to oxygen and
which may occur within a pharmaceutical product, UV illumination. The latter two causes of oxida-
are described below. tion justify the use of antioxidant chemicals, nitrogen
atmospheres during ampoule and vial filling, opaque
Oxidation–reduction external packaging, and transparent amber glass or
Oxidation is a prime cause of product instability, and plastic containers.
often, but not always, the addition of oxygen or the Trace amounts of heavy metals such as cupric,
removal of hydrogen is involved. When molecular chromic, ferrous, or ferric ions may catalyze oxi-
oxygen is involved, the reaction is known as auto- dation reactions. As little as 0.2 mg of copper ion
oxidation because it occurs spontaneously, though per liter considerably reduces the stability of peni-
slowly, at room temperature. cillin. Similar examples include the deterioration of
Oxidation, or the loss of electrons from an atom, epinephrine, phenylephrine, lincomycin, isoprenaline,
frequently involves free radicals and subsequent chain and procaine hydrochloride. Adding chelating agents
reactions. Only a very small amount of oxygen is to water to sequester heavy metals and working in spe-
required to initiate a chain reaction. In practice, it is cial manufacturing equipment (e.g., glass) are some
easy to remove most of the oxygen from a container, means used to reduce the influence of heavy metals
but very difficult to remove it all. Hence, nitrogen and on a formulation. Parenteral formulations should not
carbon dioxide frequently are used to displace the come in contact with heavy metal ions during their
headspace air in pharmaceutical containers to help manufacture, packaging, or storage.
minimize deterioration by oxidation. Hydronium and hydroxyl ions catalyze oxidative
As an oxidation reaction is complicated, it is reactions. The rate of decomposition for epinephrine,
difficult to perform a kinetic study on oxidative pro- for example, is more rapid in a neutral or alkaline
cesses within a general stability program. The redox solution with maximum stability (minimum oxidative
potential, which is constant and relatively easy to decomposition) at pH 3.4. There is a pH range for
determine, can, however, provide valuable predictive maximum stability for any antibiotic and vitamin
information. In many oxidative reactions, the rate preparation, which usually can be achieved by adding
is proportional to the concentration of the oxidizing an acid, alkali, or buffer.
species but may be independent of the concentration Oxidation may be inhibited by the use of antioxi-
of the oxygen present. The rate is influenced by tem- dants, called negative catalysts. They are very effective
perature, radiation, and the presence of a catalyst. in stabilizing pharmaceutical products undergoing
An increase in temperature leads to an acceleration a free-radical-mediated chain reaction. These sub-
in the rate of oxidation. If the storage temperature of stances, which are easily oxidizable, act by possessing
a preparation can be reduced to between 0 and 5◦ C, lower oxidation potentials than the active ingredient.
usually it can be assumed that the rate of oxidation Thus, they undergo preferential degradation or act
will be at least halved. as chain inhibitors of free radicals by providing an
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160 | An Introduction to Pharmacy

electron and receiving the excess energy possessed by or slightly alkaline. Small amounts of acids, alkalis,
the activated molecule. or buffers are used to adjust the pH of a formulation.
The ideal antioxidant should be stable and effec- Buffers are used when small changes in pH are likely
tive over a wide pH range, soluble in its oxidized to cause major degradation of the active ingredient.
form, colorless, nontoxic, nonvolatile, nonirritating, Obviously, the amount of water present can have
effective in low concentrations, thermostable, and a profound effect on the rate of a hydrolysis reac-
compatible with the container-closure system and tion. When the reaction takes place fairly rapidly in
formulation ingredients. water, other solvents sometimes can be substituted.
The commonly used antioxidants for aqueous sys- For example, barbiturates are much more stable at
tems include sodium sulfite, sodium metabisulfite, room temperature in propylene glycol–water than in
sodium bisulfite, sodium thiosulfate, and ascorbic water alone.
acid. For oil systems, ascorbyl palmitate, hydro- Modification of chemical structure may be used to
quinone, propyl gallate, nordihydroguaiaretic acid, retard hydrolysis. In general, as it is only the fraction
butylated hydroxytoluene, butylated hydroxyanisole, of the drug in solution that hydrolyzes, a compound
and alpha-tocopherol are employed. may be stabilized by reducing its solubility. This can
Synergists, which increase the activity of antioxi- be done by adding various substituents to the alkyl
dants, are generally organic compounds that complex or acyl chain of aliphatic or aromatic esters or to
small amounts of heavy metal ions. These include the the ring of an aromatic ester. In some cases less-
ethylenediamine tetraacetic acid (EDTA) derivatives, soluble salts or esters of the parent compound have
dihydroethylglycine, and citric, tartaric, gluconic, and been found to aid product stability. Steric and polar
saccharic acids. EDTA has been used to stabilize complexation has also been employed to alter the rate
ascorbic acid, oxytetracycline, penicillin, epinephrine, of hydrolysis. Caffeine reduces the rate of hydrolysis
and prednisolone. and thus promotes stability by complexation with
Reduction reactions are much less common local anesthetics such as benzocaine, procaine, or
than oxidative processes in pharmaceutical practice. tetracaine.
Examples include the reduction of gold, silver, or Esters and beta-lactams are the chemical bonds
mercury salts by light to form the corresponding free that are most likely to hydrolyze in the presence
metal. of water. For example, the acetyl ester in aspirin is
hydrolyzed to acetic acid and salicylic acid in the
Hydrolysis presence of moisture, but in a dry environment the
Drugs containing the following functional groups: hydrolysis of aspirin is negligible. The aspirin hydrol-
esters (e.g., cocaine, physostigmine, aspirin, tetra- ysis rate increases in direct proportion to the water
caine, procaine, and methyldopa), amides (e.g., vapor pressure in an environment.
dibucaine), imides (e.g., amobarbital), imines The amide bond also hydrolyzes, though generally
(e.g., diazepam), and lactam (e.g., penicillins, at a slower rate than comparable esters. For example,
cephalosporins) are among those prone to hydrolysis. procaine (an ester) will hydrolyze upon autoclaving,
Hydrolysis reactions are often pH dependent and but procainamide will not. The amide or peptide bond
are catalyzed by either hydronium ion or hydroxide in peptides and proteins varies in the lability to hydrol-
ions (specific-acid or specific-base catalysis, respec- ysis. The lactam and azomethine (or imine) bonds in
tively). Hydrolysis reactions can also be catalyzed by benzodiazepines are also labile to hydrolysis. The
either a Brønsted acid or a Brønsted base (general- major chemical accelerators or catalysts of hydrolysis
acid or general-base catalysis, respectively). Sources are adverse pH and specific chemicals (e.g., dextrose
of Brønsted acid or base include buffers and some and copper in the case of ampicillin hydrolysis).
excipients. Sometimes it is necessary to compromise The rate of hydrolysis depends on the temperature
between the optimum pH for stability and that for and the pH of the solution. A much-quoted estimation
pharmacological activity. For example, several local is that for each 10◦ C rise in storage temperature,
anesthetics are most stable at a distinctly acid pH, the rate of reaction doubles or triples. As this is an
whereas for maximum activity they should be neutral empiricism, it is not always applicable.
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Pharmaceutical analysis and quality control | 161

When hydrolysis occurs, the concentration of the polyvalent ions of opposite charge are more likely to
active ingredient decreases while the concentration of be incompatible. Thus, an incompatibility is likely to
the decomposition products increases. The effect of occur upon the addition of a large ion with a charge
this change on the rate of the reaction depends on opposite to that of the drug.
the order of the reaction. With zero-order reactions As many hydrolytic reactions are catalyzed by
the rate of decomposition is independent of concen- both hydronium and hydroxyl ions, pH is an impor-
tration of the ingredient. Although weak solutions tant factor in determining the rate of a reaction. The
decompose at the same absolute rate as stronger ones, pH range of minimum decomposition (or maximum
the weaker the solution, the greater the proportion stability) depends on the ion having the greatest effect
of active ingredient destroyed in a given time; i.e., on the reaction. If the minimum occurs at about pH
the percentage of decomposition is greater in weaker 7, the two ions are of equal effect. A shift of the mini-
solutions. Increasing the concentration of an active mum toward the acid side indicates that the hydroxyl
ingredient that is hydrolyzing by zero-order kinetics ion has the stronger catalytic effect and vice versa in
will slow the percentage decomposition. the case of a shift toward the alkaline side. In gen-
With first-order reactions, which occur frequently eral, hydroxyl ions have the stronger effect. Thus, the
in the hydrolysis of drugs, the rate of change is directly minimum is often found between pH 3 and 4.
proportional to the concentration of the reactive sub- The influence of pH on the physical stability
stance. Thus, changes in the concentration of the of two-phase systems, especially emulsions, is also
active ingredient have no influence on the percentage important. For example, intravenous fat emulsion is
decomposition. destabilized by acidic pH.
The degradation of many drugs in solution
accelerates or decelerates exponentially as the pH Decarboxylation
is decreased or increased over a specific range of Pyrolytic solid-state degradation through decarboxy-
pH values. Improper pH ranks with exposure to lation usually is not encountered in pharmacy, as
elevated temperature as a factor most likely to cause relatively high heats of activation (25 to 30 kcal)
a clinically significant loss of drug, resulting from are required for the reaction. However, solid p-
hydrolysis and oxidation reactions. A drug solution aminosalicylic acid undergoes pyrolytic degradation
or suspension, for example, may be stable for days, to m-aminophenol and carbon dioxide. The reac-
weeks, or even years in its original formulation, but tion, which follows first-order kinetics, is highly
when mixed with another liquid that changes the pH, pH-dependent and is catalyzed by hydronium ions.
it may degrade in minutes or days. It is possible that The decarboxylation of p-aminobenzoic acid occurs
a pH change of only one unit (e.g., from 4 to 3 or 8 only at extremely low pH values and at high tem-
to 9) could decrease drug stability by a factor of ten peratures. Some dissolved carboxylic acids, such as
or greater. p-aminosalicylic acid, lose carbon dioxide from the
A pH-buffer system, which is usually a weak acid carboxyl group when heated. The resulting prod-
or base and its salt, are common excipients used in uct has reduced pharmacological potency. Beta-K
liquid preparations to maintain the pH in a range that decarboxylation can occur in some solid antibiotics
minimizes the drug degradation rate. The pH of drug that have a carbonyl group on the beta-carbon of a
solutions may also be either buffered or adjusted to carboxylic acid or a carboxylate anion. Such decar-
achieve drug solubility. For example, pH in relation to boxylations will occur in the following antibiotics:
pKa controls the fractions of the usually more soluble carbenicillin sodium, carbenicillin free acid, ticarcillin
ionized and less soluble nonionized species of weak sodium, and ticarcillin free acid.
organic electrolytes.
Racemization
Interionic (ion N+ –ion N− ) Compatibility Racemization, or the action or process of changing
The compatibility or solubility of oppositely charged from an optically active compound into a racemic
ions depends mainly on the number of charges per compound or an optically inactive mixture of cor-
ion and the molecular size of the ions. In general, responding R (rectus) and S (sinister) forms, is a
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162 | An Introduction to Pharmacy

major consideration in pharmaceutical stability. Opti- The photodegradation of chlorpromazine through

cal activity of a compound may be monitored by a semiquinone free-radical intermediate follows zero-
polarimetry and reported in terms of specific rotation. order kinetics. On the other hand, alcoholic solutions
Chiral HPLC has been used in addition to polarimetry of hydrocortisone, prednisolone, and methylpred-
to confirm the enantiomeric purity of a sample. nisolone degrade by reactions following first-order
kinetics.
Epimerization Colored-glass containers most commonly are used
to protect light-sensitive formulations. Yellow-green
Members of the tetracycline family are most likely
glass gives the best protection in the UV region,
to incur epimerization. This reaction occurs rapidly
whereas amber confers considerable protection from
when the dissolved drug is exposed to a pH of an
intermediate range (higher than 3), and it results in UV radiation but little from infrared (IR) radiation.
the steric rearrangement of the dimethylamino group. Riboflavin is best protected by a stabilizer that has
The epimer of tetracycline, epitetracycline, has little a hydroxyl group attached to or near the aromatic
or no antibacterial activity. ring. The photodegradation of sulfacetamide solu-
In general, racemization follows first-order kinet- tions may be inhibited by an antioxidant such as
ics and depends on temperature, solvent, catalyst, sodium thiosulfate or metabisulfite.
and the presence or absence of light. Racemization A systematic approach to photostability testing is
appears to depend on the functional group bound to recommended covering, as appropriate, studies such
the asymmetric carbon atom, with aromatic groups as tests on the drug substance, tests on the exposed
tending to accelerate the process. drug product outside of the immediate pack; and if
necessary, tests on the drug product in the immediate
pack. The ICH Q1B Guidance28 discusses the mini-
Photochemical reactions
mum requirements for assessing photostability. Drug
Photolytic degradation can be an important limiting substance is first assessed by exposing sample powder
factor in the stability of pharmaceuticals. A drug can having a depth of not more than 3 mm to an overall
be affected chemically by radiation of a particular
illumination of not less than 1.2 million lux hours
wavelength only if it absorbs radiation at that wave-
and an integrated near-UV energy of not less than
length and the energy exceeds a threshold. Ultraviolet
200 watt hours/square meter. If the drug substance
(UV) radiation, which has a high energy level, is
shows sensitivity to photodegration, then the drug
the cause of many degradation reactions. Exposure
product will need to be tested as well. The testing of
to, primarily, UV illumination may cause oxidation
drug product uses the same light exposure that was
(photo-oxidation) and scission (photolysis) of cova-
used to test drug substance. The drug product should
lent bonds. Nifedipine, nitroprusside, riboflavin, and
be tested directly exposed to light and in its container
phenothiazines are very labile to photo-oxidation. In
closure system.
susceptible compounds, photochemical energy creates
free radical intermediates, which can perpetuate chain
reactions. Ultrasonic energy
If the absorbing molecule reacts, the reaction Ultrasonic energy, which consists of vibrations and
is said to be photochemical in nature. When the waves with frequencies greater than 20,000 Hz,
absorbing molecules do not participate directly in promotes the formation of free radicals and alters
the reaction, but pass their energy to other reacting drug molecules. Changes in prednisolone, prednisone
molecules, the absorbing substance is said to be a acetate, or deoxycorticosterone acetate suspensions
photosensitizer. in an ultrasonic field have been observed spectromet-
As many variables may be involved in a photo- rically in the side chain at C-17 and in the oxo group
chemical reaction, the kinetics can be quite complex. of the A ring. With sodium alginate, in an ultrasonic
The intensity and wavelength of the light and the size, field, it has been reported that above a minimum
shape, composition, and color of the container may power output, degradation increased linearly with
affect the velocity of the reaction. increased power.
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Pharmaceutical analysis and quality control | 163

Ionizing radiation
Shelf life estimation with upper acceptance criterion based on
Ionizing radiation, particularly gamma rays, has been 3.0
a degradation product at 25°C/60%RH

used for the sterilization of certain pharmaceutical

2.5

Degradation product (%)

products. At the usual sterilizing dose, 2.5 mRad, it
seldom causes appreciable chemical degradation. In 2.0

general, formulations that are in the solid or frozen 1.5

state are more resistant to degradation from ioniz- 1.0

ing radiation than those in liquid form. For example,
0.5
many of the vitamins are little affected by irradiation
0.0
in the solid state but are decomposed appreciably in 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
solution. On the other hand, both the liquid- and Time point (months)
solid-state forms of atropine sulfate are affected seri- Raw data Regression line
ously by radiation. Upper confidence limit Upper acceptance
criterion: 1.4

Predicting shelf life Figure 6.2 Typical one-sided shelf life estimation plot.

ICH recommended evaluation

The shelf life of a commercial drug product must be the acceptance limit. Trend analysis of data need only
be performed on test data that show a change related
determined in the commercial container closure at
to time.
the defined storage conditions. The FDA and ICH
Q1A (R2) Guidances29 require at least 12 months
stability data at the time of submission. Most products Pharmaceutical containers
require at least 24 months shelf life to be commercially
The official standards for containers apply to arti-
viable. The ICH Q1E Guidance30 recommends how
cles packaged by either the pharmaceutical manufac-
the 12 months data may be used to predict long-term
turer or the dispensing pharmacist unless otherwise
stability. Figures 6.1 and 6.2 show trending graphs
indicated in a compendial monograph. In general,
with double-sided and single-sided 95% confidence
repackaging of pharmaceuticals is inadvisable. How-
limits plots, respectively. The expiration of a product
ever, if repackaging is necessary, the manufacturer of
is the time where the confidence line intersects with
the product should be consulted for potential stability
problems.
A pharmaceutical container has been defined as
Shelf life estimation with upper and lower acceptance
criteria based on assay at 25°C/60%RH a device that holds the drug and is, or may be, in
120 direct contact with the preparation. The immediate
115 container is described as that which is in direct contact
Assay (% of label claim)

110 with the drug at all times. The liner and closure
105 traditionally have been considered to be part of the
100
container system. The container should not interact
95
physically or chemically with the formulation so as
90
to alter the strength, quality, or purity of its contents
85
beyond permissible limits.
80
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 The choice of containers and closures can have
Time point (months) a profound effect on the stability of many pharma-
Raw data Regression line
ceuticals. Now that a large variety of glass, plastics,
Upper confidence limit Upper acceptance criterion: 105 rubber closures, tubes, tube liners, etc. are available,
Lower confidence limit Lower acceptance criterion: 95
the possibilities for interaction between the packag-
ing components and the formulation ingredients are
Figure 6.1 Typical two-sided shelf life estimation plot. immense. Some of the packaging elements themselves
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164 | An Introduction to Pharmacy

are subject to physical and chemical changes that may New, unused glass containers are tested for resis-
be time–temperature dependent. tance to attack by high-purity water by use of a
Frequently, it is necessary to use a well-closed or sulfuric acid titration to determine the amount of
a tight container to protect a pharmaceutical product. released alkali. Both glass and plastic containers
A well-closed container is used to protect the con- are used to protect light-sensitive formulations from
tents from extraneous solids or a loss in potency of degradation. The amount of transmitted light is mea-
the active ingredient under normal commercial con- sured using a spectrometer of suitable sensitivity and
ditions. A tight container protects the contents from accuracy.
contamination by extraneous materials, loss of con- Glass is generally available in flint, amber, blue,
tents, efflorescence, deliquescence, or evaporation and emerald green, and certain light-resistant green and
is capable of tight re-closure. When the packaging and opal colors. The blue-, green-, and flint-colored
storage of an official article in a well-closed or tight glasses, which transmit UV and violet light rays, do
container is specified, water-permeation tests should not meet the official specifications for light-resistant
be performed on the selected container. containers.
In a stability program, the appearance of the Colored glass usually is not used for injectable
container, with special emphasis on the inner walls, preparations, since it is difficult to detect the pres-
the migration of ingredients onto/into the plastic or ence of discoloration and particulate matter in the
into the rubber closure, the migration of plasticizer formulations. Light-sensitive drugs for parenteral use
or components from the rubber closure into the usually are sealed in flint ampoules and placed in a
formulation, the possibility of two-way moisture box. Multiple-dose vials should be stored in a dark
penetration through the container walls, the integrity place.
of the tac-seal, and the back-off torque of the cap, Manufacturers of prescription drug products
must be studied. should include sufficient information on their product
labels to inform the pharmacist of the type of
dispensing container needed to maintain the identity,
strength, quality, and purity of the product. This
Glass
brief description of the proper container, such as
Traditionally, glass has been the most widely used light-resistant, well-closed, or tight, may be omitted
container for pharmaceutical products to ensure inert- for those products dispensed in the manufacturer’s
ness, visibility, strength, rigidity, moisture protec- original container.
tion, ease of re-closure, and economy of packaging.
Although glass has some disadvantages, such as the Plastics
leaching of alkali and insoluble flakes into the for- Plastic containers have become very popular for
mulation, these can be offset by the choice of an storing pharmaceutical products. Polyethylene,
appropriate glass. As the composition of glass may be polystyrene, polyvinyl chloride, and polypropylene
varied by the amounts and types of sand and silica are used to prepare plastic containers of various
added and the heat treatment conditions used, the densities to fit specific formulation needs.
proper container for any formulation can be selected. Factors such as plastic composition, processing
According to USP 35, glass containers suitable and cleaning procedures, contacting media, inks,
for packaging pharmacopeial preparations may be adhesives, absorption, adsorption, and permeability
classified as either Type I, Type II, Type III, or type NP. of preservatives also affect the suitability of a
Containers of Type I borosilicate glass are generally plastic for pharmaceutical use. Hence, biological
used for preparations that are intended for parenteral test procedures are used to determine the suitability
administration, although Type II treated soda-lime of a plastic for packaging products intended for
glass may be used where stability data demonstrate parenteral use and for polymers intended for use in
its suitability. Containers of Type III and Type NP implants and medical devices. Systemic injection and
are intended for packaging articles intended for oral intracutaneous and implantation tests are employed.
or topical use. In addition, tests for nonvolatile residue, residue on
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Pharmaceutical analysis and quality control | 165

ignition, heavy metals, and buffering capacity were As with plastic bottles, the blister package will
designed to determine the physical and chemical allow a certain amount of moisture vapor permeation
properties of plastics and their extracts. to occur, and this must be a consideration when
The high-density polyethylene (HDPE) containers, selecting the type of film used for the package. The
which are used for packaging capsules and tablets, choice of packaging materials used depends on the
possess characteristic thermal properties, a distinc- degree to which the product needs to be protected
tive IR absorption spectrum, and a density between from light, heat, and moisture. Each material has
0.941 and 0.965 g/cm3 . In addition, these containers different resistance to each of these elements and
are tested for light transmission, water-vapor perme- will affect the shelf life and storage conditions of the
ation, extractable substances, nonvolatile residue, and packaged pharmaceutical.
heavy metals. When a stability study has been per- Polyvinylchloride (PVC) offers the least resistance
formed to establish the expiration date for a dosage to moisture vapor permeation. Polyvinylidenechloride
form in an acceptable HDPE container, any other (PVdC) has characteristics similar to PVC but offers
HDPE container may be substituted provided that it, superior resistance to moisture vapor permeation.
too, meets compendial standards and that the sta- Aclar, which is a polychlorotrifluoroethylene (PVC-
bility program is expanded to include the alternative CTFE) film has the lowest water vapor permeability
container. and thus offers the best protection from moisture.
Materials from the plastic itself can leach into
the formulation, and materials from the latter can Metals
be absorbed onto, into, or through the container The pharmaceutical industry was, and to a degree
wall. The barrels of some plastic syringes bind vari- still is, a tin stronghold. However, as the price of tin
ous pharmaceutical preservatives. However, changing constantly varies, more-collapsible aluminum tubes
the composition of the syringe barrel from nylon to are being used.
polyethylene or polystyrene has eliminated the bind- A variety of internal linings and closure fold seals
ing in some cases. are available for both tin and aluminum tubes. Tin
A major disadvantage of plastic containers is tubes can be coated with wax or with vinyl linings.
the two-way permeation or breathing through the Aluminum tubes are available with lining of epoxy or
container walls. Volatile oils and flavoring and per- phenolic resin, wax, vinyl, or a combination of epoxy
fume agents are permeable through plastics to varying or phenolic resin with wax. As aluminum is able
degrees. Components of emulsions and creams have to withstand the high temperatures required to cure
been reported to migrate through the walls of some epoxy and phenolic resins adequately, tubes made
plastics, causing either a deleterious change in the from this metal presently offer the widest range of
formulation or collapse of the container. Loss of lining possibilities.
moisture from a formulation is common. Gases, such Closure fold seals may consist of unmodified vinyl
as oxygen or carbon dioxide in the air, have been resin or plasticized cellulose and resin, with or without
known to migrate through container walls and affect added color.
a preparation. Collapsible tubes are available in many combi-
Solid dosage forms, such as penicillin tablets, nations of diameters, lengths, openings, and caps.
when stored in some plastics, are affected deleteri- Custom-use tips for ophthalmic, nasal, mastitis, and
ously by moisture penetration from the atmosphere rectal applications also are available. Only a lim-
into the container. ited number of internal liners and closure seals are
Single unit does packaging in the form of blister available for tubes fitted with these special-use tips.
packages are often used to package capsule and tablet Lined tubes from different manufacturers are not
dosage forms. A typical blister package comprises a necessarily interchangeable. Although some converted
polymeric film that is molded to have a cavity into resin liners may be composed of the same base resin,
which the dosage form is placed. The polymer film is the actual liner may have been modified to achieve
then heat bonded to a paper backed foil liner. better adhesion, flow properties, drying qualities, or
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166 | An Introduction to Pharmacy

flexibility. These modifications may have been neces- products. They also serve as the primary compo-
sitated by the method of applying the liner, the curing nents to demonstrate therapeutic equivalence between
procedure, or, finally, the nature of the liner itself. generic products and the reference innovator product.
Changes in bioavailability can be thought of in
terms of changes in exposure to the drug. If these
Closures changes are substantial, then they can alter the safety
The closures for the formulations also must be stud- and efficacy profile of the compound in question. The
ied as a portion of the overall stability program. bioavailability of orally administered drugs can be
Although the closure must form an effective seal for affected by numerous factors. These include food or
the container, the closure must not react chemically or fed state, differences in drug metabolism, drug–drug
physically with the product. It must not absorb mate- interactions, gastrointestinal transit time, and changes
rials from the formulation or leach its ingredients into in dosage form release characteristics (especially for
the contents. modified release products).
The integrity of the seal between the closure and Bioequivalence is an important consideration in
container depends on the geometry of the two, the ensuring lot-to-lot consistency, including whenever
materials used in their construction, the composition evaluating changes in a marketed product’s formu-
of the cap liner, and the tightness with which the cap lation, manufacturing process, and dosage strength.
has been applied. Torque is a measure of the circu- Bioequivalence is also critical in regulatory authority
lar force, measured in inch-pounds, which must be decision making when determining whether a generic
applied to open or close a container. When pharma- product is therapeutically equivalent to the original
ceutical products are set up on a stability study, the innovator product.
formulation must be in the proposed market package. In addition, chemical equivalence, lot-to-lot uni-
Thus, they should be capped with essentially the same formity of physicochemical characteristics, and stabil-
torque to be used in the manufacturing step. ity equivalence are other factors that are important,
Rubber is a common component of stoppers, cap as they too can affect product quality. Also, bioavail-
liners, and parts of dropper assemblies. Sorption of ability and bioequivalence topics are emphasized for
the active ingredient, preservative, or other formula- solid oral dosage forms. However, many of the gen-
tion ingredients into the rubber and the extraction eral concepts can also be applied to other dosage
of one or more components of the rubber into the forms, including biologics.
formulation are common problems.
The application of an epoxy and polytetrafluo- General concepts
roethylene lining to the rubber closure reduces the
amount of leached extractives but essentially has no The terms used in this section require careful defini-
effect on the sorption of the preservative from the solu- tion, since, as in any area, some terms have been used
tion. Polytetrafluoroethylene-coated rubber stoppers in different contexts by different authors.
may prevent most of the sorption and leaching. Bioavailability is a term that indicates measure-
ment of both the rate of drug absorption and the
total amount (extent) of drug that reaches the sys-
Bioavailability and bioequivalence temic circulation from an administered dosage form.
It is specific to the parent or active drug substance as
testing contrasted to metabolites.
Equivalence is more a general and relative term
Introduction
that indicates a comparison of one drug product with
Understanding the concepts of bioavailability and another. Equivalence may be defined in several ways:
bioequivalence testing is essential in the drug devel-
opment process because they create the foundation for • Bioequivalence indicates that a drug in two or
regulatory decision making when evaluating formu- more similar dosage forms reaches the systemic
lation changes and lot-to-lot consistency in innovator circulation at the same relative rate and extent (i.e.,
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Pharmaceutical analysis and quality control | 167

the plasma level profiles of the drug obtained using • development of techniques to measure microgram
the two dosage forms are the same). or nanogram quantities of drugs in biological fluids
• Chemical equivalence considers that two or more • improvements in the technology of dosage form
dosage forms contain the same labeled quantities formulation and physical testing
(within specified limits) of the drug. • awareness of reported clinical differences from the
• Clinical equivalence occurs when the same drug literature in otherwise similar products
from two or more dosage forms gives identical • increased cost of classical clinical evaluation
in vivo effects as measured by a pharmacological • objective and quantitative nature of bioavailability
response or by control of a symptom or disease. tests
• Pharmaceutical equivalence refers to two drug • an increase in the number of chemically equivalent
products with the same dosage form and same products on the market because of patent expira-
strength. tions and the Drug Price Competition and Patent
• Therapeutic equivalence implies that two brands Term Restoration Act of 1984 (Hatch-Waxman
of a drug product are expected to yield the same Act), which established the generic drug approval
clinical result. The FDA specifically uses the term procedures that are in place today.
‘‘therapeutic equivalence’’ in the evaluation of
multi-source prescription drug products (generic The increase in the number of drugs that are
drugs). available from multiple sources frequently has placed
people involved in the delivery of healthcare in the
Area under the Concentration–Time Curve position of having to select one from among several
(AUC) is the integral of the concentration–time curve marketed products. As with any decision, the more
after administration of a single dose of drug or after data available, the more comfortable one is in arriving
achieving a steady state. The calculated area under at the final decision. The need to make these choices,
the serum, blood, or plasma concentration–time in light of the potential failure to demonstrate in vivo
curve is reported in amount/volume multiplied by equivalence between products or different batches
time (e.g., μg/mL × h or g/100 mL × h) and can of the same product, has increased the demand for
be considered representative of the amount of drug quantitative data. Bioequivalence testing represents a
absorbed. Several variants of AUC exist, including bridging alternative to clinical testing for efficacy and
AUC0-t ; AUC0-∞ ; and AUCτ , ss , corresponding to the safety in such cases and is the means by which generic
calculated area from time zero to a truncated time drugs are approved for marketing. In addition, this
point (e.g., AUC0-48 ), the total area under the curve, is also the means by which the quality of all drug
and the area when steady state has been achieved. products is maintained in situations involving major
Peak-height Concentration (Cmax ) is the peak of changes in formulation or manufacturing process.
the blood level–time curve and represents the highest Requirements for bioequivalence data on drug
drug concentration achieved after drug administra- products should be applied reasonably. The reason
tion. for bioequivalence testing should not be overlooked
Time of Peak Concentration (T max ) is the mea- (i.e., it is used as a surrogate, in certain situations,
sured length of time necessary to achieve the maxi- for the clinical evaluation of drug products). In
mum concentration (Cmax ) after drug administration. some instances, bioequivalence data cannot reliably
be obtained if the bioanalytical methodology is not
available. However, in such cases pharmacodynamic
Bioequivalence testing
data may provide a more sensitive, objective evalua-
The awareness of the potential for clinical differ- tion of a product’s therapeutic equivalence and may
ences between otherwise chemically equivalent drug be explored as an alternative evaluation method in
products has been brought about by a multiplicity of the absence of relevant bioanalytical methodology.
factors that include, among others: Basic pharmacokinetic evaluation of bioavailabil-
ity data is not necessary to show bioequivalence of
• better methods for clinical efficacy evaluation two drug products. Pharmacokinetics has its major
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168 | An Introduction to Pharmacy

utility in the prediction or projection of dosage reg- 6. Well-controlled clinical trials in humans that
imens and/or in providing a better understanding of establish the safety and efficacy of the drug
observed drug reactions or interactions that result product, for establishing bioavailability. For
from the accumulation of drug in some specific site, bioequivalence, comparative clinical trials may be
tissue, or compartment of the body. The basis for the considered. This approach is the least accurate,
conclusion that two drug products are bioequivalent sensitive, and reproducible approach, and should
must be that the drug concentrations measured in a be considered only if other approaches are not
biological matrix, or alternatively the pharmacolog- feasible.
ical response, for one drug product are essentially 7. A currently available in vitro test, acceptable to
the same for the second drug product. The more FDA, that ensures bioavailability. This approach
straightforward decisions in the evaluation of bioe- is intended only when in vitro testing is deemed
quivalence between two drug products are those in adequate, but no in vitro–in vivo correlation
which the two products are exactly superimposable (IVIVC) has been established. It also can relate to
(definitely bioequivalent). Those in which the two considerations involving the Biopharmaceutics
products differ in their bioequivalence parameters by Classification System (BCS).
a large amount, such as 50% or more, are most def-
initely not bioequivalent. Statistical evaluation of the Most bioequivalence studies involve the direct
data is necessary for all situations, particularly for measurement of the parent drug, as described in item
data that exist between these two extremes. 1 above. Bioequivalence testing in animals is not a
recommended approach due to possible differences in
metabolism, gastrointestinal physiology, weight, and
Methods for determining bioequivalence
diet.
Bioequivalence usually involves human testing but
sometimes may be demonstrated using an in vitro
Therapeutic equivalence evaluations
bioequivalence standard, especially when such an in
vitro test has been correlated with human in vivo The FDA publication Approved Drug Products with
bioavailability data. In other situations, bioequiv- Therapeutic Equivalence Evaluations31 identifies drug
alence may be demonstrated through comparative products approved on the basis of safety and effec-
clinical trials or pharmacodynamic studies. tiveness. In addition, this list contains therapeutic
The FDA has categorized (21CFR320.24) various equivalence evaluations for approved multi-source
in vivo and in vitro approaches that may be utilized prescription drug products. These evaluations have
to establish bioequivalence. These are, in descending been prepared to serve as public information and
order of accuracy, sensitivity and reproducibility, advice to state health agencies, physicians, and phar-
macists to promote public education in the area of
1. An in vivo test in humans in which the active drug drug product selection and to foster containment of
substance, as well as active metabolites when healthcare costs.
appropriate, is measured in plasma. To help contain drug costs, virtually every state
2. An in vitro test that has been correlated with has adopted laws and/or regulations that encourage
human in vivo bioavailability data. This approach the substitution of drug products. These state laws
is most likely for oral modified release products generally require either that substitution be limited
and is described in detail in FDA Guidance. to drugs on a specific list (the positive formulary
3. An in vivo test in animals that has been correlated approach) or that substitution be permitted for all
with human bioavailability data. drugs except those prohibited by a particular list (the
4. An in vivo test in humans, where urinary excre- negative formulary approach). Because of the num-
tion of the active drug substance, as well as active ber of requests for FDA assistance in preparing both
metabolites when appropriate, is measured. positive and negative formularies, it became apparent
5. An in vivo test in humans in which an appropriate that the FDA could not serve the needs of each state
acute pharmacological effect is measured. on an individual basis. The agency also recognized
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Pharmaceutical analysis and quality control | 169

that providing a single list based on common criteria Chromatographic methods

would be preferable to evaluating drug products on
of analysis
the basis of differing definitions and criteria in various
state laws. The therapeutic equivalence evaluations
The term ‘‘chromatography’’ is derived from Greek,
in this publication reflect FDA’s application of spe-
chroma meaning, ‘‘color,’’ and graphein meaning ‘‘to
cific criteria to the approved multi-source prescription
write.’’ Mikhail Tswett (1906),32 a Russian botanist,
drug products.
used the technique to separate various plant pigments
FDA classifies as therapeutically equivalent those
by passing solutions of them through glass columns
products that meet the following general criteria:
packed with finely divided calcium carbonate. The
separated species appeared as colored bands on the
1. They are approved as safe and effective. column, and based on this phenomenon, this process
2. They are pharmaceutical equivalents in that they was called chromatography. The chromatographic
(A) contain identical amounts of the same active technique is now widely used for the separation,
drug ingredient in the same dosage form and route identification, and determination of the chemical com-
of administration and (B) meet compendial or ponents in complex mixture.
other applicable standards of strength, quality, Chromatography, according to USP, can be
purity, and identity. defined as a procedure by which solutes are separated
3. They are bioequivalent in that (A) they do not by a differential migration process in a system
present a known or potential bioequivalence prob- consisting of two or more phases, one of which
lem, and they meet an acceptable in vitro stan- moves continuously in a given direction and in which
dard, or (B) if they do present such a known or the individual substances exhibit different mobilities
potential problem, they are shown to meet an by reason of differences in adsorption, partition,
appropriate bioequivalence standard. solubility, vapor pressure, molecular size, or ionic
4. They are adequately labeled. charge density. The individual substances thus
5. They are manufactured in compliance with Cur- obtained can be identified or determined by analytical
rent Good Manufacturing Practice regulations. methods.33 Thus, the term chromatography can
be applied to a group of methods for separating
This concept of therapeutic equivalence applies molecular mixtures. One of the phases is a fixed
only to drug products containing the same active bed of large surface area, whereas the other is a
ingredient(s) and does not encompass a comparison fluid that moves through or over the surface of the
of different therapeutic agents used for the same fixed phase. The components of the mixture must
condition. The FDA considers drug products to be be of molecular dimensions, which require that they
therapeutically equivalent if they meet the criteria out- be in solution or in the vapor state. The relative
lined above, even though they may differ in certain affinity of the solutes for each of the phases must be
other characteristics such as shape, scoring config- reversible to ensure that mass transfer occurs during
uration, release mechanisms, packaging, excipients, the chromatographic separation. The fixed phase is
expiration date/time, and minor aspects of labeling called the stationary phase, and the other is termed
(e.g., the presence of specific pharmacokinetic infor- the mobile phase. The stationary phase may be a
mation). The FDA believes that products classified porous or finely divided solid or a liquid that has
as therapeutically equivalent can be substituted with been coated in a thin-layer on an inert supporting
the full expectation that the substituted product will material. It is necessary that the stationary phase
produce the same clinical effect and safety profile as particles be as small and homogeneous as possible
the prescribed product. to provide a large surface area so that sorption and
As described, the concepts of bioavailability and desorption of the solutes will occur frequently and
bioequivalence testing are essential in the drug devel- efficiently. Depending on the type of chromatography
opment process by creating the foundation for regu- employed, the mobile phase may be a pure liquid or
latory decision for both innovator and generic drug a mixture of solutions (e.g., buffers), or it may be a
products. gas (pure or a homogeneous mixture).
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170 | An Introduction to Pharmacy

Modern pharmaceutical formulations are com- chromatography in which the stationary phase is a
plex mixtures including, in addition to one or more plane, in the form of a solid supported on an inert
medicinally active ingredients, a number of inert plate.
materials such as diluents, disintegrants, colors, and
flavors. To ensure quality and stability of the final Partition chromatography
product, the pharmaceutical scientist must be able to The stationary phase is a liquid supported on an
separate these mixtures into individual components inert solid. Again, the mobile phase is a liquid
prior to quantitative analysis. The complex nature (liquid–liquid partition chromatography) or a gas
of the polymers used in the manufacture of novel (gas–liquid chromatography). Paper chromatography
drug delivery systems makes the drug separation even is a type of partition chromatography in which the
more complicated. Moreover, comparison of the rel- stationary phase is a layer of water adsorbed on a
ative efficacy of different dosage forms of the same sheet of paper. In the normal mode of operations of
drug entity requires the analysis of the active ingre- liquid–liquid partition, a polar stationary phase (e.g.,
dient in biological matrices such as blood, urine, and water or methanol) is used with a nonpolar mobile
tissue. phase (e.g., hexane). This favors retention of polar
Among the most powerful techniques available to compounds and elution of nonpolar compounds and
the analyst for the resolution of these mixtures are a is called normal-phase chromatography. If a nonpolar
group of highly efficient methods collectively called stationary phase is used along with a polar mobile
chromatography. Because this technique is involved phase, then nonpolar solutes are retained favoring
so intimately in all aspects of pharmaceutical research elution of polar solutes. This is called reversed-phase
and development, the pharmacist or pharmaceuti- chromatography.
cal scientist should possess a working knowledge
of chromatographic principles and techniques. Elec- Ion-exchange chromatography
trophoresis, a separation technique especially useful This technique uses an ion-exchange resin as the
for resolving mixtures of biological molecules, has stationary phase. Ion-exchange resin is a polymeric
some similarities to chromatography. matrix with the surface of which ionic functional
groups, such as carboxylic acids or quaternary amines,
have been chemically bonded. The mechanism of sep-
Classification of chromatographic
aration is based on ion-exchange equilibrium. As the
methods
mobile phase passes over this surface, ionic solutes
Chromatographic techniques can be classified into six are retained by forming electrostatic chemical bonds
types based on the type of equilibration process. These with the functional groups. The mobile phases used
are (1) adsorption, (2) partition, (3) ion-exchange, (4) in this type are always liquid. When choosing a
permeation, (5) affinity, and (6) capillary electro- chromatographic format for the analysis of an ionic
chromatography. compound, ion-exchange is generally considered after
attempts at developing a reversed-phase method have
Adsorption chromatography proven unsuccessful. However, ion-exchange chro-
The stationary phase is a solid on which the sam- matography is the method of choice for the analysis
ple components are adsorbed. The mobile phase of inorganic ions, and it is often preferable to reversed-
may be a liquid (liquid–solid chromatography) or phase methods for the analysis of small organic ions.
a gas (gas–solid chromatography); the components
distribute between the two phases through a combi- Permeation chromatography
nation of sorption and desorption processes. Column In this technique, the stationary phase is a polymeric
chromatography is a typical example of adsorption substance containing numerous pores of molecular
chromatography in which the solid stationary phase dimensions. The mobile phase contains analytes as
is packed in a tubular column, and the mobile phase solvated molecules that are separated according to
is allowed to flow through the solid. Thin-layer their size by their ability to penetrate a sieve-like
chromatography is another example of adsorption structure (the stationary phase). Larger molecules that
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Pharmaceutical analysis and quality control | 171

will not fit into the pores remain in the mobile phase
and are not retained. This method is most suited to the Chromatography
separation of mixtures in which the solutes vary con-
siderably in molecular size. The mobile phase may be 1. Adsorption chromatography
either liquid or gaseous. Size-exclusion chromatogra- 1. Gas-solid chromatography
phy is used extensively for the preparative separations 2. Liquid column chromatography
3. High-performance liquid chromatography
of macromolecules of biological origin as well as for 4. Thin-layer chromatography
the purification of synthetic-organic polymers.
2. Partition chromatography
Affinity chromatography 1. Gas-liquid chromatography
2. Supercritical fluid chromatography
This technique utilizes highly specific interactions 3. Liquid–liquid chromatography
between one kind of solute molecule and a second 4. Paper chromatography
5. High-performance liquid chromatography
molecule covalently attached (immobilized) to the sta-
tionary phase. The immobilized molecule can be an 3. Ion-exchange chromatography
antibody to a particular protein. When a crude mix- 1. Ion-exchange chromatography
ture containing a large number of proteins is passed 2. High-performance liquid chromatography
through the column, only the protein that reacts with
4. Permeation chromatography
the antibody is bound to the column. After washing
all the other solutes off the column, the desired pro- Size-exclusion chromatography
tein is dislodged from the antibody by changing the
pH or ionic strength. 5. Affinity chromatography

Dna affinity chromatography

Capillary electro-chromatography (CEC)
6. Electrophoresis
Capillary electro-chromatography (CEC) can be
defined as a liquid chromatographic method, in Capillary electro-chromatography

which the mobile phase is electro-osmotically driven

Figure 6.3 Classification of chromatographic techniques.
through the chromatographic bed. The mobile
phase in CEC has proven to be superior over other
chromatographic methods in terms of its efficiency in
separating ionic compounds and biomolecules. of their convenience and simplicity. Column chro-
The classifications given above for the various matography offers a wide choice of stationary phases
types of chromatographic processes can be decep- and is useful for the separation of individual com-
tive in their simplicity. Except in isolated cases, pounds, in quantity, from mixtures. Both GC and
pure adsorption or partition chromatography rarely HPLC require elaborate apparatus and usually pro-
occurs. In practice, separations frequently result from vide sophisticated methods to identify and quantify
combination of adsorption and partitioning effects. very small amounts of the material. A distinction
The ultimate success of a chromatographic sepa- needs to be made between analytical and preparative-
ration depends on the ability of analysts to rec- scale chromatography. Analytical processes are used
ognize the limitations of the methods and adjust to identify and quantify tiny amounts of unknown
their experiments accordingly. The individual types materials. Preparative-scale chromatographic systems
of chromatographic techniques mentioned above are generally consist of a large cylindrical column within
shown in Fig. 6.3. The types of chromatography which the stationary material is packed. The mobile
useful in qualitative and quantitative analysis that phase is invariably a liquid, and the stationary phase
are employed in the USP assays and tests are Col- is either a solid, or a liquid supported by an adsor-
umn, Gas, Paper, Thin-Layer, and High-Pressure or bent solid. Since the column is packed with stationary
High-Performance Liquid Chromatography (HPLC). phase, liquid mobile phase must be forced through
Paper and thin-layer chromatography are ordinarily the column at a steady pressure for achieving the
more useful for purposes of identification because separation of the solutes of interest.
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172 | An Introduction to Pharmacy

Spectroscopic methods of analysis those of light. The oscillation of an electron gives rise
to electromagnetic radiation. As is illustrated in Fig.
Introduction 6.4, at each point in the direction of the beam, the
electric field and magnetic field, represented by two
Spectroscopic methods of analysis have the advantage vectors (E and H, respectively), are perpendicular
over chromatographic methods in that they give direct to each other. The wavelength (λ) is defined as the
information concerning the structure of a molecule. distance between successive maxima or minima and is
Thus, they are used to characterize molecules and, expressed in nanometers (nm, 10−9 meters), although
with sufficient information, conclusively identify both it was formerly measured in Angstroms (Å, where 1
structurally and conformationally. Spectroscopic Å = 0.1 nm). It is nm which is the usual unit used in
methods of analysis rely on the absorption or UV, and sometimes NIR spectroscopy. The reciprocal
emission of electromagnetic radiation, as a result of of wavelength (1/ν) is referred to as the wavenumber
its interaction with matter. These methods include (ν), expressed in reciprocal centimeters (cm−1 ). The
UV, visible, near-infrared (NIR), infrared (IR), wavenumber is employed particularly in describing
florescence, and Raman techniques together with the position of peak maxima for IR spectra, and
nuclear magnetic resonance (NMR) spectroscopy. sometimes for NIR spectra. The frequency in cycles
Figure 6.4 shows their relative positions in the per second (cps or Hz) is denoted by ν. The frequency
electromagnetic spectrum, and Table 6.2 provides is related to λ by ν = c/λ, where c is the velocity of
a comparison of the characteristics of the different
light in vacuum. The time required for the completion
spectroscopic methods of analysis.
of one cycle is designated by τ , which is related to ν
by τ = 1/ν.
Planck, in 1900, formulated a concept of quantum
Theory
restriction. He stated that oscillating atoms of a hot
Maxwell first expressed the concept of the electro- body can only have energies that are integral multiples
magnetic field in 1860. His equations theorized the of hν, where h is Planck’s constant (6.6256 × 10−27
existence of waves that travel through electromag- erg s; 6.62606957 × 10−34 J s; 4.135667516 × 10−15
netic fields and whose properties are identical to eV s). In other words, the energy of an oscillator

C
E

Figure 6.4 The electromagnetic spectrum.

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Pharmaceutical analysis and quality control | 173

Table 6.2 Comparative characteristics of spectroscopic methods of analysis

Technique Wavelength Source Detector Sample Information Application

(nm) type

Absorption
Spectroscopy

Ultraviolet/Far UV 200 to 380 nm Hydrogen or Photomultiplier Vapor/solution Little structural Qualitative and
deuterium lamp tube (photodiode information but quantitative analysis,
array, photon diode) the presence of confirmation analysis,
and semiconductors unsaturated multi-component
(Charge transfer sites in the analysis, derivative
devices) molecule spectroscopy

Visible 380 to 780 nm Tungsten lamp Photomultiplier Vapor/solution Presence of Quantitative analysis,
or deuterium tube and unsaturated confirmation analysis
arc lamp semiconductors sites in the (purity control)
molecule

Infrared 2.5 to 40 μm Nernst or globar Thermocouple or Gas, liquid or R–H vibrational Characterization of
unit bolometer solid (NaCl, KBr, mode molecules
and CsBr disks)

Fourier transform 2.5 to 40 μm Zirconium oxide Mercury cadmium Same as IR Structural Qualitative powers of
infrared (FTIR) or rare earth telluride (MCT), analysis FTIR coupled with
oxides (Nernst deuterated separation technique as
source), silicon triglycerine sulfate GC-FTIR and LC-FTIR
carbide (DTGS) crystal or
lithium tantalite
(LiTaO3 )

Diffuse Reflectance 1 to 10 μm Same as IR Same as IR Sample is Structural IR spectra of solid

(Specular or diffuse diluted with KBr analysis samples, i.e., drugs,
or attenuated total powder pharmaceuticals, food
reflection) products, soap powder,
coal, clay, paper, painted
surfaces, polymer foam,
catalysts

Infrared Microscopy Same as IR Same as IR Same as IR Same as IR Same as IR Flaws and variations in
bulk properties of
matrices

Pattern Recognition UV and IR Identification and

Analysis regions differentiation of plastic
materials used in
pharmaceutical packing

Hierarchical Cluster UV and IR

Analysis regions

(continued overleaf)
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174 | An Introduction to Pharmacy

Table 6.2 (continued)

Technique Wavelength Source Detector Sample Information Application

(nm) type

Emission AC-, DC, and AC Qualitative detection of

Spectrometry spark all metals and
nonmetallic elements

Flame Photometry No light source Qualitative and Group IA and IIA metals
quantitative (Quality control
analysis measurement of alkaline
or alkaline earth metals)

Plasma Emission No light Elemental analysis

source/hollow
cathodelamp

Fluorescence Visible or UV Xenon arc lamp Polycyclic aromatic

Spectroscopy range hydrocarbons (PAH)
analysis in water,
measurement of
aflatoxins

Raman 4000 to Helium/neon Photomultiplier Vibrational and Qualitative/quantitative

Spectroscopy 25 cm−1 laser detector rotational analysis of inorganic,
energy organic, and biological
modification systems

is discontinuous, and any change in the energy can change in the energy level of a molecule. Quantum
occur only by a jump between two energy states. restrictions specify certain conditions for the interac-
Planck showed that the energy in a photon of light is tion of radiation with a molecule. On many occasions,
related to wave frequency by the expression E = hν energy is absorbed only if the radiation frequency
= hc/λ. In 1903, Einstein conducted his experiments corresponds to the components of the molecular fre-
on the photoelectric effect of light. He concluded that quency. This is referred to as resonance absorption.
electrons are emitted from the surface of a specific The position of maximum absorption (λmax ) for a
metal upon its illumination with light of a relatively molecule in a particular region of the spectrum is
low wavelength, such as blue light. a function of the total structure of the molecule with
Red light, irrespective of its intensity, fails to eject a transition energy corresponding to a given wave-
an electron from a similar metal. These findings by length. The intensity of the absorption maximum
Michelson and Morley, Planck, Einstein, and others (εmax ) is a function of the probability of electromag-
could not be explained by Maxwell’s assigned wave netic radiation–molecule interaction and polarity of
properties. Considering these facts, a reliance on the the excited state. At ground state (i.e., room temper-
dual nature of light, behaving both like a wave and ature) a molecule is in its lowest energy state. The
a particle, seemed to be indispensable for resolving transition between E1 and E2 , two energy states or
many physicochemical phenomena. levels of a molecule, occurs by the interaction of elec-
tromagnetic radiation with a molecule. The difference
Molecular interactions and electromagnetic between E1 and E2 (E) is related to the frequency
radiation with a relationship, E = hv ergs.
The presence of radiation of a particular frequency Very high energies (> 108 cm−1 ) disturb and cause
is necessary, but is not always sufficient, to induce a changes in the nucleus of the atom, regardless of its
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Pharmaceutical analysis and quality control | 175

Change of Change of electron distribution

Change of spin Change of configuration
orientation
infrared Visible and ultraviolet X-ray
NMR ESR microwave

Wavenumber
cm−1 4 × 10−2 4000 12.5 × 103 25 × 103 50 × 103 107
25 400 108
Spin orientations Molecular Molecular Valence electronic transitions Inner shell Nuclear
(in magnetic field) rotations vibrations electronic transitions
NMR ESR transitions

Visible Ultraviolet X-rays

Infrared region
Radio Micro “fundamental” Near UV Vacuum UV “Soft” Gamma
waves waves region X-rays Rays
(radar)
Far “Overtone”
infrared region

Wavelength 25 cm 0.04 cm 25 µm 2.5 µm 800 nm 400 nm 200 nm 10 A° °

1A
400 µm 0.8 µm

Figure 6.5 A plane-polarized electromagnetic radiation: E, electric vector; H, magnetic vector; λ, wavelength; c, direction of
propagation.

environment. However, lower energy causes a change the high-vacuum region. Instruments typically main-
in the electronic distribution around the nucleus. tain vacuums of about 10−6 mmHg (1.33 × 10−4 Pa),
The whole range of electromagnetic radiations is since ionised molecules have to be generated in the
divided into a number of regions (Fig. 6.5). Interaction gas phase to enable them to be manipulated using
between a molecule and various kinds of electromag- magnetic or electrostatic fields. In classic mass spec-
netic radiation gives rise to a change in the electronic trometry (MS) only one method could produce the
energy and/or kinetic energy of the molecule. In charged gaseous molecules, but now quite a number
most cases, the energy absorbed is converted quickly of alternatives are available. Once the molecules are
to vibrational, rotational, and translational energy. charged and in the gas phase, they can be manipulated
However, in specific cases, emission occurs either by the application of either electric or magnetic fields
immediately as in fluorescence, or after a short time to enable the determination of their relative molec-
as in phosphorescence. These specific changes in the ular mass and the relative molecular mass of any
energy of a molecule result in the generation of a char- fragments produced by the molecules breaking up.
acteristic spectrum that can be used for both structural A number of useful introductory texts that describe
elucidation and quantitative determination. mass spectrometers and mass spectral interpretation
are available.34 – 40

Mass spectroscopic methods

of analysis Identification of drug metabolites
Metabolism is an important component in the drug
Introduction
discovery and development process, and LC-MS has
A mass spectrometer works by generating charged an important role in identifying drug metabolites.41
molecules or molecular fragments either in a high The pathways of Phase I and phase 2 drug metabolism
vacuum or immediately before the sample enters are well known, and it is possible to derive useful
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176 | An Introduction to Pharmacy

information even from a single quadrupole instru- Some applications of mass spectrometry
ment by using extracted ion chromatograms to search in quantitative analysis
for predicted metabolites. For example, formation
Mass spectrometric detectors are able to carry out pre-
of a monoglucuronide of a drug results in a shift
cise and accurate quantification of analytes. However,
of 176 amu from the molecular ion of the parent.
it is generally necessary to use an internal standard
However, the process of searching for metabolites is
in analyses, since the instrumentation is more sub-
easier if tandem MS is available. The preferred mode
ject to sensitivity fluctuations than simpler detectors,
of metabolite profiling in the preliminary analysis of
such as the UV–visible detectors used in HPLC anal-
metabolites is to use product-ion scanning. The pre-
dicted ion for a metabolite is selected by the first yses. The selection of an internal standard has to be
quadrupole and subjected to fragmentation in the made carefully so that its mass spectrometric behav-
collision cell, and the fragments are analysed by the ior is reproducible and closely similar to that of the
third quadrupole. This enables acquisition of clean analyte. The internal standards labelled with stable
metabolite spectra that are free from any interfer- isotope (described below) are ideal, since they mimic
ing solvent background. If a quantitative analysis is the analyte very closely, but often a close structural
required, selected-reaction monitoring may be carried analog of the analyte will suffice.
out, in which a critical transition is monitored. For The most common application of MS to quanti-
example, the transition produced by loss of a glu- tative analysis of biomedical samples is in the quan-
curonide moiety from a glucuronide metabolite might titative determination of drugs and their metabolites
be monitored if it gives a very specific response for that in biological fluids and tissues. The advantage of MS
particular metabolite. Constant neutral-loss scanning in this area is that its selectivity means that it is less
is especially useful for searching for a particular class subject to interference by other compounds extracted
of metabolite, since it can readily detect metabolites from the biological matrix along with the compound
resulting from both Phase I and phase 2 metabolism. of interest. The greatest accuracy in such analyses is
For example, glucuronide metabolites for which the afforded by using as internal standards analogs of the
loss of the glucuronide moiety (−177 amu) is a major compound being measured that are labelled with sta-
fragmentation pathway might be monitored. If the ble isotopes. An isotopomeric internal standard of a
masses of the metabolites fall in a range (e.g., between drug co-elutes with it from a chromatographic column
400 and 700 amu), the first quadrupole is set to scan (sometimes deuterated compounds elute very slightly
between 400 and 700 amu and the second quadrupole earlier than the unlabelled compound) and should
to scan in the range 400–177 amu to 700–177 amu. have an almost identical response factor. Figure 6.6
In this way, any metabolites that are, for example, shows the negative ion chemical ionization (NICI)
methylated or undergo additional hydroxylation fol- mass spectra of the trimethylsilyl oxime derivative of
lowed by glucuronidation are picked out, as well as prednisolone and its tetradeuterated analogue. The
simple glucuronides. deuterated analogue of prednisolone can be used as
Ion-trap instruments can also be used to good an internal standard in the determination of pred-
effect in drug-metabolism studies and have approx- nisolone in a biological matrix. On the basis of the
imately ten times the sensitivity of triple-sector mass spectra shown the ions at m/z 457 and 472 are
quadrupole instruments when used to examine monitored for prednisolone and those at m/z 461 and
full-scan spectra. This is advantageous in the 476 for the tetradeuterated internal standard.
first phase of metabolite identification when the Since isotopomeric internal standards co-elute
metabolites are unknown. Another advantage of trap with the analyte, they aid in the recovery of the ana-
instruments is that fragmentation of selected ions lyte from the chromatographic system (carrier effect).
can be carried out several times with all the ions, Figure 6.7 shows a selected-ion chromatogram of
apart from the molecular ion of the metabolite of prednisolone methyl oxime/trimethylsilyl (MO/TMS)
interest, being ejected from the trap before the next derivative42 (monitored as the sum of the ions m/z 457
fragmentation. This process produces clean spectra and 472, Fig. 6.6), which was extracted from aque-
for the metabolite. ous humor after addition of 10 ng of tetradeuterated
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Pharmaceutical analysis and quality control | 177

prednisolone (the MO/TMS derivative was monitored

100 472 OTMS
N–OCH3 as the sum of the ions m/z 461 and 476, Fig. 6.6); the
457
TMSO OTMS analysis was carried out using GC-MS. Similar types
of approaches can be taken in LC-MS analysis.
H3CO–N
Relative abundance

602
0
Dissolution
100 476 OTMS
461 N–OCH3
TMSO OTMS
Dissolution is the process by which a solid enters
D into solution. The earliest reference to dissolution is
H3CO–N
the 1897 article by Noyes and Whitney, titled as
D D D
606 ‘‘The rate of solution of solid substances in their own
0 solution.’’43 The authors suggested that the rate of dis-
400 500 600
solution of solid substances is determined by the rate
m/z
of diffusion of a very thin layer of saturated solution
Figure 6.6 NICI spectra of trimethylsilyl prednisolone oxime that forms instantaneously around the solid particle.
and its tetradeuterated isotopomer. They developed the mathematical relationship that
correlates the dissolution rate to the solubility gra-
dient of the solid. Their equation is still the basic
formula upon which most of the modern mathe-
matical treatments of the dissolution phenomenon
revolve.
220 Prednisolone MO/ TMS Interestingly, the work of Noyes and Whitney,
together with the studies that followed in the early
part of the twentieth century, was primarily based on
m/z 457 + 472 the physicochemical aspects of dissolution applied
to chemical substances. The most prominent part
of these investigations that deserve recognition
are those of Nernst and Brunner, in 1904,44 for
their application of Fick’s law of diffusion to the
Relative abundance

Noyes–Whitney equation, and those of Hixson and

Crowell, in 1931,45 for their development of the
52 D4-Prednisolone MO/ TMS famous ‘‘Cube Root Law’’ of dissolution.46 The
Hixson–Crowell equation is

m/z 461 + 476 1/3 1/3

Q0 − Qt = KtHC

where Qt is the amount of drug released in time

t, Q0 is the initial amount of drug in the dosage
form/product, and KHC is the rate constant for
Hixson–Crowell cube root equation, which describes
5 6 7 8 the surface area–volume relationship. This equation
Time (min) applies to products, such as powders and tablets,
where the dissolution occurs in the planes that are
Figure 6.7 Prednisolone extracted from aqueous humor in parallel to the surface of the dosage form.
comparison with D4 -prednisolone (10 ng) added as an Two more alternative explanations were avail-
internal standard (both as their trimethylsilyl oximes). able, as reviewed by William Higuchi in 1961,47
by the 1950s. The interfacial barrier model consid-
ered that interfacial transport, rather than diffusion
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178 | An Introduction to Pharmacy

through the film, is the limiting step, due to a high a General Chapter on Drug Release in USP21 (1985),
activation energy level for the former, first proposed the presence of 23 monographs for modified-release
by Wilderman in 1909. Another model was Danck- dosage forms in USP22/NF18 (1990), the adoption
werts’ model, which appeared in 1951. According to of the reciprocating cylinder (USP apparatus 3) for
this, constantly renewed macroscopic packets of sol- extended-release products in 1991, and the adoption
vent reach the solid surface and absorb molecules of of the flow-through cell in (USP apparatus 4) for
solute, delivering them to the solution. extended-release products in 1995.
By the middle of the twentieth century, emphasis In the late 1960s, dissolution testing became a
started to shift to the examination of the effects of mandatory requirement for several dosage forms. The
dissolution behavior of drugs on the biological activity role of dissolution in the absorption of drug products,
of pharmaceutical dosage forms. One of the earliest however, is still far from being understood completely.
studies, with this purpose in mind, was conducted by Although considerable efforts were made to establish
J Edwards in 1951, on aspirin tablets. He reported, in vitro/in vivo correlations between release of drug
‘‘because of its poor solubility, the analgesic action of from the formulation and drug absorption, the limited
aspirin tablets would be controlled by its dissolution knowledge of the complex composition and hydro-
rate within the stomach and the intestine.’’48 No in dynamics of the gastrointestinal fluids remains a real
vivo studies, however, were conducted by Edwards to barrier. In spite of the reported success of several in
support his postulate. vitro/in vivo correlation studies, dissolution cannot
About eight years later, Shenoy and colleagues be relied upon as a predictor of therapeutic efficiency.
proved the validity of Edwards’s suggestion of the Rather, it is a qualitative tool that can provide valu-
in vitro/in vivo correlation by demonstrating a able information about the biological availability of a
direct relationship between the bioavailability of drug, as well as batch-to-batch consistency. Another
amfetamine from sustained-release tablets and its area of difficulty is the accuracy and precision of
in vitro dissolution rate. Other studies, especially the testing procedure, which is dependent, to a large
those reported by Nelson, Levy, and others,49 – 54 extent, on the strict observance of so many subtle
confirmed, beyond doubt, the significant effect of the parameters and detailed operational controls.
dissolution behavior of drugs on their pharmaco- In spite of these shortcomings, dissolution is con-
logical activities. Nelson, in 1957,54 was the first to sidered, today, as one of the most important qual-
explicitly relate the blood levels of orally administered ity control procedures performed on pharmaceutical
theophylline salts to their in vitro dissolution rates. dosage forms, and dissolution studies have become an
Due to the importance of these findings, dissolution essential part of drug applications to regulatory bod-
testing began to emerge as a dominant topic within ies worldwide. Whether or not it has been correlated
both the pharmaceutical academia and the drug with biological effectiveness, the standard dissolution
industry. test is a simple and inexpensive indicator of a prod-
During this 20-year period from 1950 to 1970, a uct’s physical consistency. If one batch differs from
number of studies were conducted, especially in the the other in its dissolution characteristics, or if the
United States, that confirmed the significance of the dissolution profiles of the production batches show a
dissolution–bioavailability relationship in pharma- consistent trend upwards or downwards, it sounds a
ceutical product development. As a result, the basket- sure warning that some factor in the raw material, for-
stirred-flask test (USP apparatus 1) was adopted as mulation, or process is out of control.30 Additionally,
an official dissolution test in six monographs of the dissolution data seem to be a useful tool in the early
USP/NF, in 1970. Also, due to the sustained inter- stages of drug development and molecular manipu-
est in the subjects of dissolution and gastrointestinal lation. In the early stages of research, steps may be
absorption, an explosion in the number of mono- taken to optimize characteristics that influence sub-
graphs of the dissolution requirements in subsequent sequent data concerning biological availability. Based
USP/NF editions was noted. Notable developments on simple dissolution testing, selection of a proper
during this evolution are the adoption of the paddle salt for a new drug can be done at an early drug
method (USP apparatus 2) in 1978, the publication of development stage.
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Pharmaceutical analysis and quality control | 179

Definition of dissolution and theoretical solid surface and, many times, is the limiting factor in
concepts for the release of the drug from the dissolution process. The speed of wetting directly
dosage forms depends on the surface tension at the interface (inter-
facial tension) and upon the contact angle between
Dissolution is defined as the process by which solid
the solid surface and the liquid. Generally, a contact
substances enter in solvent to yield a solution. Stated
angle of more than 90◦ indicates poor wettability.
simply, dissolution is the process by which a solid
Incorporation of a surfactant, either in the formula-
substance dissolves. Fundamentally, it is controlled
tion or in the dissolution medium, lowers the contact
by the affinity between the solid substance and the
angle and enhances dissolution. Also, the presence of
solvent.’ The physical characteristics of the dosage
air in the dissolution medium causes the air bubbles
form, the wettability of the dosage unit, the penetra-
to be entrapped in the tablet pores and act as a bar-
tion ability of the dissolution medium, the swelling
rier at the interface. For capsules, the gelatin shell is
process, the disintegration, and the deaggregation of
extremely hydrophilic, and, therefore, no problems in
the dosage forms are a few of the factors that influence
wettability exist for the dosage itself, although it may
the dissolution characteristics of drugs. Wagner pro-
exist for the powders inside.
posed a scheme, depicted in Fig. 6.8, for the processes
After the solid dosage form disintegrates into gran-
involved in the dissolution of solid dosage forms.55
ules or aggregates, penetration characteristics play a
This scheme was later modified to incorporate
prime role in the deaggregation process. Hydrophobic
other factors that precede the dissolution process of
lubricants, such as talc and magnesium stearate, com-
solid dosage forms. Carstensen56 proposed a scheme
monly employed in tablet and capsule formulations,
incorporating the following sequence:
slow the penetration rate and, hence, the deaggrega-
1. Initial mechanical lag tion process. A large pore size facilitates penetration,
2. Wetting of the dosage form but, if it is too large, it may inhibit penetration by
3. Penetration of the dissolution medium into the decreasing the internal strain caused by the swelling
dosage form of the disintegrant.
4. Disintegration After deaggregation and dislodgment occur, the
5. Deaggregation of the dosage form and dislodge- drug particles become exposed to the dissolution
ment of the granules medium and dissolution proceeds. Figure 6.932 graph-
6. Dissolution and occlusion of some particles of the ically presents the model proposed by Carstensen.
drug

Carstensen explained that the wetting of the solid

dosage form surface controls the liquid access to the
Occlusion

Solid Disintegration Granules Deaggregation

dosage or Fine
forms aggregates particles
“concentration
% Dissolved

of drug”

Dissolution

Dissolution
Dissolution Dissolution
(major)
(minor) (major)

Mechanical lag
+
Drug in vitro or in vivo
wetting

Absorption (in vivo) Disaggregation

Disintegration
Drug in blood and other fluids and tissues Time

Figure 6.8 Schematic illustration of dissolution process of Figure 6.9 The S-shaped dissolution curve of solid dosage
solid dosage forms. forms.
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180 | An Introduction to Pharmacy

It is apparent from Fig. 6.8 that the rate of dis- The rate of dissolution of drug substance is deter-
solution of the drug can become a rate-limiting step mined by the rate at which solvent–solute forces of
before it appears in the blood. However, when the attraction overcome the cohesive forces present in the
dosage form is placed into the gastrointestinal tract solid. This process is rate-limiting, when the release of
in solid form, there are two possibilities for the rate- solute into solution is slow and the transport into the
limiting step. The solid must first dissolve, and the bulk solution is fast. In this case, the dissolution is said
drug in solution must then pass through the gastroin- to be interfacially controlled. Dissolution may also be
testinal membrane. Freely water-soluble drugs tend to diffusion controlled, where the solvent–solute inter-
dissolve rapidly, making the passive diffusion of the action is fast, compared to transport of solute into
drug or the active transport of the drug rate-limiting the bulk solution. In a diffusion-controlled process, a
step for absorption through the gastrointestinal mem- stationary layer of solute adjacent to the solid–liquid
brane. Conversely, the rate of absorption of poorly interface is postulated and is commonly referred to
water-soluble drugs will be limited by the rate of dis- as the diffusion layer. The saturation concentration
solution of the undissolved drug or disintegration of of solute develops at the interface and decreases with
dosage form. distance across the diffusion layer.

Appendix A: Example specifications

Table A.1 ABC1234 injection specifications

Attribute Method Acceptance criteria

Appearance Visual Clear, colorless solution and essentially free of particles or foreign
matter

Identification Reversed-phase HPLC Method Conforms to Reference Standard (RRT 1.00 ± 0.05)
ABC-2012-0001

Assay Reversed-phase HPLC Method 90.0–110.0% of label claim

ABC-2012-0001

Impurities Reversed-phase HPLC Method Specified Identifed Impurities ABC0001 (RRT ˜ 0.37): ≤ 0.30% area;
ABC-2012-0001 ABC0002 (RRT ˜ 1.15): ≤ 1.00% area; ABC0003 (RRT ˜ 1.58): ≤ 3.00% area
Specified Unidentifed Impurities RRT ˜ 1.08: ≤ 0.20% area
Unspecified Unidentified Impurities Any other individual Impurity≤
0.10% area
Total Impurities ≤ 4.00% area

Enantiomeric purity Chiral HPLC Method ≤ 1.00% area

ABC-2012-0002

pH USP <791> 5.5 ± 0.3

Particulate matter USP <788> Light Obscuration Particle Count particles per container ≥10 μm: ≤
6000 particles per container ≥25 μm: ≤ 600
Microscopic Particle Counta particles per container ≥10 μm: ≤ 3000,
particles per container ≥25 μm: ≤ 300

Sterility USP <71> No growth

Endotoxin USP <85> < 3.5 EU/mg of ABC1234

a Microscopic particle count will be performed only if the light obscuration particle count exceeds the acceptance criteria.
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Pharmaceutical analysis and quality control | 181

Table A.2 ABC1234 injection specifications

Attribute Method Acceptance criteria

Lyophilized Cake

Appearance Visual White to off-white cake or powder, essentially free of foreign matter

Identification Reversed-phase HPLC Method Conforms to Reference Standard (RRT 1.00 ± 0.05)
ABC-2012-0003

Assay Reversed-phase HPLC Method 90.0–110.0% of label claim (5.0 mg ABC1234/vial)

ABC-2012-0003

Impurities Reversed-phase HPLC Method Specified Identifed Impurities ABC0001 (RRT ˜ 0.37): ≤ 0.30% area;
ABC-2012-0003 ABC0002 (RRT ˜ 1.15): ≤ 1.00% area; ABC0003 (RRT ˜ 1.58): ≤ 2.00% area
Specified Unidentifed Impurities RRT ˜ 1.08: ≤ 0.20% area
Unspecified Unidentified Impurities Any other individual impurity ≤
0.10% area
Total Impurities ≤ 3.00% area

Enantiomeric purity Chiral HPLC Method ≤ 1.00% area

ABC-2012-0004

Moisture content USP <921> Record result

Content uniformity USP <905> Reversed-phase Conforms to USP and Ph. Eur. requirements
HPLC Method ABC-2012-0005

Sterility USP <71> No growth

Endotoxin USP <85> < 3.5 EU/mg of ABC1234

Reconstitution time Visual ≤ 120 seconds

Reconstituted Solution

Appearance Visual Clear, colorless solution, essentially free of particles and foreign matter

pH USP <791> 5.0 ± 0.3

Particulate matter USP <788> Light Obscuration Particle Count particles per container ≥10 μm: ≤
6000 particles per container; ≥25 μm: ≤ 600
Microscopic Particle Counta particles per container ≥10 μm: ≤ 3000;
particles per container ≥25 μm: ≤ 300

a Microscopic particle count will be performed only if the light obscuration particle count exceeds the acceptance criteria.
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182 | An Introduction to Pharmacy

Table A.3 ABC5678 tablet (10- and 100-mg) specifications

Attribute Method Acceptance criteria

Appearance Visual White to off-white round convex tablets

Identification Reversed-phase HPLC Method Conforms to Reference Standard (RRT 1.00 ± 0.05)
ABC-2012-0006

Assay Reversed-phase HPLC Method 90.0–110.0% of label claim

ABC-2012-0006

Impurities Reversed-phase HPLC Method Specified Identifed Impurities ABC0001 (RRT ˜ 0.37): ≤ 0.30% area; ABC0002
ABC-2012-0006 (RRT ˜ 1.15): ≤ 1.00% area; ABC0003 (RRT ˜ 1.58): ≤ 1.50% area
Specified Unidentifed Impurities RRT ˜ 1.08: ≤ 0.20% area
Unspecified Unidentifed Impurities Any other individual impurity ≤ 0.10%
area
Total Impurities≤ 3.00% area

Enantiomeric purity Chiral HPLC Method ≤ 1.00% area

ABC-2012-0007

Contentuniformity USP <905> Reversed-phase Conforms to USP and Ph. Eur. requirements
HPLC Method ABC-2012-0008

Dissolution USP <711> Reversed-phase Record result

HPLC Method ABC-2012-0009

Moisture content USP <901> Record result

Tablet breaking force USP <1217> Record result

X-ray powder diffraction USP <941> Consistent with a reference pattern

Microbial enumeration USP <61> or Ph. Eur. 2.6.12 Total Aerobic Microbial Count ≤ 103 CFU/g Total Yeast and Molds Count ≤ 102
tests CFU/g

Microbial specified USP <62> or Ph. Eur. 2.6.13 Absence of E. coli

Microoganisms Test

Appendix B: 21 CFR food and drugs 211.3 (Definitions) The scope of the regulations are
explained for human prescription and OTC drug
PART 211 Current good manufacturing products including drugs used to produce medi-
practice for finished pharmaceuticals cated animal feed. Reference is made to Part 210.3
of the chapter that gives definitions for all signifi-
Subpart A: General provisions cant terms used in the regulations.

211.1 The regulations in this part contain the min- Subpart B: Organization and personnel
imum current good manufacturing practice for
preparation of drug products for administration 211.22 (Responsibilities of Quality (QC) unit) The
to humans or animals. QC unit has total responsibility for ensuring that
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Pharmaceutical analysis and quality control | 183

adequate systems and procedures exist and are 211.72 (Filters) Filters to be used for liquid filtration
followed to ensure product quality. shall not release fibers into products.
211.25 (Personnel qualifications) Personnel, either
supervisory or operational, must be qualified by
Subpart E: Control of components and drug
training and experience to perform their assigned
product containers and closures
tasks.
211.28 (Personnel responsibilities) The obligations 211.80 (General requirements) Written procedures
of personnel engaged in the manufacture of drug must be available that describe the receipt, identi-
products concerning their personal hygiene, cloth- fication, storage, handling, sampling, testing, and
ing, and medical status are defined. approval or rejection of components (raw materi-
211.34 (Consultants) The qualifications (education, als) and drug products.
training, and experience, or any combination 211.82 (Receipt and storage of untested components,
thereof) of consultants must be sufficient for the drug product containers, and closures)
project to which they are assigned. 211.84 (Testing and approval or rejection of compo-
nents, drug product containers, and closures)
Subpart C: Buildings and facilities 211.86 (Use of approved components, drug prod-
Buildings and facilities are considered acceptable only uct containers, and closures) Materials shall be
if they are suitable for their intended purpose and rotated so that the oldest approved stock is used
can be cleaned and otherwise maintained. Design and first.
construction features for lighting, pest control, and 211.87 (Retesting of approved components, drug
maintenance are described below. product containers, and closures) Materials shall
be retested or reexamined as necessary after stor-
211.42 (Design and construction features) age for long periods or after exposure to air, heat
211.44 (Lighting) or other conditions that might adversely affect the
211.46 (Ventilation, air filtration, air heating and component, drug product container, closure.
cooling) 211.89 (Rejected components, drug product contain-
211.48 (Plumbing) ers, and closures) These items shall be identified
211.50 (Sewage and refuse) and controlled to prevent their use in manufactur-
211.52 (Washing and toilet facilities) ing.
211.56 (Sanitation) 211.94 (Drug product containers and closures) Con-
211.58 (Maintenance) tainers and closures (product contact materials)
must protect the product and must be nonreac-
Subpart D equipment tive with or additive to the product, suitable for
Equipment must be designed, constructed, of ade- their intended use, and controlled using written
quate size, suitably located, and able to be main- procedures.
tained and cleaned to be considered suitable for its
intended use. Regarding the use of automatic equip- Subpart F: Production and process controls
ment, data processors, and computers, there is a need
for input/output verification and for proper calibra- 211.100 (Written procedures and deviations) Written
tion of recorders, counters, and other electrical or standard operating procedures (SOPs) for each
mechanical devices. production process and control procedure are
necessary. Any deviation from an SOP must be
211.63 (Equipment design, size, and location) investigated, recorded, and approved prior to final
211.65 (Equipment construction) product acceptance.
211.67 (Equipment cleaning and maintenance) 211.101 (Charge-in of components) The procedures
211.68 (Automatic, mechanical, and electronic equip- used to formulate a batch shall be written and fol-
ment) lowed.
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184 | An Introduction to Pharmacy

211.103 (Calculation of yield) Actual yields and theo- 211.134 (Drug product inspection) Packaged and
retical yields shall be determined. All products are labeled products shall be inspected for correct
to be formulated to provide not less than 100% labels.
of the required amount of active ingredient. The 211.137 (Expiration dating) As supported by appro-
identity and quantity of each component incorpo- priate stability studies, products on the market
rated into a batch must be recorded. shall bear an expiration date.
211.105 (Equipment identification) Equipment shall
be properly identified. Subpart H: Holding and distribution
211.110 (Sampling and testing of in-process materials
211.142 (Warehousing procedures) Describes the
and drug products) Significant in-process steps are
requirements for warehousing holding product
to be identified and appropriate sampling, testing,
under appropriate conditions of light, tempera-
and approvals obtained before proceeding further
ture, and humidity.
in the production cycle. Rejected material must be
211.150 (Distribution procedures) Written proce-
controlled.
dures describing product distribution shall be
211.111 (Time limitations on production) If required,
prepared.
time limitations will be placed on in-process steps.
211.113 (Control of microbiological contamination)
Subpart I: Laboratory controls
Appropriate procedures are to be prepared for
the control and prevention of microbiological 211.160 (General requirements) The general require-
contamination. The sterilization process must be ments for laboratory control mechanisms are
validated. described.
211.115 (Reprocessing) Reprocessing of product is 211.165 (Testing and release for distribution) There
allowed providing there are written procedures shall be written procedures in the form of spec-
covering the methods and QC unit review to be ifications, standards, sampling plans, and test
used. procedures that are used in a laboratory for con-
trolling components and finished drug products.
Subpart G: Packaging and labeling control Acceptance criteria for sampling and approval
shall be adequate to support release of product for
211.122 (Materials examination and usage crite-
distribution.
ria) Labeling and packaging materials are to be
211.166 (Stability testing) There shall be a written
received, identified, stored, sampled, and tested
testing program designed to assess the stability
following detailed written procedures.
characteristics of drug products. The results of
211.125 (Labeling issuance) Strict control shall be
this testing shall be used in assigning appropriate
exercised over labeling for use in drug product
storage conditions and expiration dates.
labeling operations.
211.167 (Special testing requirements) There
211.130 (Packaging and labeling operations) There
are special testing requirements for sterile
shall be written procedures designed to ensure
and/or pyrogen-free ophthalmic ointment and
that correct labels, labeling, and packaging mate-
controlled-release dosage form products.
rials are used for drug products. Special controls
211.170 (Reserve samples) Reserve sample quantity
must be exercised over labeling to ensure that only
and retention times are described.
the correct labels are issued to packaging for a
211.173 (Laboratory animals) Animals used in any
specific product and that the quantities used are
testing shall be maintained and controlled in a
reconciled with the quantity issued.
manner suitable for use.
211.132 (Tamper-resistant packaging requirements
211.176 (Penicillin contamination) Drug products
for over-the-counter (OTC) human drug prod-
cannot be marketed if, when tested by a prescribed
ucts) Provides details of tamper-resistant packag-
procedure, found to contain any detectable levels
ing.
of penicillin.
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Subpart J: Records and reports These data can be used as part of the total lot
accountability, should the need arise, to trace its
211.180 (General requirements) Describes record distribution and/or for its recall.
retention time and availability for inspection. 211.208 (Drug product salvaging) Drug products
211.182 (Equipment cleaning and use log) A written that have been stored improperly are not to be
record of major equipment cleaning, maintenance, salvaged.
and use shall be included in major equipment logs.
211.184 (Component, drug product container, clo-
sure, and labeling records) Deals with the issues References
of the receipt, testing, and storage of components,
drug product containers, and closures. Details the 1. International Conference on Harmonization, Topic
various records and documents that should be Q6A. Specifications: Test Procedures and Acceptance
Criteria for New Drug Substances and New Drug
generated during the manufacture of drug prod-
Products: Chemical Substances, 2000. Available at
ucts and that are to be available for review. http://www.ich.org/products/guidelines/quality/article/
211.186 (Master production and control records) A quality-guidelines.html (accessed 18 February 2013).
master production record must be prepared for 2. Williams RL. Medicine quality faces challenges. Chem.
Eng. News 2011; 89(26): 58–61.
each drug product, describing all aspects of its
3. United States Pharmacopoeial Convention. United
manufacture, packaging, and control. Individ- States Pharmacopoeia, 34th edn, and National
ual batch records are derived from this approved Formulary, 29th edn. Baltimore: United Book Press,
master. 2011.
4. About USP. http://www.usp.org/about-usp (accessed 5
211.188 (Batch production and control records)
February, 2012).
Batch production and control records with 5. European Directorate for the Quality for Medicines
information about the production and control of and Healthcare of the Council of Europe. European
each batch are prepared. Pharmacopoeia, 7th edn. Strasbourg, France, 2010.
6. Membership and observership. http://www.edqm.eu/
211.192 (Production record review) All drug product
site/Membership-Observership-608.html (Accessed 5
batch records shall be reviewed and approved by February, 2012).
the QC unit (QA/QC) before the batch is released. 7. British Pharmacopoeia Commission. British Pharma-
211.194 (Laboratory records) Complete records of copoeia 2012. London, England: Stationery Office,
2011.
any laboratory testing shall be maintained to
8. Welcome to the website of the British Pharmacopoeia.
include raw data, test procedures and results, http://www.pharmacopoeia.gov.uk (Accessed 5 Febru-
initials or signatures of personnel performing ary, 2012).
the test or reviewing the results of tests, periodic 9. Japan Ministry of Health, Labour, and Welfare. The
Japanese Pharmacopoeia, 16th edn. Tokyo, Japan,
equipment calibration, and stability test results.
2011.
211.196 (Distribution records) Distribution records 10. Japan Ministry of Health, Labour, and Welfare. The
include warehouse shipping logs, invoices, bills Japanese Pharmacopoeia, 15th edn (in English). Tokyo,
of lading, and all documents associated with dis- Japan, 2006.
11. JP online. http://www.pmda.go.jp/english/pharmacopo
tribution. These records should provide all the
eia/online.html (Accessed 5 February, 2012).
information necessary to trace lot distribution to 12. United States Pharmacopoeial Convention. USP Mono-
facilitate product retrieval if necessary. graph Backgrounder. Rockville, MD, 2008.
211.198 (Complaint files) Written records of com- 13. Monographs. http://www.pharmacopoeia.gov.uk/mono
graphs.php (Accessed 5 February, 2012).
plaints received from consumers and professionals
14. United States Pharmacopeia, 35th edn, and National
are to be maintained along with the report of Formulary, 30th edn, and supplements, Vol 1.
investigations and responses. Rockville, MD: United States Pharmacopeial
Convention. 2012; 765–784.
15. United States Pharmacopoeial Convention. Chapter
Subpart K: Returned and salvaged drug products <1151>, Pharmaceutical dosage forms. United States
Pharmacopoeia, 35th edn, and National Formulary,
211.204 (Returned drug products) Records are to be
30th edn. Baltimore: United Book Press, 2012.
maintained of drug products returned from distri- 16. United States Pharmacopeia, 35th edn, and National
bution channels and the reason for their return. Formulary, 30th edn, and supplements, Vol 1.
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Rockville, MD: United States Pharmacopeial 32. Tswett M. Physikalisch-chemische Studien uber das
Convention. 2012; 37–41. Chlorophyll Die Adsorptionen. Berichte der Deutschen
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edn, and National Formulary, 30th edn. Baltimore: Convention; Rockville, MD, 2003: 2126.
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Rockville, MD, and supplements. United States Phar- ciples and Applications. Hoboken, NJ: Wiley, 2007.
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/understandingUSPNF.html. (Accessed 10 Nov, 2011). tation. Chichester: Wiley, 1998.
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Formulary, 30th edn, and supplements, Vol 1. Mass Spectrometry: Instrumentation, Applications and
Rockville, MD: United States Pharmacopeial Strategies of Data Interpretation. Chichester: Wiley,
Convention. 2012; 74–130. 2007.
40. Williams DH, Fleming I. Spectroscopic Methods in
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41. Oliveira EJ, Watson DG. Liquid chromatography-mass
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ceutical Inspection Co-operation Scheme). Retrieved 15 44. Nernst, W. Theorie der Reaktionsgeschwindigkeit in
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25. Connors KA, et al. Chemical Stability of Pharmaceuti- 45. Hixson AW, Crowell JH. Dependence of reaction veloc-
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27. Allen Loyd V. Dosage form design and development. York: Marcel Dekker, 1991.
Clin. Therapeut. 2008; 30(11): 2102–2111. 47. Higuchi T. Rate of release of medicaments from oint-
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Q1B Stability Testing: Photostability Testing of New 1961; 50: 874–875.
Drug Substances and Products, 1996. Available at 48. Edwards LJ. The dissolution and diffusion of aspirin
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53. Levy G, Leonards JR, Procknal JA. Interpretation of 55. Wagner JG. Biopharmaceutics and Relevant Pharma-
in vitro dissolution data relative to the gastrointestinal cokinetics. Hamilton IL: Drug Intelligence Publications,
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54. Nelson E. Solution rate of theophylline salts and effects Proceedings of the 2nd Wisconsin Up-date Conference.
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607–614. sity of Wisconsin, 1982.
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7
Pharmaceutics

Modern-Day drug discovery and development 189 Drug stabilization 248

Metrology and pharmaceutical calculations 190 Complex formation 250

Molecular structure, properties Interfacial phenomena 251

and states of matter 196
Colloidal dispersions 251
Thermodynamics 223
Coarse dispersions 252
Solutions and phase equilibria 229
Rheology 257
Separation methods 232
Appendix A: sodium chloride equivalents,
Ionic solutions and electrolytic equilibria 233 freezing-point depressions, and hemolytic
effects of certain medicinals in aqueous solution 258
Tonicity, osmoticity, osmolality and osmolarity 237
Appendix B: Isotonic solution values 280
Chemical kinetics 245
References 282

Modern-Day drug discovery are controlled at the molecular and physiological

level. Drug discovery involves the identification of
and development
candidates, synthesis, characterization, screening, and
assays for therapeutic efficacy. Drug discovery is still
Medical and pharmaceutical research provides a basis
a lengthy, expensive, difficult, and inefficient process
for the development of new therapeutic approaches
with a low rate of new therapeutic discovery. The
to human and animal disease. This process of drug
outcome of a successful drug discovery program is
discovery research can be basic (seeking an under-
the generation of a therapeutic entity where none
standing of biological phenomena that are unknown) previously existed or the replacement of established
or applied (using principles that are known to pro- therapies in favor of a newer modality that is safer and
duce a desired new product or effect). In either case, more efficacious.1 The main function of the pharma-
drug discovery research results from an unmet clin- ceutical industry is to create products (i.e., drugs that
ical need, a recognized deficit in treatment options. have an impact on healthcare). Drug development is
Drug discovery is the process by which drugs are the process of bringing a new drug to the market
discovered or designed. In the past most drugs were once a lead compound has been identified through
discovered either by identification of the active ingre- drug discovery. Drug development includes preclinical
dient from traditional remedies or by serendipitous research (microorganisms/animal) and clinical trials
discovery. Today we know how disease and infection (human). Products of this type can be foreseen to
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190 | An Introduction to Pharmacy

some extent through knowledge and study and thus Metrology and pharmaceutical
are amenable to planned research and development
calculations
(R&D). For example, if the cause of a disease has been
identified as an infection by a microorganism, a search
One of the first technical operations that the student
can be undertaken for an agent that will prevent or
of pharmacy must learn is the manipulation of bal-
cure the infection. However, in some instances, the
ances, weights, and measures of volume. This entails a
etiology of a disease is unknown despite intensive
study of the various systems of weights and measures,
investigation. In this situation, the pathway to a sat-
their relationships, and a mastery of the mathematics
isfactory cure or method of prevention cannot be
involved to understand the testing, manufacturing,
foreseen or forecast. In such cases, products may only
and compounding of pharmaceutical preparations:
be developed after application of careful investiga-
tions, from a revolutionary new approach, or perhaps
• Weights and measures – An accumulation of facts
from a serendipitous finding. concerning the various systems, with tables of
Although much of the drug discovery research in conversion factors and practical equivalents. The
the United States is carried out by major pharmaceuti- relationships among the various systems of weights
cal manufacturers and biotechnology companies, this and measures are clarified.
research is dependent on a vast and growing back-
• Weighing and measuring – A discussion of the var-
ground of scientific knowledge generated by diverse ious types of balances, particularly prescription
organizations. Universities, private institutes, gov- balances and methods of using, testing, and pro-
ernmental laboratories, and industrial research all tecting them; also of various devices and methods
play significant roles in developing new technologies for measuring large or small volumes of fluids.
and knowledge that provide the basis for discov-
• Density and specific gravity – A considera-
ery and the ultimate generation of a new product. tion of the mass/volume ratio of a substance
This new knowledge may involve development of a (density), and the ratio of the weight (mass)
new technology, improved scientific methodology and of one substance to the weight (mass) of
instrumentation, or increased understanding of the another substance taken as the standard
basic molecular or cell biology underlying a disease. (specific gravity).
The major objective of research in the pharmaceu-
• Pharmaceutical calculations – A review of basic
tical industry is to produce safe drugs that prevent, mathematical principles and their use in solving
cure, or ameliorate disease. Interim research goals pharmaceutical problems.
that lead to this major objective are to

Weights and measures

• Understand the molecular basis of biological mech-
anisms in health and disease. Weight is a measure of the gravitational force act-
• Develop new biological testing procedures relevant ing on a body; weight is directly proportional to the
to human and veterinary medicine. body’s mass. The latter, being a constant based on
• Develop a quantitative understanding of the inter- inertia, never varies, whereas weight varies slightly
action of drugs with key biological systems, lead- with latitude, altitude, temperature, and pressure.
ing to the more rational design of drugs. The effect of these factors is usually not considered
• Understand the absorption, transport, and mode unless very precise weighing and large quantities are
of action of drugs. involved.
• Develop drugs of low toxicity, reproducible deliv- Measure is the determination of the volume or
ery, and high specificity for a given pathological extent of a body. Temperature and pressure have
state or target organ. a pronounced effect, especially on gases or liquids.
These factors, therefore, are considered when making
The above points illustrate how drug discovery precise measurements.
research is used to develop new products that fulfill All standard weights and measures in the US are
clinical needs. derived from or based on the United States National
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Pharmaceutics | 191

Prototype Standards of the Meter and the Kilogram. been directed toward scientific accuracy and sim-
The standards are made of platinum-iridium, and are plicity, and during the twentieth century toward
in the custody of the National Institute of Standards international uniformity.
and Technology (NIST) in Washington, DC.
Historical metrology, also referred to as docu-
History mentary metrology, is concerned with the study of
A brief outline of the origin of the many systems of monuments and records of ancient periods. Induc-
weights and measures may help clarify the essential tive metrology is concerned with the accumulation of
distinctions between them. The sense of the weight of data concerning the measurement of large numbers
a body cannot be conveyed intelligibly to the mind of objects that have been referred to as standards
unless a means of comparison is chosen. As weight but which have no exact measure except by statutory
is the measure of the gravitational force of a body, regulation.
this force is expressed in terms of standards of resis-
tance, which exactly balance the body and keep it The English systems
in equilibrium when used with a mechanical device In Great Britain, in 1266, the 51st Act of the reign of
constructed for this specific purpose. Such standards Henry III declared:
are termed weights and the mechanical devices are
called balances or scales. that by the consent of the whole realm of Eng-
The standards that have been chosen by vari- land the measure of the King was made – that
ous nations are arbitrary, and instances are common is to say, that an English silver penny called
where different standards are in use at the same time the sterling, round and without clipping, shall
in the same country. Many of the ancient standards weigh thirty-two grains of wheat, well dried
clearly are referable to variable parts of the human and gathered out of the middle of the ear;
body, such as nail, foot, span, pace, cubit (length of and twenty pence (pennyweights) do make an
the forearm), and fathom or faethm (stretch of the ounce and twelve ounces a pound, and eight
arms). In the history of metrology three periods may pounds do make a gallon of wine, and eight
be traced: wine gallons do make a bushel, which is the
eighth of a quarter.

• The Ancient period, during which the old clas-

The 16-ounce pound (avoirdupois pound), undoubt-
sical standards originated, terminated with the
edly of Roman origin, was introduced at the time of
decline of the Roman Empire. The unit of distance
the first civilization of the British island. However,
used by all nations for maritime measurements,
according to Gray, the word ‘‘haberdepois’’ was first
the nautical or meridian mile (1/60 of a degree
used in English laws in 1303. A statute of Edward I
of the earth’s equatorial circumference) is exactly
(AD 1304) states:
equal to 1000 Egyptian fathoms or 4000 Egyptian
cubits. These Egyptian measurements, which have that every pound of money or of medicines is
persisted for more than 4000 years, were based of twenty shillings weight, but the pound of
on astronomical or meridian measurements that all other things is twenty-five shillings weight.
were recorded imperishably in the great Pyramid The ounce of medicines consists of twenty
at Ghizeh, whose perimeter is exactly 500 of these pence, and the pound contains twelve ounces
fathoms, or 1/2 nautical mile. [the troy pound], but in other things the pound
• The Medieval period extended to the sixteenth cen- contains fifteen ounces, in both cases the ounce
tury. During this period the old standards were weighing twenty pence.
lost, but their names were preserved, and European
nations adopted various independent standards. These laws unfold the theory of the ancient
• The Modern period extends from the sixteenth weights and measures of Great Britain, and reveal
century to the present. Since the seventeenth cen- the standards (i.e., a natural object, grains of wheat).
tury, the efforts of most enlightened nations have A difference existed then between the troy and the
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192 | An Introduction to Pharmacy

avoirdupois pound, but the weights now in use are the level of the sea in the latitude of London, a length
1/16 heavier than those of Edward I, due to the that was found to be 39.1393 inches. The pound troy
change subsequently made in the value of the coin (containing 5760 gr) was determined by comparison
by the sovereign. In addition, the true pennyweight with a given measure of distilled water under specified
standard was lost, and, in the next revision of conditions. Thus, a cubic inch of distilled water was
the weights and measures, the present troy and weighed with brass weights in air at 62◦ F, the barom-
avoirdupois standards were adopted. eter at 30 inches, and it weighed 252.458 gr. The
The troy weight is of still earlier origin. The great standard for measures of capacity in Great Britain
fairs of the eighth and ninth centuries were held at (either dry or liquid) is the imperial gallon, which
several French cities, including Troyes, the gathering contains 10 lb avoir (each 7000 gr) of distilled water
place of traders from all countries. Coins were fre- weighed in air at 62◦ F, the barometer standing at 30
quently mutilated, so they were sold by weight, and inches. The bushel contains eight such gallons.
the standard weight of Troyes for selling coin was George Washington, in his first annual message
adopted for precious metals and medicines in all parts to Congress, in January 1790, recommended the
of Europe. The troy ounce and the avoirdupois ounce establishment of uniformity in currency, weights, and
were originally intended to have the same weight, but measures. Action was taken with reference to the cur-
after the revision it was found that the avoirdupois rency and recommendations were made by Thomas
ounce was lighter by 42 1/2 gr (grains) than the troy Jefferson, then the Secretary of State, for the adop-
ounce. The subsequent adoption of troy weight by the tion of either the currently used English systems or a
London College of Physicians in 1618, on the recom- decimal system. However, nothing was accomplished
mendation of Sir Theodore Turquet de la Mayerne until 1819–1820, when efforts again were made in
who compiled their first pharmacopeia, has entailed the United States to secure uniformity in the stan-
upon all apothecaries who are governed by British dards that were in use by the several states. Finally,
customs to this day the very great inconvenience of after a lengthy investigation, on June 14, 1836, the
buying and selling medicines by one system of weights Secretary of the Treasury was directed by Congress
(the avoirdupois) and compounding them by another to furnish each state in the Union with a complete
(the apothecary or troy). set of the revised standards, and thus the troy pound
In the next century efforts were made toward (5760 gr), the avoirdupois pound (7000 gr), and the
reforming the standards, and in 1736 the Royal Soci- yard (36 inches) are all identical with the British
ety began the work that ended in the preparation, standards. However, the US gallon is quite differ-
by Mr. Bird under the direction of the House of ent; the old wine gallon of 231 inch3 – containing 58
Commons, of the standard yard and standard pound 372.2 gr of distilled water at its maximum density,
troy in 1760. Copies of these were prepared and no weighed in air at 62◦ F, the barometer standing at 30
intentional deviation has been made since. inches – was retained. The bushel contained 77.274 lb
The growing popularity of the French metric of water under the same conditions, thus making the
system – and the desirability of securing a standard dry quart about 16 percent greater in volume than the
that could be recovered easily in case of loss or liquid quart.
destruction, and that should be commensurable with In 1864 the use of the metric measures was legal-
a simple unit – prompted steps in England to secure ized in Great Britain, but was not made compulsory,
these advantages in 1816. The labors of English scien- and in 1866 the United States followed the same
tists led to the adoption of the imperial measures and course. By the US law of July 28, 1866, all lengths,
standards, which were legalized on January 1, 1826; areas, and cubic measures are derived from the inter-
imperial standards are now in use in Great Britain, national meter equivalent to 39.37 inches. Since 1893
thus introducing another element of confusion into an the US Office of Standard Weights and Measures has
already complicated subject. In this system the yard is been authorized to derive the yard from the meter: one
equivalent to 36 inches, and its length was determined yard equals 3600/3937 m, and the customary weights
by comparison with a pendulum beating seconds of are referred to the kilogram by an Executive Order
mean time, in a vacuum, at a temperature of 62◦ F at approved April 5, 1893. Capacities were to be based
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Pharmaceutics | 193

on the equivalent; dm3 equals one liter, the decimeter For all practical purposes, calibration of length
being equal to 3.937 inches. The gallon still remains standards in industry and scientific laboratories is
at 231 inch3 and the bushel contains 2150.42 inch3 . accomplished by comparison with the material stan-
This makes the liquid quart equal to 0.946 liter and dard of length: the distance between two engraved
the dry quart equal to 1.1013 liter, whereas the impe- lines on a platinum-iridium bar, the International
rial quart is 1.1359 liter. The customary weights are Prototype Meter, which is kept at the International
derived from the international kilogram, based on the Bureau of Weights and Measures.
value that one avoir lb equals 453.5924277 g and that The kilogram is defined independently as the mass
5760/7000 avoir lb equals one troy lb. of a definite platinum-iridium standard, the Inter-
Avoirdupois weight is used in general in the United national Prototype Kilogram, which also is kept at
States for commercial purposes, including the buying the International Bureau of Weights and Measures.
and selling of drugs on a large scale and occasionally The liter is defined as the volume of a kilogram of
on prescription orders. water, at standard atmospheric pressure, and at the
temperature of its maximum density, approximately
The metric system 4◦ C. The meter is thus the fundamental unit on which
The idea of adopting a scientific standard for the basis are based all metric standards and measurements of
of metrology that could be reverified accurately was length and area and of volumes derived from linear
suggested by a number of individuals after the Renais- measurements.
sance. Jean Picard, the seventeenth-century French Of basic scientific interest is that on October 14,
astronomer, proposed that the length of a pendulum 1960, the 11th General Conference on Weights and
beating one second of time at sea level, at latitude 45◦ Measures, meeting in Paris, adopted a new interna-
should be taken as a unit. tional definition for the standard of length: the meter
In 1783, the Scottish inventor James Watt first is now defined as the length equal to 1,650763.73
suggested the application of decimal notation, and wavelengths of the orange-red light of the krypton-86
the commensurability of weight, length, and volume. isotope. This standard will be used in actual measure-
The French National Assembly in 1790 appointed a ments only when extreme accuracy is needed.
committee to decide the preferability of the pendulum The kilogram is the fundamental unit on which
standard or a terrestrial measure of some kind as a all metric standards of mass are based. The liter is
basis for the new system. The committee reported in a secondary or derived unit of capacity or volume.
1791 in favor of the latter, and commissions were The liter is larger by about 27 ppm (parts per million)
appointed to measure an arc of meridian and to per- than the cube of the tenth of the meter (the cubic
fect the details of the commensurability of the units decimeter): 1 liter = 1.000027 dm3 .
and of nomenclature. However, certain inaccuracies The relative length of the yard and meter are
were inherent in the early standards, so they do not based on the relation: 1 m = 39.37 inch, contained
bear the intended exact relationships to each other. in the Act of Congress of 1866. From this relation it
The present accepted standards are defined in pub- follows that 1 inch = 25.40005 mm (nearly). In recent
lications of the National Institute of Standards and years engineering and industrial interests the world
Technology (NIST). over have urged the adoption of the simpler relation,
In its original conception, the meter was the fun- 1 inch = 25.4 mm exactly, which differs from the
damental unit of the metric system, and all units of preceding value by only 5 ppm. This simpler relation
length and capacity were to be derived directly from has not as yet been adopted officially by either Great
the meter, which was intended to be equal to one Britain or the United States but is in wide industrial
ten-millionth of the earth’s quadrant. Furthermore, use.
it originally was planned that the unit of mass, the In the United States, the abbreviation ‘‘cc’’ (for
kilogram, should be identical with the mass of a cubic centimeter) still persists in general use and is
cubic decimeter of water at its maximum density. At taken as synonymous for the more correct milliliter.
present, however, the units of length and mass are The US Pharmacopeia (USP) IX and National For-
defined independently of these conceptions. mulary (NF) IV adopted the term milliliter with its
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194 | An Introduction to Pharmacy

abbreviated form mil, but it proved so unpopular in Statistics

practice that the following pharmacopeial convention
The laws of physics in connection with mathematical
directed the return to the older term cubic centimeter
models and tools are quite capable to deterministically
(cc). However, in 1955, USP XV and NF X once again
describe natural phenomena. But the more complex
adopted the term milliliter with the abbreviation mL.
the situation to be described gets, i.e., the more influ-
National jealousies and the natural antipathy to
ences need to be considered if we wanted to describe
changing established customs interfered greatly with
them accurately, the more we find our results to be
the adoption of the metric system during the early
erroneous. And in a scale where quantum effects also
part of the nineteenth century. At present the metric
play a role, we have to deal with true uncertainty.
system is in use in every major country of the world.
Statistics gives us a means to deal with proba-
In the United States and Great Britain it is legalized
bilities or errors in measurements. With the help of
for reference to and definition of other standards,
statistics, we can (among others) describe data, calcu-
and it is in exclusive use by nearly all scientists and
late estimates of its distribution, and decide whether
by increasing segments of industry and the public. In
to reject a hypothesis in a rational and reproducible
the United States the metric system was legalized in
manner.
1866, but not made compulsory; in the same year
the international prototype meter and kilogram were
Data
adopted as fundamental standards. The US silver
coinage was based upon the metric system, the half Data may come in discrete steps, as for instance, the
dollar being exactly 12.5 g and the quarter and the number of patients that benefit from a certain therapy,
dime being of the proportionate weights. or they may be continuous, meaning that the values
As corporations became more international, the can have infinitely many manifestations, even in a
need for a universal standard increased. Since 1875 finite interval. An example for continuous data are,
there has been established and maintained an Interna- for instance, the masses of tablets.
tional Bureau of Weights and Measures, with head- In reality, however, all our measuring devices
quarters in Paris. This Bureau is managed by an have a limited measuring accuracy, so in principle all
international committee that enjoys universal repre- experimental data come in discrete quantities. This is
sentation. One objective of the committee is to make important when statistical methods demand continu-
and provide prototypes of the meter and kilogram ous data as a prerequisite, like the Mann–Whitney U
for the subscribing nations; approximately 40 such test. We have to deal carefully with values that occur
copies have been prepared. multiple times – statisticians call them ‘‘ties.’’ (Ties are
The US prototype standards of both the meter not supposed to occur with continuous data because
and the kilogram mass, constructed of a platinum- there will always be a difference, however small it may
iridium alloy, were brought from Paris in 1890 and are be. But in gathering real data, ties become real, too,
now in the custody of the NIST in Washington, DC. because of the limited precision of the measurement.)
They have been reproduced and distributed by the
US government to the various states having bureaus
Data visualization
needing such replicas. The original US prototype In statistics we want to explore data and make infer-
meter was taken back to Paris in 1957 for reveri- ences from it. An important first step is to visualise the
fication and was found to have altered only 3 parts data. The human brain has developed extraordinary
in 100,000,000 after 67 years of use. Thus, there was capabilities for pattern recognition, and thus we can
no demonstrable change within the limits of exper- grasp important statistical parameters like location
imental error. With the adoption of the krypton-86 and spread of the data, or spot correlations, clusters,
wavelength of light definition for the meter the differ- outliers, and so on, with a single glance.
ent countries have the means to check their prototype
meter bars without returning them to Paris at peri- Stem-and-leaf plot
odic intervals for comparison with the international A simple means to display data is the stem-and-leaf
meter bar. plot. It puts the data in order and provides visual
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Pharmaceutics | 195

information on the location, spread, and form of the versus a placebo. Or it may be desired to estimate
data. It retains a least two significant digits of each the average drug content and variability of a batch of
data point. tablets. In virtually all such experiments, it is not real-
A stem-and-leaf plot is constructed as follows:2 istic to observe all possible experimental units. In fact,
sometimes the entire population of conceivable obser-
1. Split each score or value into two sets of digits. vations cannot be identified completely. The potential
The first or leading set of digits is the stem, and the experimental material for a clinical study comparing
second, or trailing, set is the leaf. an antipsychotic drug to a placebo would include not
2. Draw a vertical line, and list all possible stem dig- only patients but also persons with the disease who
its left to the line from lowest to highest. are not yet diagnosed. All of these people are the pop-
3. For each data point write the leaf values on the ulation or universe. Clearly, one would not perform
line labeled by the appropriate stem number. an experiment that included the entire population for
many reasons:
If appropriate, you can list each stem digit twice and
put leaves starting with digits 0 to 4 on the first line, • All of these people could not be identified.
and leaves starting with digits 5 to 9 on the second. • The time or money to conduct such a huge experi-
ment is not available.

Example 1 • To include so many people in such an experiment

could be dangerous or unethical.
A stem-and-leaf plot
It is not necessary to run such a large experiment to
Consider the heights of the students of my statistics arrive at a fair conclusion regarding the efficacy of
class: Their heights in centimetres are as follows: 195, the drug. In fact, in most cases, the test consists of a
191, 198, 185, 158, 170, 160, 158, 172, 165, 185, relatively small sample taken from a relatively large
169, 187, 180, 178, 172, 180, 173, 168, 168, 172, population.
174, 160, 184, and 171. Another more concrete example is the process of
sampling in quality control. It may be of interest to
Table 7.1 Stem-and-leaf estimate the proportion of defective tablets or the
plot of students’ heights average drug content and uniformity of tablets in a
production batch. Certainly in the latter case every
15 88 tablet in the batch would not be examined because the
test is destructive, i.e., the tablet is destroyed during
16 005889
the analysis for drug content. Rather, a sample of
20 tablets would be chosen to estimate the average
17 01222348
drug content of the more than 1 million tablets in the
18 004557 batch.
Thus, in typical experiments in the pharmaceuti-
19 158 cal sciences, a small sample from the population is
examined in order to make inferences about the large
The corresponding stem-and-leaf plot is presented in
population.
Table 7.1.
Summary numbers
In the next step we try to reduce the amount of data.
Samples and populations We can try to specify a distribution by a mathemat-
Many experiments have as an objective the definition ical model (e.g., normal distribution) and a finite set
or comparison of two or more groups of data. For of parameters of that distribution. A sentence like,
example, one may wish to compare the efficacy of two ‘‘The data follow a normal distribution with mean μ
antihypertensive agents or a new antipsychotic drug and variance σ 2 .’’ contains more information than a
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196 | An Introduction to Pharmacy

thousand or more data points. This is because any (usually normal or atmospheric pressure, 1.013 bar) it
normal distribution is completely determined by its is the temperature that decides in which state water is
mean and its variance (or its standard deviation, the present; at normal pressure ice melts at 0◦ C and boils
square root of the variance). at 100◦ C. What we are observing at these tempera-
tures are phase transitions from the solid state to the
liquid state (melting) and from the liquid state to the
Molecular structure, properties gaseous state (boiling). If we lower the temperature of
and states of matter water vapor below 100◦ C, we observe condensation
(gas to liquid transition) and if we further lower the
Introduction temperature below 0◦ C, we observe freezing of the
liquid water to ice.
Pharmaceuticals are made up of molecules, the prop-
In this section we will describe the different states
erties of which are determined by their shape and elec-
of matter (including a few ‘‘exotic states,’’ which
tronic structure (i.e., the nature of their bonds). These,
nevertheless do play a role in some pharmaceutical
in turn, are determined by the constituent atoms and
applications) and highlight their most important char-
how those atoms are held together (bonded). A strik-
acteristics. We will also discuss how we can describe
ing example of this is the element carbon. This can
the different states of matter in phase diagrams and
exist in a variety of forms – including nanotubes
identify a few experimental techniques that can be
and buckyballs – but the two forms that illustrate
used to determine the characteristics of a given state
the difference in bonding most strongly are graphite
of matter. Because most drugs and dosage forms used
and diamond. Both are entirely composed of carbon
atoms, but one is a hard crystalline material, colorless in the pharmaceutical field are solid at room temper-
in its pure form (diamond), the other a black greasy ature, we will discuss the solid state in a little more
material used in pencils and as a lubricant. detail than the other states of matter.
Atoms are built from neutrons, protons, and elec-
trons; the former are much more massive than the Solids, liquids and gases – a question
electrons. The properties of these subatomic units are of intermolecular forces
given in Table 7.2. The fundamental ideas for atomic When we think about states of matter, we usu-
structure and bonding were developed in the early ally think of them in terms of solids, liquids, and
part of the twentieth century. gases. These distinctions are based on the interactions
between the molecules (or in some cases atoms or ions)
of the matter in question. Since in the pharmaceutical
States of matter
field we are most often dealing with molecules, the
In everyday life we usually consider three states of discussions below will mainly consider molecules as
matter: the solid state (solids), the liquid state (liq- the components forming the various states of matter,
uids), and the gaseous state (gases). For example, and the reader should keep in mind that in many
water can be differentiated into the three states: ice, cases the word ‘‘molecule’’ could be exchanged for
liquid water, and water vapor, and at a given pressure the words ‘‘atom’’ or ‘‘ion.’’

Table 7.2 Masses and charges for the neutron, proton and electron

Subatomic particle Mass/kg Relative mass Charge/C Relative charge

Proton 1.673 ×10−27 1837 1.602 ×10−19 1

Neutron 1.675×10−27 1839 0 0

Electron 9.109×10−31 1 −1.602 ×10-19 −1

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Pharmaceutics | 197

In the solid state of a drug, the drug molecules enthalpy H [J] of the material.
are held together by comparatively strong interac-
tions, which do not allow the molecules to change Q = H (7.1)
their position but only to vibrate around a fixed posi-
It follows that a gas has a higher enthalpy than a
tion. These intermolecular interactions result in some
liquid and a liquid has a higher enthalpy than a solid
important properties of solids. A given mass of a solid
for a given material. At the same time, the number
at a given temperature and pressure has a defined vol-
of ways in which the molecules can be arranged with
ume and keeps its shape, if no external forces (such as
respect to each other also increases. This is known
in milling, agglomeration or tableting operations) are
as the entropy S [J K−1 ] of the system and is often
acting on the solid material. Similarly, a given mass
described as the ‘‘disorder’’ of the system. It follows
of a liquid has a defined volume at a given tempera-
that upon a state change due to heating, both the
ture and pressure (like solids, liquids are practically
enthalpy and the entropy of the material increase.
incompressible), but in contrast to a solid, its shape
Since every system has a tendency to exist in the lowest
can vary and will take on the shape of the container it
enthalpy and the highest entropy form, it depends on
is placed in. The reasons for this are again the interac- the temperature T of a given system (here considered
tions between the molecules in the liquid state. These solely as the material in question) in which form it
are still considerably strong, but the kinetic energy is present. This can be summarized in form of the
of the molecules is now sufficiently high to allow equation:
the molecules to change their positions (not only to
vibrate around a fixed position) and to move relative G = H − TS (7.2)
to each other by diffusion or convection. This is also
the reason why the density of a liquid is usually lower where G [J] is the free energy of the system.
than that of a solid (with the most important liquid If a liquid is heated, the temperature of the liquid
in the pharmaceutical field being the exception: water will increase. How much the temperature increases as
has its highest density at normal pressure at 4◦ C, i.e., a function of the added heat energy depends on the
in the liquid state). A gas, on the other hand, does not heat capacity of the liquid. The heat capacity, C, can
have a defined shape or volume (in fact, gas molecules be defined as the amount of heat energy, Q, required
will fully occupy each volume available to them) and to change the temperature, T, of a given material by a
thus has a very low density, depending on the volume given temperate interval T (measured in kelvin, K):
it occupies. This is due to the fact that intermolecular
C = Q/T (7.3)
interactions in real gases are very weak and, in fact,
are considered zero for an ideal gas. Since interactions In this form C is an extensive variable, i.e., its value
between the molecules (or between atoms or ions) are will depend on the mass of the material. To convert
very strong or strong in solids and liquids, these two the heat capacity into an intensive variable, i.e., a
states of matter are also summarized as condensed variable whose value is independent of the mass of
matter. In contrast, since the molecules in the liq- the material (measured in kg) or its amount (measured
uid and gas state are able to change their positions, in mol), the heat capacity is usually expressed as either
these two states of matter are summarized as fluid specific heat capacity, Csp [J K−1 kg−1 ], or molar heat
matter. capacity, Cmol [J K−1 mol−1 ].
In any case, the result of heating the liquid for a
Changes between the states of matter given period of time is that the temperature of the
Upon the heating (at constant pressure), for example, liquid increases. However, when the liquid starts to
of a solid drug material (usually in a crystalline form, boil, i.e., the state of the material changes from the
see below), the solid transforms into a liquid (melt) liquid to the gaseous (vapor) state, we observe that the
and further into a gas (if it is not chemically degraded temperature of the material stays constant during this
in the heating process). Heat (Q, a form of energy, state transition. This temperature is the boiling point
unit: joules, J) is transferred into the material during (T b in Fig. 7.1). Similarly, when a solid melts, the
the heating process. This leads to an increase in the temperature of the material stays constant during this
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198 | An Introduction to Pharmacy

systems (see equation 7.2, G = H – TS, note the

Temperature
minus sign between H and S), we can conclude
that a phase transition occurs when the free energy
of the gas (or liquid) is lower than that of the liq-
uid (or solid) at a given temperature for the material
T b boiling point Gas in question. At a given pressure, the temperature that
Liquid gas
denotes the boiling or melting point is the temperature
Tm melting point at which G for this process is zero, i.e., at exactly
Liquid
Solid Solid liquid the boiling or melting point (for a given pressure), the
two states can coexist.
Time So far we have considered the temperature as
being decisive for a given material in what state of
Figure 7.1 Heating curve of a material undergoing a state matter it is present. However, to fully describe a
transition from solid to liquid and from liquid to gas. Note that given state of matter, we require a second intensive
the temperature stays constant during the state transitions. variable, pressure, p. If we plot temperature on the
x-axis and pressure on the y-axis of a coordinate
system, and determine the state of a given material
state transition (melting point, T m in Fig. 7.1). This is at any temperature–pressure combination, we obtain
because when a substance boils, the liquid and vapor the phase diagram of the material in question. Let us
state are in equilibrium, and when a substance melts, again consider water.
the solid and liquid state are in equilibrium. Any heat Figure 7.2 shows the (partial) phase diagram of
that is applied to the system will be used to bring water as a function of pressure and temperature.
about the state transition until the liquid (or solid) We can differentiate three areas, those of solid water
has completely gone into the vapor state (or liquid (ice), liquid water (water), and water vapor. To fully
state). Only then does the temperature rise further. describe the state of water in each of these areas,
The energy used for boiling the liquid is known as we need to specify the temperature and pressure at
latent heat of vaporization (or boiling) and in the which the material is present. For example, water
case of condensation, the energy released is known exists in the liquid state at both temperature–pressure
as latent heat of condensation. The amount of energy combinations indicated in the diagram by the sym-
used in the vaporization process is identical to the heat bol  and, in fact, at an infinite possibility of other
of condensation released in the condensation process, temperature–pressure combinations in the region of
since these processes are reversible. liquid water. The same holds true for the areas of
During a phase transition the heat capacity of the solid water and water vapor. The different areas of
material is infinitely high (all heat energy is used to the phase diagram are separated by boundary lines,
bring about the state change), and such transitions are known as the phase boundaries. At combinations of
termed first-order phase transitions. The same holds pressure and temperature which lie on these phase
true for the state transition from a solid to a liquid boundaries, two states of water exist in equilibrium.
(latent heat of melting) or from a liquid to a solid The curves a, b, and c in Fig. 7.2 are known as the
(latent heat of freezing). In melting and boiling pro- sublimation (or re-sublimation) curve (solid and gas
cesses, the change is endothermic (the system absorbs in equilibrium), the melting (or freezing) curve (solid
energy), whereas in freezing and condensation pro- and liquid in equilibrium), and the boiling (or con-
cesses, the change is exothermic (the system releases densation) curve (liquid and gas in equilibrium). Note
energy). At the melting and boiling point, the change the orientation of the melting curve b in Fig. 7.2:
in Gibbs free energy (G) is zero. However, as dis- its slope is negative; that is, at constant tempera-
cussed above, the enthalpy and the entropy of the ture ice can melt if the pressure is increased (this is
material are increasing (i.e., H and S have positive the principle of ice-skating). Most other compounds
values). Taking into account the relationship between behave oppositely; they can solidify under pressure,
the free energy and the enthalpy and entropy of the so their melting curves will have a positive slope. This
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Pharmaceutics | 199

SCF 5
22100 CP

Vapor pressure (atm)

4

2
Normal Normal
Pressure (kPa)

melting point boiling point 1

101.3
0
b 0 50 100 150
Liquid Water Temperature (°C)
Solid
water vapour
water
c
Figure 7.3 Temperature dependence of the vapor pressure
a of water.
0.611
TP
0.13
−79 0 0.01 100 374
Temperature (°C) temperature. This is true not only for water but for all
substances, since an increase in temperature increases
Figure 7.2 Partial phase diagram of water. The curves a, b, the likelihood for molecules to leave the condensed
and c are the sublimation (or re-sublimation) curve (solid and
phase, as the increased kinetic energy of the molecules
gas in equilibrium), the melting (or freezing) curve (solid and
counteracts the attractive forces holding the molecules
liquid in equilibrium), and the boiling (or condensation) curve
together in the condensed phase. Different liquids
(liquid and gas in equilibrium), respectively. TP: triple point,
CP: Critical point, SCF: region in which water exists as have different vapor pressures at given temperatures.
supercritical fluid.  shows two different pressure and A liquid will boil at a temperature at which its vapor
temperature combinations at which water exists in the fluid pressure equals the pressure exerted onto the liquid by
state. Note that the temperature and pressure axes are not the surrounding pressure of the environment. Taking
linear. again the example of water, at 100◦ C the vapor
pressure of water is 101.3 kPa, so under normal (sea
level) condition of atmospheric pressure, water will
is termed the anomality of water and also explains the boil. At 20◦ C, however, the vapor pressure of water is
observation that ice has a lower density than liquid only 2.3 kPa, so it will not boil under these conditions.
water. An interesting consequence of this is that water, for
To determine, for instance, the position of the example, on a high mountain (where the atmospheric
boiling curve in the phase diagram of water, we have pressure is lower than at sea level) will boil at a lower
to determine the vapor pressure of water at various temperature than 100◦ C.
temperatures. If we place a liquid in a vacuum at a At this point it let us make a quick stop and con-
temperature T, some of the molecules of the liquid sider the question why drying (for example, of wet
will leave the liquid phase and will go into the free granules, to take a pharmaceutical example) occurs
space above the liquid until an equilibrium is reached, even if the temperature is far below 100◦ C at normal
in which the same number of molecules from the atmospheric conditions (i.e., below the boiling point
free space above the liquid will go into the liquid as of water). To understand this, we have to differentiate
are leaving the liquid (this is a dynamic equilibrium). between the processes of boiling and evaporation. We
As long as there is still liquid water left (note: it is have seen that, in a closed system, molecules from the
not important how much water is left), the resulting liquid will leave the liquid phase until the equilibrium
pressure is known as the vapor pressure of the liquid, vapor pressure for the given temperature is reached.
and will constitute a point on the boiling curve at However, in an open system (for example, wet gran-
the temperature T. Figure 7.3 shows the temperature ules in a laboratory) some molecules from the surface
dependence of the vapor pressure of water. In a closed of the liquid will have a sufficiently high kinetic energy
system the vapor pressure increases with increasing to leave the liquid and are then transported away. This
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200 | An Introduction to Pharmacy

process takes place at any temperature also below the or be formed by increasing the pressure, and thus
boiling point of the liquid, and its rate depends on the critical point marks the end of the boiling curve.
factors such as The region in the phase diagram at temperatures and
pressures higher than that of the critical temperature
• The surface area between the liquid and the air is known as the supercritical fluid region (SCF). For
(evaporation is a surface phenomenon) water, the critical point is at approximately 374◦ C and
• The temperature of the liquid (the number of 22.1 MPa, and for CO2 the critical point is at approx.
molecules with a sufficiently high kinetic energy 31.1◦ C and 7.38 kPa. Supercritical fluids have gained
to leave the liquid phase increases with increasing pharmaceutical importance since this state of matter
temperature) combines properties of gases, such as low viscosity
• The air above the liquid (if there is an air stream, and high diffusivity, with properties of liquids, such
transport of the molecules away from the liquid is as a high capacity to dissolve other substances.
facilitated) From Fig. 7.2 we can see another critical point
• The humidity of the air above the liquid (evapora- in the phase diagram, known as the triple point (TP
tion of water molecules from a liquid will be faster in Fig. 7.2). At this combination of temperature and
if the air is dryer), as well as other factors. pressure, all three states of water coexist in a dynamic
equilibrium. For water the triple point is at 0.01◦ C
It should be noted that evaporation takes place from and 0.61 kPa. The triple point also marks the low-
the surface of a liquid, whereas boiling takes place est temperature at which a liquid can exist, so the
also in the liquid (that is the reason why water vapor temperature range for liquids to exist is between the
bubbles are formed in boiling water). triple point and the critical point of the material. Sim-
We have seen how we can determine the boiling ilarly, sublimation and re-sublimation can only occur
curve for a liquid to construct the phase diagram of at temperatures below the triple point (see sublima-
a substance. Similarly, we can determine the subli- tion curve in Fig. 7.2). Since sublimation (in the same
mation curve, although experimentally this is more way as boiling) occurs when the vapor pressure of the
difficult due to the much lower vapor pressure of solid material equals that of the gas phase, sublima-
solids. The melting curve can be determined by tion should only occur under atmospheric conditions
thermo-analytical methods. This is usually done by if the pressure at the triple point of the system is above
determining the cooling curve of a material at various 101.3 kPa (1 atm). For example, solid CO2 (dry ice)
pressures as a function of time. sublimates at atmospheric pressure at −78.5◦ C since
As we have already discussed for the boiling of its triple point is at −56.4◦ C and 517 kPa. For the
a liquid, during the phase transition from the liquid same reason, in the pharmaceutically relevant process
to the solid, the temperature does not decrease. If of freeze drying (which at least in the primary drying
we are heating a liquid in a closed container, the phase is based on the sublimation of water), an aque-
vapor pressure will also increase. However, since the ous solution or dispersion is initially frozen (below the
space above the liquid is limited, further heating will temperature of the triple point of water) and is then
increase the number of molecules in the space above subjected to a reduced pressure (below the pressure
the liquid, and thus the density of the gas phase will of the triple point of water). In the earlier mentioned
increase. At a certain, material-dependent tempera- real-life example, however, we also observe that wet
ture, the density of the gas phase will be equal to the clothes on a washing line (i.e., at atmospheric pres-
density of the liquid, so that there will no longer be sure) at or below freezing temperature (so the water
a phase boundary between the liquid and gas phase, in the clothes is frozen to ice) eventually will be dry.
and both are now indistinguishable (this is called a We thus observe sublimation also for substances for
supercritical fluid). The temperature (critical temper- which the triple point has a pressure below 1 atm.
ature) and pressure (critical pressure) combination at The reason for this is that in an open system like that
which a supercritical fluid is formed is known as the on a washing line, the partial pressure (see below) of
critical point (CP in Fig. 7.2). At temperatures above the solid does not attain the vapor pressure of the
the critical temperature a liquid can no longer exist material at the triple point. The situation is similar to
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Pharmaceutics | 201

the one discussed above for liquids in an open and

closed system (evaporation versus boiling). 104
Ice VII

10 3 Ice VI
Phases Ice V

In the examples discussed above, we have talked 102 Ice III

Ice II Critical point
about states of matter, and we have considered the Liquid
+
101
solid, liquid, and gaseous state. In the phase diagrams
we have seen that these states of matter constitute

Ice I
100

P [MPa]
different phases of a material. It is, however, possible Vapour
and, in fact, very likely that a solid material can in 10−1
its own right exist in different phases. We can define
10−2
a phase as a volume element of a system, separated
from other volume elements of the system by a phase 10−3
Triple point
boundary. The physical properties within the phase do
not show abrupt changes, which means that the phase 10−4

is physically homogeneous. If two phases coexist, such

10−5
as at the phase boundaries in the phase diagram, the 200 300 400 500 600 700 800
T [K]
physical properties between the phases, however, are
different. For example, at normal pressure and 0◦ C,
Figure 7.4 Phase diagram of water, showing several solid
the density of ice is approximately 920 kg/m3 ; and
forms of ice (Ice I – VII). Note that the temperature is given in
that of liquid water is approximately 999.8 kg/m3 . kelvin [K], and the pressure axis is in shown in logarithmic
Note that water makes an exception from most other form.
materials, in that its higher density is as a liquid rather
than as a solid at the equilibrium of liquid water
and ice. other temperature–pressure combinations at which
Let us again consider the phase diagram of water, three phases coexist in equilibrium. However, unlike
but now have a look at a larger temperature and the triple point between ice I, water, and water vapor,
pressure range (Fig. 7.4). We can see that different these are conditions in which either two solid phases
forms of ice can exist (termed ice I to ice VII). These and liquid water or three solid phases coexist.
all constitute a solid state of water but are all different Earlier, we have stated that to fully describe a sys-
in the molecular arrangement of the water molecules. tem in one of the areas of the phase diagram, we have
They therefore have different physical properties, and to specify both its pressure and temperature. Pressure
these change abruptly at the phase boundary. These and temperature are known as the degrees of freedom
different solid forms of water thus constitute different of the system. The number of degrees of freedom can
water phases. While these different ice phases may be defined as the least number of intensive variables
not be relevant in pharmaceutical applications, they (i.e., of variables that do not depend on the amount of
nevertheless show that molecules in the solid state material or its mass) of the system that are indepen-
can be arranged in different ways and thus give rise dent of other variables of the system and that can be
to the existence of different solid phases. At any given changed without changing the number of phases that
temperature and pressure, only one such solid form are coexisting. For any sample within an area of the
can be thermodynamically stable, but other forms phase diagram (e.g., in the area of liquid water or in
may exist as metastable forms for considerable times the area of ice III, etc.), we can freely change pressure
at conditions where another form is the stable form. and temperature (until we reach a phase boundary)
This will become important when we are considering without changing the number of phases present (one
crystalline solids in more detail later in this section. phase).
The phase diagram of water in Fig. 7.4 also shows If two phases coexist (such as for systems on
that for a given chemical compound, more than one the phase boundaries), the situation is different. If
triple point can exist. In fact, in Fig. 7.4 we can see six we change the pressure of the system, we cannot
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202 | An Introduction to Pharmacy

freely change the temperature but have to change each other. So even though NaCl is dissociating into
the temperature to a specific value, if we don’t want Na+ and Cl− ions, in the current discussion these do
to change the number of phases. In the case of two not constitute two chemical entities because the Na+
phases coexisting, the system thus only has one degree concentration is not independent of the Cl− concen-
of freedom. This is important, for example, in moist tration. The same holds true, for example, for H3 O+
heat sterilization, such as sterilization in an autoclave. and OH− ions from the auto-protolysis of water. The
To have both liquid water and water vapor present in independent chemical entities of a system are called
the sterilization process (this is most effective in killing components and are defined as the least number of
microorganisms) at 106 kPa, the temperature has to chemically independent entities required to describe
be 121◦ C (if no air is present in the autoclave). If we the composition of the system. A little tongue-in-
raise the temperature to 134◦ C, we have to increase cheek, we might say that the phase is physically
the pressure to 312 kPa to maintain the coexistence defined, whereas the component is chemically defined
of liquid water and water vapor. (however, note that chemically a Na+ ion is very dif-
Finally, if we are at a triple point in the phase ferent to a Cl− ion). For multicomponent systems we
diagram, i.e., three phases are coexisting, we cannot can formulate Gibbs’ phase law as follows:
change either pressure or temperature without getting
a change in the number of phases, which means that F=C−P+2 (7.5)
here the system has zero degrees of freedom. where C represents the number of components.
From these considerations, Gibbs’ phase rule can For the examples of a salt solution, F = 2 –
be formulated as follows: 1 + 2 =3. We can see pressure, temperature, and
F=3−P (7.4) salt concentration here as the degrees of freedom of
the system. In most cases, phase diagrams of two
where F is the number of degrees of freedom and P is component systems are given at a constant pressure,
the number of phases coexisting (one, two, or three). usually normal atmospheric pressure (i.e., one degree
So far, we have only considered phase diagrams of freedom is used up). In this case we can express
of a single chemical component (e.g., H2 O). It is, Gibbs’ phase law for a two component system as F* =
however, also possible to have a single phase system 3 – P, with F* being the remaining degrees of freedom
which consists of more than one component. Let us of the system. An example of such a phase diagram
now consider, for example, a salt solution. Here we will be discussed with Eutectics.
have a single phase system (the salt molecules are
dissolved as sodium and chloride ions in water, and Crystalline solids
the system is homogeneous). However, in this case, we The solid state of matter is perhaps the most important
can vary not only pressure and temperature without state in pharmaceutics since the starting material for
getting a phase change but also the salt concentration most formulations and the majority of orally admin-
until we get a saturated solution of the salt in water. istered dosage forms are in a solid form (most often
In this case, we have three independent variables as tablets or as powders, pellets, or granules in hard
that can be changed without changing the number gelatine capsules).
of phases coexisting. Of course, as with pressure and Crystals are defined by a high degree of order, with
temperature changes, this can only be done within a three-dimensional periodicity in position for atoms
limits, i.e., until we reach a boundary line in the or ions and, additionally, with configurational peri-
phase diagram. If we, for example, increase the salt odicity for molecules that form the crystal. Most solid
concentration above the saturation solubility of NaCl forms of drugs are used in the crystalline state, and
at the given pressure and temperature, the excess salt most pharmaceutically relevant crystals are formed
will form a second, solid phase, coexisting with the by organic molecules. Not all solids, however, are
salt solution phase. crystalline as some are amorphous.
In the example of a salt solution, we have to con- The reason for the high degree of order of crystals
sider two chemical entities, H2 O and the salt (e.g., lies in the strong interactions between the atoms, ions,
NaCl). These chemical entities must be independent of or molecules that form the crystal. As we have seen
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Pharmaceutics | 203

earlier, in the case of diamond, carbon atoms form now look for the smallest unit which, when endlessly
a periodic three dimensional tetrahedral network of repeated, forms the crystal structure. Since there may
covalently bonded sp3 hybridized carbon atoms. Dia- be different ways to do this, the unit cell of a given
mond is thus an example of a crystal formed by crystal is the one with the shortest dimensions, and
atoms through covalent bonds. Most inorganic mate- that includes angles that deviate the least from a right
rials form ionic crystals. A pharmaceutically relevant angle. The unit cell is a geometric construction and
example is NaCl. Here the crystal is formed by sodium does not take into account the size and shape of the
and chloride ions, held together by ionic interactions. crystal forming atoms, ions, or molecules, nor the
In the case of NaCl, each sodium ion is surrounded by type and strength of interactions between them. For
six chloride ions, and each chloride ion by six sodium this reason, it is possible to summarize the types of
ions. The number of ions (or atoms or molecules) unit cells into only seven crystal systems, which can be
that each ion has as its nearest neighbors is called the understood as unique unit cell shapes and which can
coordination number. The coordination number for be differentiated with respect to the relative lengths
NaCl is, therefore, six. For ionic crystals, the coor- on their axes a, b, and c and the angles α, β, and
dination number depends on the relative size of the γ between the axes. These seven crystal systems are
cation and the anion. If the size difference is very called cubic, tetragonal, orthorhombic, monoclinic,
large, the most often found coordination number is triclinic, rhombohedral (or trigonal), and hexagonal
four, and if the size differences are small, a coordina- (Fig. 7.5).
tion number of eight is found. Higher coordination While there are only seven crystal systems, there
numbers are found in metal crystals (eight or twelve), are 14 Bravais lattices. This is because additional
and the coordination number of diamond is four. points can be present in a unit cell, other than the
If atoms or ions are held together by covalent points at the corners of the unit cell, without changing
or ionic interactions, the resulting crystals have very the essential symmetry elements of the crystal system.
high melting points and are often hard and brittle. In If there is an additional point in the centre of the unit
metals, the crystalline structure is formed by cations, cell, these lattices are called body (or volume) centered
where the electrons are delocalized. This is the reason (for example, body centered (cubic I in Fig. 7.5)). If
for both the high coordination numbers of metal there are additional points in the centre of each side
crystals as well as the ductile behavior of many metals. (face) of the unit cell, they are called face-centered
Most drugs are organic molecules. The crys- (for example, face centered (cubic F in Fig. 7.5), and
tals formed by these substances are held together if an additional point is present at the centre of two
by dipole–dipole interactions, hydrogen bonds, or opposite faces of the unit cell, they are called base-
London forces. Since these are at least an order of centered (for example, base-centered (monoclinic C
magnitude weaker than ionic or covalent interactions, in Fig. 7.5). Bravais lattices without extra points
the melting points of molecular crystals are lower than are called simple or primitive, for example cubic
those of the aforementioned crystalline structures. For P in Fig. 7.5. The 14 Bravais lattices are shown
example, the melting points of paracetamol (molec- in Fig. 7.5.
ular crystal), NaCl (ionic crystal), copper (metal Every crystalline material belongs to one of these
crystal), and diamond (covalent crystal) are 169◦ C, Bravais lattice types but differs in their lattice param-
801◦ C, 1084◦ C, and 3550◦ C, respectively. eters, and for each unit cell we can define three axes,
We have already seen that different types of crys- with a length characteristic for the individual crystal,
tals can have different coordination numbers. In fact, and three angles, also characteristic for this crystal.
since crystals are periodically organized, we can define For example, NaCl crystals belong to the crystal sys-
a specific unit cell characteristic for each crystal. A unit tem: cubic, Bravais lattice type: face-centered. The
cell is defined as the smallest unit of a crystal, which, only lattice parameter we need is the length of one
if repeated, could generate the whole crystal. For this axis, a = 5.6402 Å, since for a cubic crystal the axes
we imagine the atoms, ions, or in the case of drug a = b = c, and the angles α = β = γ = 90◦ . Parac-
crystals, molecules, as points in a lattice, disregarding etamol (polymorphic form I) belongs to the crystal
their actual shape. Within the crystal structure we system: monoclinic, Bravais lattice type: primitive,
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204 | An Introduction to Pharmacy

Three axes at right angles;

all equal:

Cubic P Cubic I Cubic F

Three axes at right angles;

two equal:

Tetragonal P Tetragonal I

Three axes at right angles;

all unequal:
P C I F
Orthorhombic

Three axes, one pair not

at right angles, all unequal:

Monoclinic P Monoclinic C

Three axes not at right angles;

all unequal:

Triclinic P

Three axes equally

inclined, not at
right angles; all equal:
Rhombohedral

Three axes coplanar at 120°,

fourth axis at right angles
to these:
Hexagonal

Figure 7.5 The 14 Bravais lattices.

a = 11.74 Å, b = 9.396 Å, c = 7.117 Å and β = 97.47◦ single lattice point may be vacant (vacancy) or occu-
(α = γ = 90◦ , for a monoclinic unit cell). pied by a different atom, ion, or molecule from the
In the above discussion, we have considered the ones that form the crystal (substitutional point defect;
crystalline structure as infinitely periodic. In reality this would constitute a chemical impurity). It is also
most crystals, however, will show defect structures, possible that there may be additional lattice points
i.e., structures in which there are packing mistakes (interstitial point defects), either from the same or a
of some kind, so the crystalline structure of a real different atom, ion, or molecule.
crystal will not be perfect. Depending on the number The dislocation is an example of a line defect,
of these defects in a crystalline material, properties and the grain boundary is an example of a planar
of the crystalline substance may vary, for example, defect (Fig. 7.7). A grain boundary marks an interface
its behavior in a milling process. Point defects occur between different crystalline regions, called crystal-
at a single lattice point (Fig. 7.6). For example, a lites. Such a material is termed polycrystalline and
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Pharmaceutics | 205

able to crystallize in more than two, and in some

case even more than ten, different crystalline forms.
SI V These different polymorphs are also termed polymor-
phic modifications of the substance in question. It is
I
S important to note that different modifications of a
S drug may not necessarily form crystals with a dif-
ferent type of Bravais lattice. Although this is, of
course, possible, it is also possible that two poly-
Figure 7.6 Point defects in a crystal lattice. V: vacancy, S: morphic forms of a drug both have, for example, a
substitutional point defect (different atom, ion, or molecule
monoclinic unit cell. In this case, however, the lat-
from the ones that form the crystal), I: interstitial point defect
tice parameters of the two polymorphic forms will
(different atom, ion, or molecule from the ones that form the
be different. Also, for some polymorphic forms, for
crystal), SI: self-interstitial point defect (same atom, ion, or
molecule as the ones that form the crystal). example, of drug substances, the molecules present in
the lattices of the different modifications will adopt
different molecular conformations (termed confor-
mational polymorphism), while other polymorphic
pairs will contain the drug molecules with the same
conformation (termed packing polymorphism).
Polymorphism is important in the pharmaceuti-
cal field, since the physical properties of different
Dislocation polymorphic forms are often considerably different,
which can have consequences for important quality-
relevant attributes of a drug substance or dosage
form. Differences may be encountered in, for example,
Grain boundary
dissolution rate, solubility, flow properties, behavior
under mechanical stress (for example during milling,
Figure 7.7 Dislocation (a line defect) and grain boundary (a
tableting, agglomeration), hygroscopicity, etc. These
planar defect).
differences may be sufficiently large so that different
polymorphic forms may have different bioavailabil-
is the reality for most crystalline materials, including ities. It is thus possible, or even common, that for
drug substances. a given drug regulatory approval is only given to a
specific polymorphic form of the drug.
Polymorphism While often different polymorphic forms of a
An important property of many chemical entities, drug form macroscopically different crystals, such
including most drug molecules, is that they are able as needle-like versus plate-like crystals (the macro-
to crystallize in several different crystalline forms, scopic appearance of a crystal is also known as the
termed polymorphic forms. These different crystalline habit of the crystal), it is important to note that dif-
forms consist of the same molecules, but these are ferent polymorphic forms may not necessarily look
arranged in different ways. If the crystal former is an different macroscopically, and thus it may be difficult
element (as we have seen in the case of carbon), dif- to differentiate these by visual inspection or in the
ferent polymorphic forms are termed allotropes. For light or electron microscope alone. It is also possi-
molecular crystals, the crystal is held to together by ble that if one and the same polymorphic form of
secondary forces, as outlined above. Since these inter- a crystal is crystallized, for example, from different
actions are fairly weak (compared to ionic, metal, solvents or from either a solution or the melt, it may
or covalent crystals), and because the molecules may adopt different crystal habits. So while the habit is
adopt different molecular configurations in the crys- important, most notably for further processing of the
talline structures, it is not surprising that most phar- drug powder, it is also important to have techniques
maceutical drugs show polymorphism, and are often available to unambiguously identify the crystalline
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206 | An Introduction to Pharmacy

structure of a drug and its polymorphic form. This curve of form II. Since the stable polymorph is the
will be discussed in the section on Methods to Char- one with the lower vapor pressure, in the case of a
acterize Solids, where some techniques to identify and monotropic pair of polymorphs, one form (here form
characterize polymorphs (or indeed solid state forms I) is always the stable form until either of the forms
in general) will be mentioned. melts. Note that after melting there is no difference
If a drug can crystallize in different polymorphic between the melts of the substance, irrespective of
forms, it should be noted that at any given condition the polymorphic solid form. Should initially form II
of pressure and temperature, only one polymorphic have been generated by cooling from a melt (accord-
form can be the thermodynamically stable form. All ing to Ostwald’s rule this is not unlikely to happen
other polymorphic forms that may form under these in a practical scenario), then if conversion occurs to
conditions will be only metastable. Metastable here the stable form I, this conversion will be irreversible.
means that these polymorphs can form but even- The situation is different for enantiotropic systems
tually will convert to the stable form over time if (Fig. 7.8b). Here form II has a lower vapor pressure
the environmental conditions are not changed. The than form I at low temperature (so it is the stable
metastable forms, on the other hand, are not unsta- polymorph at these temperature conditions), but at
ble (in contrast to amorphous forms which will be higher temperatures there is a crossover in the subli-
discussed in the next section), since (sometimes con- mation curves of the two polymorphs before either of
siderable) activation energy is required to bring about
a phase transition from the metastable to the stable
polymorphic form. For some metastable polymorphs,
therefore, the polymorphic transition may be very
Vapour pressure

slow and may take much longer than the shelf life
of the drug product containing a metastable poly-
morphic form. In general, if not precluded by a too
II
low solubility of the stable form, most drugs will
be manufactured in solid dosage forms in the stable
polymorphic form. However the drug ranitidine-HCl, I
which can exist in two polymorphic forms, is manu-
factured using both polymorphs, i.e., the metastable
polymorph is ‘‘practically’’ stable enough to allow
Temperature
safe manufacturing.3
(a)
It is often found that not the most stable, but a less
stable (often the least stable) polymorphic form of a
substance crystallizes first, for example, upon cooling
Vapour pressure

of a melt. This is known as Ostwald’s rule. While not

II I
universally applicable (not being a law, but rather a
rule), it nevertheless highlights the importance in drug
development to carefully check which polymorphic
form of a drug one is indeed dealing with.
I
Let us consider a given set of two polymorphs of a
substance. Because the solid state forms are different, II
their phase diagrams will also be different, and the
overall phase diagram of this polymorphic substance Temperature
will be the superimposed phase diagram of the two (b)
forms. This is illustrated in Fig. 7.8. We can differ-
entiate two possible scenarios, shown in Figs. 7.8a Figure 7.8 Phase diagrams of (a) a monotropic and (b) an
and b. For the monotropic system (Fig. 7.8a), the enantiotropic polymorphic system. The solid lines represent
sublimation curve of form I is below the sublimation stable states.
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Pharmaceutics | 207

these forms melts. After the crossover, form I now has a gradual decrease of the thermodynamic properties
the lower vapor pressure and is the stable form. This below T m .
means if we have form II present at low temperature, At temperatures above the glass transition tem-
this is the stable form, but upon heating at a certain perature (T g , Fig. 7.9) the material is said to be in
temperature, polymorphic conversion will take place the super-cooled liquid state (sometimes also called
and form I is the stable form. If we now cool down the rubbery state), the viscosity of which is typically
form I again, conversion back to form II will occur. between 10−3 and 1012 Pa s. In the super-cooled liq-
In other words, the process is reversible. uid state, the molecules are able to follow any further
decrease of temperature to attain equilibrium con-
Amorphous solids ditions. However, cooling of the super-cooled liquid
In the previous section we have seen that a crystalline increases the viscosity of the system, and upon further
solid is characterized by its long-range positional cooling the molecules are not able to reach equilib-
order. Amorphous solids lack the long-range order rium any longer. At this temperature, the T g , the
seen in crystals, although short-range order over sev- molecules are ‘‘kinetically frozen in’’ and the super-
eral molecular dimensions may exist. The molecular cooled liquid solidifies into a glass. (Note that in a
arrangement is thought to represent that of a frozen glass the molecules still show some mobility.) The T g
liquid with the rheological properties of a solid. represents the temperature at which the system falls
Heating of a crystalline material leads to a grad- out of equilibrium. Amorphous solids are therefore
ual increase in the thermodynamic properties such non-equilibrium solids and the glass transition is a sec-
as enthalpy and entropy until the melting point, T m , ond order phase transition. Unlike melting or boiling,
is reached (Fig. 7.9). As we have seen, a significant the heat capacity is not infinitively high at the phase
increase in thermodynamic properties marks the first transition, but jumps from one value to another. The
order transition (melting) from the solid to the liquid non-equilibrium state of a glassy amorphous system
state. Above the melting temperature, the material has special implications: the fundamentals of thermo-
exists as a molten liquid. This is a reversible pro- dynamics only apply to systems in equilibrium, and
cess, so upon cooling, crystallization of the melt therefore, the behavior of the glassy state cannot be
occurs whereby the molecules rearrange themselves predicted from regular thermodynamics.
in their crystal lattice. However, if the liquid is cooled Due to the high viscosity of the resulting glass
sufficiently fast below its melting temperature, crys- (viscosity is usually greater than 1012 Pa s), it appears
tallization may be prevented so that a super-cooled as a solid. The T g represents a characteristic thermal
liquid is formed, and the slope of the equilibrium event for an amorphous systems, but it should be
liquid line (Fig. 7.9) may be followed, resulting in noted that the T g is a kinetic property of the material,
and its exact position depends, for example, on the
cooling rate of the super-cooled liquid, i.e., on its
thermal history.
Liquid In principle, the amorphous state can be produced
in two ways:
Volume, enthalpy,

Super-cooled liquid
entropy

Glass
1. From a liquid state, either by rapidly cooling the
molten liquid or by fast evaporation of a solvent
Crystal
from a solution, hence ‘‘freezing in’’ the molecular
arrangement of the liquid (vitrification), or
TK Tg Tm
Temperature
2. By gradually inducing and increasing defects in the
crystal lattice until the amorphous state is gener-
Figure 7.9 Thermodynamic relationship of crystalline and ated (amorphization).
amorphous solids as a function of temperature. Shown are the
melting temperature (T M ), the glass transition temperature The vitrification process (1) is also termed the thermo-
(T G ), and the Kauzmann temperature (T K ). dynamic pathway to form amorphous materials, and
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208 | An Introduction to Pharmacy

the amorphization process (2) has been named the the kinetic pathway gradually increases the number of
kinetic pathway. A schematic representation of the crystal defects, thereby creating non-equilibrium crys-
conversion from crystalline to amorphous is depicted talline states. Such materials, still crystalline but with
in Fig. 7.10. increasing number of defects, are termed defective
If the amorphous state is produced via the ther- crystals.
modynamic pathway, the crystalline material has to While the thermodynamic pathway is commonly
be transferred to a liquid state, either by melting employed in order to deliberately generate the amor-
or by dissolution in an appropriate solvent. If the phous state, the kinetic pathway is usually associated
kinetic pathway is followed, the crystalline lattice with the unintentional amorphization of a crystalline
is continuously disrupted by mechanical processing material, for example when the actual objective of a
like milling, inducing crystal defects. As long as the milling process is to reduce the particle size of the
crystal defects remain small in number, the mate- crystalline material, not to change its solid state form.
rial still exhibits crystalline properties. However, if a It should be noted that not every preparation tech-
critical number of defects are introduced, the crystal nique to convert a crystalline drug into its amorphous
cannot retain its structure and converts to the amor- counterpart is suitable for every drug, e. g. thermo-
phous state. The main difference between these two labile drugs cannot be converted to the amorphous
approaches is that while the thermodynamic pathway form by using heat based methods; drugs that are
abruptly destroys the long-range order of the crystal, insoluble in a range of organic solvents cannot easily

(i) Thermodynamic path Liquid or in solution

Crystal

Heating or dissolution

Loss of molecular order

gain of molecular mobility
gain of molecular mobility
Loss of molecular order

molecular mobility

Quench-cooling or fast
Partial loss of

solvent evaporation
(ii) Kinetic path

Loss of molecular order

gain of molecular mobility

Mechanical processing

Defective Amorphous
crystal

Figure 7.10 Schematic representation of the crystalline to amorphous conversion via the thermodynamic and kinetic
pathways.
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Pharmaceutics | 209

be spray-dried to amorphize the substance, and some The explanation for this is that due to the lower onset
methods (milling) may not completely convert certain of the T g , the super-cooled liquid state is maintained
drugs into the amorphous state. We have now seen at lower temperatures, therefore decreasing the value
a variety of methods that can be used to generate of enthalpy and entropy further.
the amorphous state of a drug. The question arises For practical purposes, this means that for a given
whether the amorphous state generated is the same in material an amorphous system which is prepared by
all cases. one method is not identical to the amorphous sys-
Let us take a closer look at the T g , an important tem prepared by another method. Even if the method
feature in the amorphous state. Above the T g the is the same but parameters are varied, the resulting
system is still in an equilibrium state; below the T g the amorphous states will not be identical. So, unlike
system has fallen out of equilibrium. Let us imagine the ‘‘crystalline state,’’ which has defined properties,
that the T g did not exist: in Fig. 7.9 we see that there is no ‘‘amorphous state’’. Depending on the
the decrease of the temperature would eventually preparation method, sample history, geometry and
lead to the super-cooled liquid line intersecting with mass, and the experimental heating and cooling rates,
the crystal line. This would cause the super-cooled the amorphous states can differ considerably in prop-
liquid eventually to have a lower entropy than the erties, especially in physical stability (recrystallization
crystal upon further cooling. This, however, is not to the crystalline state).
considered possible. The theoretical temperature at From Fig. 7.9 we can see that the amorphous state
which the super-cooled liquid would attain the same has higher thermodynamic properties, like enthalpy
properties as the crystal is known as the Kauzmann and entropy, compared to the crystal. What Fig. 7.9
temperature, T K (see Fig. 7.9). The kinetic nature of does not show, however, is that the properties of the
the glass transition is evident from its dependence amorphous state are time-dependent. As time passes,
on the heating and cooling rates, which means that we observe that the amorphous state decreases in
the T g does not exist at a defined temperature. Slow properties such as enthalpy even though the temper-
cooling rates lead to a prolonged super-cooled liquid ature is kept constant. This phenomenon is called
state and result in a T g with a lower temperature, as relaxation, and it has its origin in the instability of
displayed by T g II in Fig. 7.11. As the super-cooled the amorphous state. The molecules may be frozen
liquid is cooled at a slower rate, the system is able in, but they still have some molecular mobility left.
to adjust to the temperature dependent increase in This is sufficient for the molecules to relax over time
viscosity, resulting in a lower temperature for the and rearrange themselves in a more thermodynami-
glass transition. Glasses created by slower cooling cally favorable way. By doing this, they decrease their
rates also show lower values of enthalpy and entropy enthalpy, and this is also considered an important
than glasses that are created by faster cooling rates. factor in the stability of amorphous systems. This
relaxation can be visualized in a differential scanning
calorimetry (DSC) thermogram, in which the relax-
Liquid ation appears as an endothermic peak on top of the
glass transition event.
In recent years the amorphous state of drugs has
Volume, enthalpy,

gained increasing interest in pharmaceutics due to

entropy

Glass I its favorable solubility properties, compared to its

Glass II crystalline counterpart.4 Many new drugs show insuf-
Crystal ficient solubility for oral dosage form development.
Because of its higher energy, the solubility of amor-
TgII TgI Tm
Temperature phous forms is often orders of magnitude higher than
for crystals and, thus, this solid form is attractive
Figure 7.11 Thermodynamic relationship of glasses created in dosage form development. However, issues when
by different cooling rates. Glass I has been cooled fast, and dealing with the amorphous state, such as physical
glass II has been cooled slowly. and chemical instabilities, remain. Also, to date, the
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210 | An Introduction to Pharmacy

prediction of physical and chemical stability of drugs does not have to be 1:1 (monohydrates), and, for
in the amorphous state still proves challenging, since, example, hemihydrates (the molar ratio of drug to
for example, the application of stress tests is not water molecules in a hemihydrate is 2:1) or dihydrates
straightforward for amorphous systems (they don’t (the molar ratio of drug to water molecules is 1:2)
behave in an Arrhenius fashion). are not uncommon. Some drugs can form different
hydrates (for example, mono- and dihydrates), and
Solids with more than one component even within one group of hydrates, polymorphism
In the previous sections we have discussed crystalline may occur, further increasing the possibilities of a
and amorphous solids on the basis of single com- given material to crystallize in many different forms,
ponent systems, i.e., we were considering a single with different physicochemical properties.
chemical entity (e.g., the drug molecules). In this Not all hydrates, however, have a fixed stoi-
section we will expand the discussion on solids by chiometric ratio between the drug and the water
introducing a second component. molecules. If the water molecules can be incorporated
into channels that may be present in a non-hydrate
Solvates and co-crystals crystalline structure, many different ratios of water to
Not only can most drugs crystallize in different poly- drug molecules are possible, depending, for example,
morphic forms, but they can also incorporate other on the relative humidity of the air surrounding the
molecules to form crystalline structures. For example, hydrate. These types of hydrates are called channel
during a crystallization process from a solvent, solvent hydrates.
molecules may be incorporated into the crystalline If a stoichiometric hydrate loses its water (for
structure. This occurs if the solvent molecules can example, by heating), the water in most cases will
interact with the drug molecules through hydrogen leave the crystal at a defined temperature. If we are
bonding or other weak interactions. In this case a measuring the weight loss of a hydrate as a func-
new crystalline structure of the drug and the solvent tion of temperature (these types of measurements
molecules may be formed. These crystalline structures are called thermogravimetric measurements), typical
are termed solvates. In the specific case of water as weight loss curves, as shown in Fig. 7.12, are obtained
the additional molecule to be incorporated into the for stoichiometric hydrates. In case of a dihydrate, for
crystalline structure, the solvate is called a hydrate. example, water may be leaving the crystal initially to
Hydrates can also form from crystalline or amor- form a monohydrate that is then losing the remaining
phous non-hydrate drug substances by addition of water at a higher temperature, so two steps in the
water molecules from the air or during a dissolu- weight loss curve may be observed (Fig. 7.12b). For
tion process in water. Thus, hydrate formation of a a given mass of material, if the molecular weights
drug (if the drug can indeed form hydrates, which of the drug and the solvate molecule (18 g mol−1 in
is compound specific) may even occur during the case of water) are known, the stoichiometric ratio of
oral administration of the drug. This is of pharma- drug to solvate molecules can be determined by these
ceutical significance, for in most cases the resulting measurements. In some cases the water only leaves the
hydrate will have lower water solubility than the crystal upon melting of the material. In contrast, for
respective non-hydrate, which may even result in a channel hydrates the water molecules are leaving the
lower bioavailability. For example, partial hydrate crystalline structure often before melting and over a
formation has been made responsible for erratic broader temperature range. If the water in a stoichio-
bioavailability of carbamazepine and theophylline metric hydrate leaves the crystal before melting this
after administration of the drug in a non-hydrate may result in a collapse of the crystalline structure
form.5,6 altogether, leading to the formation of an amorphous
Since the water molecules (or other solvent material. In the case of channel hydrates, the result of
molecules) are incorporated into the crystalline water leaving the crystal may be a non-hydrate with
lattice in a regular structure, the molar ratio of almost the same crystalline structure as the hydrate
drug to solvent molecules will take on fixed ratios (same crystal lattice type and similar, but not iden-
(stoichiometric hydrates). However, this molar ratio tical, lattice parameters), sometimes called a vacant
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Pharmaceutics | 211

a higher likelihood of formation of a stable co-crystal.

(a)
100 Typical co-crystal formers used in the pharmaceutical
field include maleic acid, tartaric acid, nicotinamide,
6%
95 saccharin, and many others. Since co-crystals have
Heat flow

Weight (%)
other properties, including solubility, hygroscopicity,
90 and pharmaceutical processability, they offer interest-
ing possibilities in drug development. Co-crystals (for
85 example, the carbamzepine–nicotinamide co-crystal
Endothermic and the carbamazepine–saccharin co-crystals) can
Temperature also show polymorphism.8

(b)
100 Eutectics
4%
Above we have considered solid state materials con-
95 taining two components but forming a single phase.
4% Weight (%)
Heat flow

Eutectics are an important example of a solid mix-

90
ture of crystals (in contrast to co-crystals, which
are ‘‘mixed crystals’’, rather than a ‘‘crystalline mix-
85
ture’’). Eutectics thus contain two phases. However,
Endothermic in eutectic mixtures the two phases (two materials)
Temperature are intimately mixed and thus often show different
properties from simple physical mixtures of the two
Figure 7.12 Thermogravimetric weight loss curves (–––) and components.
corresponding DSC curves (–––) of (a) a hypothetical
Let us consider two crystalline materials, A and B,
monohydrate and (b) a hypothetical dihydrate. Note that the
with meeting points T mA and T mB , that are miscible in
water loss also appears as an endothermic event in the DSC
the molten state, i.e., they form a single liquid phase.
thermogram. Other thermal events in the DSC curves (e.g., a
polymorphic conversion, or melting) are not accompanied by This is shown in form of a phase diagram in Fig. 7.13.
a weight loss in the thermogravimetric curves. If we have a mixture of the two materials at the mixing
ratio R1, at a temperature where both materials are
molten (so we are in the liquid area of the phase
hydrate, before further polymorphic conversion to the diagram), and we now reduce the temperature of
stable non-hydrate form occurs. this melt, at the intersection with the melting curve,
Of recently increasing pharmaceutical interest are
co-crystals.7 Unlike salts, in which the drug (as an
anion or cation, depending on the nature of the drug) Temperature Temperature
is bound by ionic interaction to the counterion, in
a co-crystal the drug and the co-crystal former (see
below) are interacting via weaker interactions, in most R1 Liquid
Tm
cases by hydrogen bonding, as is the case for solvates. A

However, in contrast to solvates, both components Tm

B
of the co-crystal are solid at room temperature. If
Liquid +
the hydrogen bond between the two molecules is Liquid
solid A
+ solid B
formed by similar molecular moieties (for example, e
two carboxylic acid groups), this is known as a solid A + solid B
supramolecular homosynthon, whereas a hydrogen
bond between two different moieties of the two com- A Eutectic B
ponents (for example, a phenol group and an amide 100% point = e 100%
group) is known as a supramolecular heterosynthon.
Generally, the formation of a heterosynthon leads to Figure 7.13 Phase diagram of two materials, A and B.
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212 | An Introduction to Pharmacy

we will observe crystallization of compound A. As pure compound B crystallizing together at the eutectic
A will crystallize, but not B, this means that the point, we will have the crystallization of an A-rich
composition of the remaining melt will change and it and a B-rich phase of the two corresponding solid
will become more B-rich. We thus follow the melting solutions. This plays a major role in the formation of
curve upon further lowering of the temperature until metal alloys.
we reach the lowest point of the melting curve of
A. If we lower the temperature further, now B will Amorphous mixtures
also crystallize. Similarly, if we have a B-rich mixture, We have discussed above that the amorphous form
B will crystallize when the temperature is lowered of a solid is thermodynamically unstable and tends
to the melting curve of B. This, in turn, will lead to crystallize back to the stable crystalline form or a
to the remaining melt having relatively more A than metastable polymorphic form. In order to make use
the original melt, and we follow the melting curve of the advantages, including a higher dissolution rate
of B until we reach its lowest point, which is the and solubility that amorphous solids offer, especially
same as for an A-rich system. The ratio of A and B for poorly water soluble drugs, it is therefore often
at this point is called the eutectic mixture for these necessary to stabilize the amorphous form. One
two compounds, and the temperature in the phase way of achieving this is to use two components (for
diagram is known as the eutectic temperature (e), example, a drug and an excipient) in the formation
the lowest temperature at which both compounds of a solid amorphous material. In most cases this
crystallize together. In other words, at the eutectic will be an amorphous, hydrophilic polymer. If
point both crystalline A and B and the melt are an amorphous polymer (such as, for example,
in equilibrium. For the eutectic mixture of sodium polyvinypyrrolidone (PVP), PVP-vinylacetate
chloride and water, this occurs at a salt concentration copolymer (PVPVA), hydroxypropylmethylcellulose
of 22.4% and a eutectic temperature of −22◦ C. (HPMC), HPMC-acetatesuccinate (HPMCAS), and
For a given two compound system, the ratio of the various polymethacrylates) is melted together with the
compounds at the eutectic mixture can be estimated drug to form a single phase melt, this can be cooled
from the theoretical melting curves of the two com- down rapidly to form a single phase amorphous
pounds, using a simplified form of the Schröder–Van material, known as a glass solution (do not confuse
Laar equation: the amorphous glass solution with the crystalline
  solid solution, mentioned above). In this solid form
H0 1 1
ln x = − (7.6) the drug and the polymer are molecularly mixed with
R T0 T
each other. For this to be successful, it is required
where x is the mole fraction of one compound in that the two compounds show mutual solubility,
the mixture, H0 and T 0 are the corresponding heat for example, have similar solubility parameters. It
of fusion [J mol−1 ] and melting temperature [K] of is often advantageous for the physical stability of
the pure compound, respectively, T is the melting glass solutions if some interactions between the drug
point of the binary mixture at x, and R is the gas and polymer occur (usually hydrogen bonding), since
constant [8.314 J K−1 mol−1 ]. However, it should be this will lower the molecular mobility (especially of
noted that for this approach to be valid, a number the low molecular weight drug) and thus will slow
of assumptions are made: there is no solid solution down the processes of nucleation and crystal growth,
formation between the two compounds (see below), which lead to the crystallization of the amorphous
the melt has to be an ideal mixture, and the heat material. The polymers used for the formation of
capacities of the pure compounds in the melt and as a glass solutions often have a high glass transition
solid should be fairly similar. temperature (T g ) so that the resulting glass transition
In the phase diagram shown above, we did not temperature of the glass solution will be higher
consider the possible formation of a solid solution than the T g of the pure amorphous drug, further
between the two compounds. If this occurs, then there stabilizing the drug against crystallization. If the glass
will be partial miscibility between the compounds in transition temperatures of the two pure amorphous
the solid state, and rather than pure compound A and components are known, the resulting glass transition
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Pharmaceutics | 213

temperature of the glass solution in various mixing Methods to characterize solids

ratios of the two compounds can be estimated based We have seen that a pharmaceutical solid can be
on the Gordon–Taylor equation: present during development or in a final dosage form
w1 Tg1 + Kw2 Tg2 in various polymorphic forms. It can also be present
Tg12 = (7.7) in form of hydrates or other solvates. Salt forma-
w1 + Kw2
tion is possible, as is the formation of a co-crystal.
where T g12 is the glass transition temperature [K] Solvates, salts and co-crystals in their own right can
of the mixture; T g1 and T g2 are the glass transition show polymorphism. The drug may also be partly
temperatures [K] of the single amorphous compounds or fully amorphous, either on its own or in form
(e.g., the drug and the polymer); w1 and w2 are the of a glass solution or amorphous suspension. All of
weight fractions of each compound in the mixture; these solid state forms will differ in many of their
and K is a constant, depending on the glass transition physical properties, and this can be relevant for the
temperatures and amorphous densities of the single drug and dosage form if, for example, solubility, dis-
compounds: solution rate, and chemical and physical stability are
Tg1 ρ1 affected. It is thus obvious that we require a thor-
K= (7.8) ough identification and, in many cases quantification,
Tg2 ρ2
of the various solid state forms of a drug that we
where ρ 1 and ρ 2 are the densities of the single amor- may encounter in preformulation, formulation, dur-
phous components. It should be noted, though, that ing storage and upon administration of the dosage
this equation assumes volume additivity, i.e., the form. It is also obvious that this task is more complex
absence of specific molecular interactions and, as such, for solids than, for example, if the drug is present
can often only be used as an estimate for the actual in liquid form or in a solution, for in these cases all
glass transition temperature of the glass solution. differences of the solid state forms disappear.
In most cases the T g of the glass solution is pre- The list of analytical techniques that are useful to
dicted by using the T g of the drug and polymer. investigate solid state properties is almost endless, and
However, in real situations a third component can be it is convenient to differentiate the techniques avail-
present: moisture. It is known that moisture can accel- able to the pharmaceutical scientist according to the
erate crystallization from the amorphous state, and different levels at which they probe the solid material.
this effect can be explained by the plasticizing effect Most spectroscopic techniques, such as Raman and
of water. The T g of water is approximately 139 K, infrared (IR) spectroscopy, but also solid state nuclear
which is significantly lower than the T g of commonly magnetic resonance (NMR), near IR spectroscopy and
used pharmaceutical materials. In the same way that others are probing predominately molecular proper-
a high T g polymer is added for stability, a low T g ties. If a drug, for example, can crystallize in different
compound can lower the T g of the system. If the polymorphic forms, these forms still contain the same
Gordon–Taylor equation is extended to a third com- molecules, and as such, the resulting spectra should
ponent, it is obvious that even small amounts of a be identical. Indeed, that is (almost) the case. How-
low T g compound can have a significant effect on ever, the fingerprint regions of the resulting spectra
the T g and, hence, on stability. Therefore, moisture will also be influenced by the neighboring molecules,
should be excluded during manufacturing and storage for example, by the unit cell of the crystalline forms.
of amorphous systems. Because these are different between different polymor-
If the two components (for example, the drug phic forms, the resulting spectra, for example, for IR
and the polymer) are not miscible on a molecular and Raman measurements, will also (subtly) be dif-
level, the formation of a solid suspension may occur ferent. If the polymorphic pair shows configurational
upon cooling of a melt of the two components. These differences between the molecules, the differences in
systems will show two glass transition temperatures, the resulting spectra will be larger than if the con-
one for the drug (or possibly a drug rich phase, if figuration of the drug molecules is the same in both
there is partial miscibility) and one for the polymer polymorphs. It is often necessary to use multivariate
(or the polymer rich phase). data analytical tools, such as principal components
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214 | An Introduction to Pharmacy

analysis or partial least squares analysis, to identify example IR spectra (Fig. 7.14a) and Raman spectra
the different solid state forms using IR or Raman (Fig. 7.14b) of different solid state forms of the drug
spectroscopy. It is advisable, in any case, to use such indomethacin.
techniques if a quantification of different solid state The next level of analytical techniques, and in
forms that are present at the same time is desired. many ways the ‘‘gold standard’’ techniques to char-
Generally, differences in the spectra between a non- acterize and quantify different solid state forms of
solvate and a solvate form are larger than between two a drug, are the techniques that probe an assembly
polymorphic forms, and differences between the spec- of molecules. These techniques have been termed
tra of a crystalline and an amorphous form may be ‘‘particulate level techniques,’’ and include X-ray
even larger, with the spectra in IR and Raman mea- diffraction (mostly used in the forms of X-ray powder
surements being less well defined (peak broadening diffraction, XRPD), and various thermal analytical
and peak merging) for amorphous forms, compared techniques (of which DSC plays the largest role in
to their crystalline counterparts. Figure 7.14 shows pharmaceutical analysis). These will be described

γ indomethacin
α indomethacin
0.7
Amorphous indomethacin
γ indomethacin
α indomethacin 0.6
Amorphous indomethacin
1.0 0.5
Intensity [a.u.]

0.4
0.8
Absorcance [a.u.]

0.3
0.6 0.2

0.1
0.4
0.0
0.2
−0.1
0 500 1000 1500 2000 2500 3000 3500
500 1000 1500 2000 2500 3000 3500 4000
Raman shift [cm−1]
Wavenumber [cm−1]

γ indomethacin
α indomethacin
0.7
γ indomethacin Amorphous indomethacin
α indomethacin
Amorphous indomethacin 0.6
1.0
0.5
Intensity [a.u.]

0.8
Absorcance [a.u.]

0.4

0.6 0.3

0.2
0.4
0.1
0.2
0.0
1500 1550 1600 1650 1700 1750 1800 1500 1550 1600 1650 1700 1750 1800
Wavenumber [cm−1] Raman shift [cm−1]
(a) (b)

Figure 7.14 (a) Infrared spectra of amorphous indomethacin, and the α- and γ -polymorphic crystalline forms of indomethacin.
The lower figure shows the wavenumber region of 1500–1800 cm−1 (C=O stretch), where differences between the different solid
state forms can be clearly visualised. Individual traces are offset for clarity. (b) Raman spectra of amorphous indomethacin, and
the α- and γ - polymorphic crystalline forms of indomethacin. The lower figure shows the wavenumber region of
1500−1800 cm−1 (C=O stretch), where differences between the different solid state forms can be clearly visualised. Individual
traces are offset for clarity.
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Pharmaceutics | 215

briefly below. It should be noted, however, that also levels of amorphous content since the halo will be
terahertz spectroscopy, probing the phonon modes of obscured by the stronger crystalline diffraction peaks.
solids, is a particulate level technique, as are the vari- XRPD is one of the most commonly used tech-
ous microscopic and electron microscopic techniques. niques in the pharmaceutical industry for solid-state
X-ray powder diffraction is one of the most impor- analysis because it may be used for the identifi-
tant analytical techniques used in solid-state analysis. cation and quantification of polymorphs, solvates,
An X-ray powder pattern is the result of scattering of hydrates and amorphous forms, based on their unique
an incident monochromatic X-ray beam by the lattice diffraction patterns. It does not require large sam-
of the crystalline material.The resulting diffractogram ple sizes, and unlike thermal methods, it is a non-
is based on constructive and destructive interference destructive technique. This is potentially advanta-
of the diffracted X-ray beams. This phenomenon is geous in the early stages of pharmaceutical devel-
described by Bragg’s law: opment, and despite its limitations in detecting low
levels of amorphous material, XRPD has been used
nλ = 2d sin θ (7.9) both qualitatively and quantitatively in the character-
ization of partially crystalline systems. Quantification
where n is the order of reflection (an integer); λ is of the crystalline content can be achieved by measur-
wavelength of the incident beam [Å]; d is distance ing the area or the height of the main peaks in the
between the planes in the crystal [Å]; and θ is angle diffractogram and of the amorphous content by mea-
of beam diffraction. suring the amorphous scattering in the diffractogram.
Constructive interference takes place when the However, quantitative analysis using XRPD has to
scattered X-rays are in phase, i.e., the phase difference be carried out carefully, for physical characteristics
that the scattered X-rays reflected from two neighbor- such as sample height, surface character and shape,
ing planes of the crystal lattice is an integer (Fig. 7.15). and the presence of microcrystallinity may influence
Each crystalline material will exhibit a diffractogram, the outcome of the measurements. Figure 7.16 shows
which is unique to the specific compound and its solid example diffractograms of different solid state forms
state form, and individual peaks may be attributed to of the drug indomethacin.
the crystalline structure. As amorphous solids do not DSC is used in the study of both crystalline and
possess an ordered lattice, no diffraction occurs and amorphous materials. Two types of DSC instruments
no diffraction pattern is obtained. Rather, a diffuse are available: power-compensated DSC and heat-flux
‘‘amorphous halo,’’ showing one or several broad
maxima, is observed. XRPD is particularly useful to
detect small amounts of crystallinity in an amorphous
γ indomethacin
sample, for the residual crystallinity results in small
α indomethacin
diffraction peaks on an amorphous halo. However, Amorphous indomethacin
the technique is of limited use for the detection of low
2000
Intensity [counts]

In ys
cid ra
Λ en X-
tX d 1000
-ra te
ac
ys iffr
D

d
θ
A 0
θ C
5 10 15 20 25 30 35
AB = BC = d sin θ
d B Angle [°2θ]

Figure 7.15 Diffraction of X-ray beams by planes of a crystal Figure 7.16 X-ray powder diffraction patterns of amorphous
lattice. A, B, and C are points in the crystal planes; d is the indomethacin, and the α- and γ -polymorphic crystalline
distance between two planes. forms of indomethacin. Individual traces are offset for clarity.
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216 | An Introduction to Pharmacy

DSC. In power-compensated DSC a reference and a enthalpy versus temperature at constant pressure:
sample pans are placed on two individual furnaces,  
and the temperature difference between them is main- δh
Cp = (7.11)
tained at zero by varying the heat that is required to δT p

keep both pans at the same temperature. The param-

The advantages of DSC for analytical purposes
eter recorded is the difference in energy input which
lie in the requirement of only small sample sizes
is required to maintain the samples at the same tem-
(typically 2 to 6 mg), the broad temperature range,
perature, for example, during a melting process. In
and in the speed of the experiments (heating rates
heat-flux DSC one heating element is used for sample
of 5 to 20 K min−1 are typically employed). DSC can
and reference. Heat is applied to both via an electri-
be used to analyze both crystalline and amorphous
cally heated thermoelectric disc, and the temperature
materials, and unlike XRPD, it is possible to directly
difference between sample and reference is monitored.
detect the amorphous content through the presence
The obtained signal is converted to heat flow [mW]
of a T g .
via the following relationship:
The thermal behavior of a solid sample may be
analyzed, for example, in terms of
Ts − Tr
Q = (7.10)
Rγ
• Melting point and melting enthalpy of polymor-
where Q is heat energy [J]; Rγ is the thermal resistance phic crystalline materials
[K J−1 ]; T s is the sample temperature [K]; and T r is • Conversion temperature of two enantiotropic
the reference temperature [K]. polymorphic forms
In DSC, thermal events connected to the sample • Enthalpy and temperature of the loss of solvate
are presented in a thermogram, in which endothermic molecules from solvates
and exothermic energy deviations from the reference • Heat capacity difference and temperature of the
pan are recorded as a function of time or temperature. glass transition of amorphous material
Endothermic events include processes such as evapo- • Enthalpy and temperature of any crystallization
ration, melting, and some solid–solid transitions. In events of amorphous material
contrast, the recrystallization of an amorphous form • Temperature of decomposition
and other solid–solid transitions are exothermic. It is • Extent of interactions in mixtures (e.g., with excip-
possible to use DSC not only to determine the tem- ients).
perature of these events but also to calculate the heat
of the respective reaction. Quantification, for example, of amorphous con-
As we have seen above, any change in the enthalpy tent in a sample is also possible. However, despite
of a system at constant pressure can be described by the many advantages that make DSC one of the most
the change in heat. Hence, the area under a DSC widely used techniques, it has to be considered that
peak is directly proportional to the heat absorbed or the analyzed sample is subjected to thermal treat-
released by the thermal event if the sample mass is ment, which destroys or at least changes the sample
known. and may induce thermal artifacts. Therefore, care has
The determination of the heat capacity, Cp , for to be taken in the interpretation of thermograms to
the amorphous state is of particular interest, for the avoid misleading conclusions. Moreover, DSC ther-
glassy and the super-cooled liquid state exhibit dif- mograms are often difficult to interpret if multiple
ferent values for their respective Cp s, and the heat overlapping thermal processes are involved. Every
capacity will change in a stepwise fashion at the glass DSC thermogram is a compromise between sensi-
transition temperature. The extent of the difference tivity and resolution as both are dependent on the
in heat capacity (Cp ) is an important characteristic heating rate, but in opposite ways. To increase the
for amorphous materials. The enthalpy of a system sensitivity, the scan rate may be increased; however,
increases as its temperature is increased. The heat this may lead to decreased resolution, for the scan rate
capacity can be obtained as the slope of a plot of may be too rapid to separate close thermal events.
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Pharmaceutics | 217

components, due to their different responses to the

γ indomethacin
α indomethacin underlying and modulated heating rates. Processes
14 Amorphous indomethacin that occur at defined temperatures, such as crystal-
12
10 lization, evaporation, relaxation, and decomposition
8
6 will appear in the non-reversing heat flow signal.
Heat flow [W/g]

4
2
As the reversing component is related to the sam-
0 ples’ heat capacity, for example, the glass transition
−2
−4 event is visible in the reversing signal. This enables
−6
−8
Glass transition
Melting of α
the separation of the glass transition event from any
−10 Recrystallization
−12
and γ endothermic relaxation.
Endothermic polymorph
−14
0 20 40 60 80 100 120 140 160 Liquid crystals
Temperature [°C]
We have seen that crystalline solids are defined by long
Figure 7.17 DSC thermograms of amorphous range order in three dimensions. In contrast, liquids
indomethacin, and the α- and γ - polymorphic crystalline lack long-range order (as do amorphous solids). When
forms of indomethacin. The thermogram of the amorphous some solid materials are heated, they do not directly
form shows a glass transition and recrystallization event, in show a phase transition to the liquid state but instead
addition to the melting. Individual traces are offset for clarity. enter into a different state of matter, between the
solid and the liquid state. This state of matter is
called the liquid crystalline state. Liquid crystals (also
Figure 7.17 shows example DSC thermograms of called mesophases) show structural properties which
different solid state forms of the drug indomethacin. are intermediate between those of crystalline solids
Modulated temperature DSC (MTDSC) is an and liquids. It should be noted, however, that liquid
alternative to conventional DSC.9 In MTDSC a sine crystals are not simply a mixture of solids and liquids
wave modulation is applied to a linear temperature but, indeed, a separate state of matter. Also, it is
program. The obtained heat flow signal is analyzed important to note that not every organic material
by applying a discrete Fourier Transform algorithm, is able to exist in a liquid crystalline state. We will
which results in the deconvolution of the measured discuss a few structural considerations of molecules
heat flow signal into reversing and non-reversing that can exist in the liquid crystalline state below.
components. The non-reversing signal comprises the These molecules are termed mesogens and usually
kinetically controlled events that are dependent on are anisotropic organic molecules, mostly of rod-like
the absolute temperature alone, and the reversing shape.
signal is a function of the samples’ heat capacity In a thermogram we observe a first order phase
and rate of temperature change. The heat flow transition, when we, for example, cool a melt that at
signal of a sample will be a combination of these a certain temperature transforms into a liquid crystal.
two components. The total heat flow signal may, Similarly the transition from a solid to a liquid crystal
therefore, be expressed as is a first order transition. Being situated between the
solid and the liquid state of matter, liquid crystals also
dQ are a condensed state of matter.
= Cp /dT + f (t, T) (7.12)
dt There are two principal types of liquid crystals:
where dQ/dt is the heat change over time (heat flow) thermotropic liquid crystals (TLC) and lyotropic liq-
[J s−1 or W]; Cp is the ‘‘thermodynamic’’ heat capacity uid crystals (LLC). TLCs are formed by heating a
[J K−1 ]; T is the temperature [K]; and f(t,T) is the crystalline solid. In contrast, LLCs are formed by the
kinetic response. addition of a liquid (in most pharmaceutical cases,
Conventional DSC records the reversing and non- water), to a usually solid mesogen. If we are apply-
reversing heat flow simultaneously and is not able ing Gibbs’ phase law, we can say that the minimum
to resolve them. MTDSC is able to separate the number of components in a TLC is one and in a
heat capacity (reversing) and kinetic (non-reversing) LLC is two, if a single phase liquid crystal is formed.
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218 | An Introduction to Pharmacy

The number of degrees of freedom to describe a TLC extended disc-like micelles, leading to a bilayer
is two (temperature and pressure) and for a LLC is structure as repetition unit. As such, the lamellar
three (temperature, pressure, and the concentration phase has a one-dimensional, long-range, positional
of the mesogen). order (from layer to layer) but only long-range orien-
tational order within the layers. It is also possible that
Lyotropic liquid crystals a lamellar liquid crystalline phase may be dispersed
LLCs can be understood as associations of differently in excess water (so that we get a two phase system).
shaped micelles. Micelles are colloidal assemblies of The resulting lamellar liquid crystalline particles form
amphiphilic molecules, e.g., surfactant molecules and concentric bilayers and are termed liposomes. Phos-
phospholipids, i.e., molecules that have a polar head pholipids are pharmaceutically relevant examples of
group and a lipophilic, non-polar tail group. We can lamellar liquid crystal forming molecules.
differentiate the following types of LLC, shown in Hexagonal phase (Fig. 7.18b): This type of LLC
Fig. 7.18. consists of hexagonally packed rod-like micelles. As
Lamellar phase (Fig. 7.18a): This is pharmaceu- such, the hexagonal phase has a two-dimensional,
tically perhaps the most important liquid crystalline long-range, positional order (normal to the symmetry
phase and consists of a layered packing of indefinitely axis of the rods) but only long-range, orientational

(a) (b)

(c) (d)

Figure 7.18 Schematic representation of several types of lyotropic liquid crystals: (a) lamellar phase, (b) hexagonal phase, (c)
cubic phase, and (d) lyotropic nematic phase.
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Pharmaceutics | 219

order within the rods. Depending on the nature of the ring systems). These ring systems are connected by a
solvent (polar or non-polar), hexagonal phases can polar central group (C) and linked to two terminal
exist in a normal and in a reversed form. In the nor- groups (T1 and T2 ), of which at least one usually is an
mal form the polar head groups of the mesogens are alkyl chain. However, not all these structural elements
pointing outwards, and in the reversed form inwards necessarily have to be present in a mesogen. Addition-
into the rod-like micelles that are forming the hexag- ally, lateral substituent groups may be present in the
onal phase. As we have just discussed for the lamellar mesogen molecular structure (LS1 and LS2 ).
phase, also the hexagonal phase of some amphiphilic As was the case for LLC, several types of TLC
molecules may be dispersed into colloidal particles, can be differentiated. It is beyond the scope of this
known as hexosomes. section to give a detailed description of all TLC types
Cubic phase (Fig. 7.18c): This type of LLC con- that have been described in the literature (there are
sists, in the simplest case, of a cubic packing of over 20 different types of smectic TLC alone). We
spherical micelles. As such, the cubic phase has a will thus restrict the description of different TLCs
three-dimensional, long-range, positional order, like here to three types: nematic phases, chiral nematic
a crystalline solid. In contrast to a solid crystal, how- phases (cholesteric phases), and fluid smectic phases
ever, the mesogens in the micelles forming the cubic (including smectic A and smectic C). Schematic rep-
phase show rotational–diffusional motion and not resentations of these TLCs are shown in Fig. 7.19.
merely vibrations, as in the case of crystals. Micel- Above, we have already described a lyotropic
lar cubic phases can also exist in a normal and in a nematic phase, formed by elongated micelles. In case
reverse form, depending on the nature of the solvent. of a thermotropic nematic phase, individual rod-like
Moreover, bicontinuous cubic phases exist, which molecules (not micelles) show an orientational long-
cannot simply be interpreted as assemblies of spheri- range order, again in the absence of any positional
cal micelles, and some bicontinuous cubic phases may long-range order. The orientation of the long axes of
also be dispersed into particles called cubosomes. the rod-like molecules, however, is not the same for all
Lyotropic nematic phase (Fig. 7.18d): This LLC is molecules and varies around a preferred orientation,
composed of rod-like micelles and shows a long-range known as the director of the nematic phase (n̂). This
orientational order with respect to the symmetry axis can be expressed using the order parameter S:
of the micelle. There is no long-range positional order
in this type of LLC. S = 0.53 cos2  − 1 (7.14)
As we could expect from the increasing degree of
order, the viscosity of the liquid crystals increases as where  is the angle between the director and the ori-
we go from lyotropic nematic to lamellar, hexagonal, entation of the molecular length axis of the molecule
and cubic liquid crystals. Many surfactant and phos- (see Fig. 7.20). This is, of course, an average value,
pholipid mesogens may also show liquid crystalline depending, for example, on the temperature. In the
polymorphism, i.e., they are able to self-assemble into ideal case of complete parallel arrangement of the
different LLCs, depending on the concentration of the molecules, S would have the value of unity.
mesogens and temperature.

Thermotropic liquid crystals

The typical structure of a rod-like mesogen able to
exist in a thermotropic liquid crystalline state is
T1 R1 C R2 T2

LS1 LS2 (a) (b) (c) (d)

(7.13)

The rod-like shape of the mesogen is usually formed Figure 7.19 Schematic representation of several types of
by two ring systems (R1 and R2 , which can be aro- thermotropic liquid crystals: (a) nematic, (b) smectic A, (c)
matic or aliphatic and may also consist of condensed smectic C, and (d) chiral nematic (cholesteric) phase.
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220 | An Introduction to Pharmacy

Liquids
^
n The liquid state of matter is an intermediate state
between the solid (and potentially the liquid crys-
talline state) and the gaseous state of matter. It is thus
not surprising that the liquid state of matter shares
some commonalities with both solids and gases. As
Figure 7.20 Schematic showing the angle  between the
director (n̂) and the orientation of the molecular length axis of for solids, liquids are practically incompressible under
a molecule in a nematic liquid crystal. pressure (except if very high pressures are used) and
have a high density. This is the reason that solids and
liquids are summarized as condensed states of matter.
The chiral nematic phase can be regarded as a Usually, however, the density of liquids is lower than
special form of a nematic phase. If the mesogen is that of solids for a given material, with water being
chiral (see above), the director field may adopt a an important exception, as we have discussed above.
helical superstructure, so that we have nematic layers
Unlike solids, however, the molecules in a liquid can
whose directors are shifted by a constant angle from
move and change places by diffusing under the influ-
layer to layer. The distance between two nematic
ence of heat energy (diffusion). This is a property that
layers with the same director is known as the pitch
liquids have in common with gases and the reason
of the chiral nematic phase. Since the pitch height of
that gases and liquids are summarized as fluid states
some cholesteric mesophases is in the order of the
of matter. While liquids show in general a much
wavelength of visible light, they may be colored, and
higher tendency to be miscible with each other than
since the pitch height is sensitive to temperature, such
solids, not all liquids are miscible (unlike gases, which
liquid crystals may be used as sensitive thermometers,
are always completely miscible with each other), and
with a specific color indicating a specific temperature.
in many cases mixing two liquids will lead to the for-
Smectic phases have a layered structure, similar to
mation of a two phase system of the two immiscible
the lamellar structure of LLCs. However, in contrast
liquids or a two phase system of a liquid A-rich phase
to the lamellar phase, the smectic phase usually does
and a liquid B-rich phase if the liquids show partial
not form a bilayer structure. Depending on the angle
miscibility. In these cases the two liquids will form
the rod-like molecules have with respect to the layer,
an interface with a corresponding interfacial tension.
we can differentiate the smectic A phase (in which the
molecules are oriented perpendicular to the layers) Since the interfacial tension γ is the intensive variable
from the smectic C phase (in which the molecules are of the interfacial free energy Gs (with the interfa-
tilted with respect to the layers). cial area A being the extensive variable; Gs = γ A),
Several drugs have been identified to be able two phase liquid systems have a higher energy if the
to exist as thermotropic liquid crystals at elevated interfacial area between the liquids is increased. An
temperatures,10 including fenoprofen sodium, feno- example for this is an emulsion, in which one liquid
profen calcium,11 and itraconazole.12 phase is dispersed in the form of droplets in the other.
Both LLC and TLC can be identified by charac- The system will try to minimize its free energy, and
teristic appearances (textures) in the polarizing light thus the dispersed droplets will fuse together (coales-
microscope, as well as by electron microscopic inves- cence) over time to reduce the interfacial energy by
tigation. Also, the liquid crystals show characteristic reducing the interfacial area. To reduce the surface
peak sequences when investigated by X-ray diffrac- free energy of emulsions and thereby to stabilize the
tion. Since the distances between the repetition units in dispersed nature of the emulsion, surfactants can be
liquid crystals are larger than in crystals, the diffrac- added to the emulsion to reduce the interfacial tension
tion angles are smaller and, therefore, small angle between the two liquid phases.
X-ray diffraction is usually used as an analytical tech- Generally, the principle ‘‘like dissolves like’’ can
nique, in contrast to wide angle X-ray diffraction, be applied, and liquids with similar polarity (for
which is usually used in powder diffractometry of example, water and ethanol, or benzene and cyclohex-
crystalline solids. ane) will be miscible, whereas liquids with different
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Pharmaceutics | 221

polarities (for example, water and benzene) will be remains constant if the shear stress or shear rate
immiscible or show partial miscibility. is increased. Water and ethanol are examples of
Another property liquids have in common with Newtonian liquids. Not all liquids, however, show
gases is that they are isotropic. This means their ideal flow behavior, and these liquids are called non-
physical properties are uniform in all directions or Newtonian liquids. Many pharmaceutically relevant
orientations. This is not the case for crystalline solids liquids are non-Newtonian. If the viscosity decreases
and liquid crystals, which are anisotropic (with the with increasing shear stress, the liquid shows pseudo-
exception of cubic crystals and liquid crystals). The plastic flow behavior (also called shear thinning), and
anisotropic nature of most crystals (and liquid crys- in the opposite case, when the viscosity increases as
tals) is also the reason for their optical birefringence, shear stress is increased, the liquid shows dilatant flow
making them visible in the polarized light microscope. behavior (also called shear thickening). Time, how-
Conversely, liquids will be invisible in the polarized ever, does not change the viscosity for a given shear
light microscope under cross polarization. stress for pseudoplastic and dilatant liquids (nor for
If we investigate a liquid with X-ray diffraction, Newtonian liquids). This is, however, not always the
we only measure the characteristic halo we have case. A pseudoplastic liquid shows a certain viscosity
already discussed in the context of amorphous solid for a certain shear stress. If the stress is kept con-
materials (amorphous materials are also isotropic and stant, for some liquids a further decrease in viscosity
show no long-range order, which would give rise to can be observed. When the shear stress is removed,
peaks in a diffractogram). However, also like amor- the system does not immediately return to its origi-
phous materials, liquids are not without near order, nal state, but the viscosity gradually increases. This
and certain distances between the molecules of a liquid behavior is termed thixotropy. For pharmaceutical
may be preferred over others, due to intermolecular suspensions this is advantageous, for the suspension
interactions. This can also be determined from X-ray can be homogenized by shaking and can be poured
diffraction measurements, by calculating the radial easily. After some time, the viscosity increases again,
distribution function g(r), which can be generated stabilizing the suspension against sedimentation.
by a Fourier transformation of the diffraction pat- While many polymer solutions used in pharma-
tern, and presents the average spatial distribution in ceutical applications are pseudoplastic liquids, con-
a liquid (or in a amorphous solid). centrated pastes may show dilatant flow behavior,
An important property relevant for many phar- and many suspensions and ‘‘semisolids,’’ such as
maceutical applications of liquids is their viscosity. creams and ointments, show thixotropy. Note that
Viscosity is the resistance to flow or, in other words, a semisolid is a pharmaceutical term used to describe
the resistance of the liquid to be deformed under a creams, ointments, etc. These are solids at rest, but
shear stress (due to the intermolecular interactions they start to flow (become liquid) at low shear stresses.
of molecules in a liquid). If a shear stress (a force F To describe pseudoplastic and dilatant liquids, we
[N] applied parallel to the fluid’s surface A [m2 ], F/A can extend Newton’s viscosity equation to a power
[N m−2 ]) is applied to a liquid, this will result in a law, known as the Ostwald–de Waele equation:
velocity gradient in the liquid (dv/dx [s−1 ]). The ratio
between the two is called viscosity η [Pa s] F/A = K(dv/dx)n (7.17)

η = (F/A)/(dv/dx) (7.15) where K is the flow consistency index [Pa sn ]; and

n is the flow behavior index [no unit]. n = 1 for a
This equation is usually rearranged to give Newton’s
Newtonian liquid, n < 1 for a pseudoplastic liquid
law of viscosity:
and n > 1 for a dilatant liquid.
F/A = ηdv/dx (7.16) The viscosity of liquids decreases with increasing
temperature, due to the higher molecular mobility.
Liquids can be differentiated by their viscosi- Gases, in contrast, not only have much lower vis-
ties and the type of viscosity they have. A Newto- cosities than liquids but also show an increase in
nian liquid (ideal viscosity) is a liquid in which η viscosity as temperature is increased (due to higher
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222 | An Introduction to Pharmacy

collision rates of the gas molecules at elevated temper- Charles’ law states that if a given mass of a gas is
atures). For example, water has a viscosity of 1.002 heated at constant pressure, the volume of the gas is
× 10−3 Pa s at room temperature and 0.35 × 10-3 Pa s directly proportional (K2 ) to its absolute temperature
at 80◦ C. Air, on the other hand, has a viscosity 1.79 (T):
× 10−5 Pa s at room temperature. Amorphous solids
in the glassy state have viscosities in the order of 1012 V/T = K2 (7.19)
Pa s or higher.
Avogadro’s law states that equal volumes of pure
gases at constant temperature and pressure contain
Gases
the same number of particles (n):
Gases play an important role in the pharmaceutical
field, for example, in the use of medical gases (e.g., V/n = K3 (7.20)
oxygen, nitrous oxide, carbon dioxide, compressed
air), as functional excipients in aerosols and inhalers, The volume that one mole of gas molecules occu-
and in quality control of drugs and dosage forms. Fur- pies (the molar volume) is 22.4 L at 0◦ C and a pressure
ther, oxygen from the air may contribute to oxidative of 1 atm. The number of molecules in a mole of gas is
degradation of drugs, and water molecules from air 6.022×1023 .
can initiate hydrolytic degradation. Water molecules These three laws can be regarded as special cases
in air (especially at high relative humidity) may also of the ideal gas law:
decrease the physical stability of amorphous drugs
pV = nRT (7.21)
or glass solutions, as we have seen, since water is a
potent plasticizer, lowering the glass transition tem- where R is the ideal gas constant [8.314 J (mol−1
perature of amorphous materials and thus increasing K−1 )]. Note that K1 in Boyle’s law is nRT, K2 in
the likelihood of crystallization. Charles’ law is nR/p, and K3 in Avogadro’s law is
The gaseous state of matter is characterized by RT/p in the ideal gas law.
very weak interactions between the molecules (for Finally, if we take into account the ideal gas law
real gases), which in fact are assumed to be completely (which assumes no interactions between the molecules
absent for ideal gases (see below). The consequence of forming the gas), we arrive at Dalton’s law, which
this is that in gases the molecules constantly change states that the total pressure (ptof ) of a mixture of
their positions by diffusion or convection and have gases equals the sum of their partial pressures (p1 to
a very low viscosity and density. This makes gases pn ):
easily compressible under pressure (in contrast to
liquids and solids). Also, in contrast to solids and ptof = p1 + p2 + . . . + pn (7.22)
liquids, different gases are always completely miscible
Related to Dalton’s law is Henry’s law, which
with each other. For example, air is a mixture of
states that at constant temperature the amount of a
several gases: approximately 78.1% nitrogen, 20.9%
gas (n) that dissolves in a given volume V (c = n/V)
oxygen, 0.9% argon, 0.03% carbon dioxide, and
of a given liquid is directly proportional (K4 ) to the
small concentrations of neon, helium, methane, and
partial pressure of that gas in equilibrium with the
other gases.
liquid (p1 ).
If we are completely disregarding the weak inter-
actions between gas molecules, we can fully describe c/p1 = K4 (7.23)
the behavior of gas by the ideal gas law. Historically,
the properties of gases have been described in a set of While all the above laws hold true for many gases
laws, which we will have a quick look at first. over reasonable temperature and pressure ranges, and
Boyle’s law states that the product of absolute thus can be used fairly well to describe the behavior
pressure (p) and volume (V) is constant (K1 ) at con- of gases, they do not take into account the fact that
stant temperature: interactions between the gas molecules do take place
and that the gas molecules occupy a part of the total
pV = K1 (7.18) volume of the gas (albeit usually a very small part).
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Pharmaceutics | 223

Deviations of the behavior of gases from the ideal It should be noted that the van der Waals equation
situation become more important as, for example, is just one of many models that have been developed
pressure is increased or temperature is decreased. We to better describe the behavior of gases, especially at
can also understand this by the fact that gases can be extreme conditions, and that many other models exist.
liquefied if the temperature is lowered (this would not This is, perhaps, an opportune moment to remind us
be possible if the gas molecules did not interact with that a model is a mathematical description of a phys-
each other). On the other hand, many gases behave ical reality, and not the physical reality itself. It is up
very closely to ideal gases, and this can be seen, for to the given situation (and possibly the required pre-
example, if we determine the molar volumes of some cision) as to which model is best used in a particular
gases. For the gases that make up more than 99% situation.
of air, we find that nitrogen, oxygen, and the noble
gases indeed have molar volumes of 22.4 L. Other Plasma
gases, though, already at 0◦ C and a pressure of 1 atm, We will finally briefly discuss the plasma state of
have molar volumes that differ slightly from that of matter. Plasma is actually the most common state of
ideal gases. Carbon dioxide, for example, has a molar matter in the universe (for example, stars are matter
volume of 22.3 L and that of ammonia is 22.1 L. in the plasma state). Plasma is formed by a phase
As stated above, for real gases we have to take transition from gases if these are heated to very high
into account that the gas molecules occupy a certain temperatures. At a certain temperature the electrons
volume in the given volume of a gas and that interac- of the gas molecules or atoms leave the atoms, lead-
tions between the gas molecules can occur. These ing to an ionization of the gas. Plasma thus contains
interactions, for example, could be dipole–dipole charged molecules or atoms and free electrons and
interactions if the gas molecules contain polar bonds conducts electricity (unlike gases). Due to the very
(these interactions are termed Keesom forces). Even in high temperature of plasma, it is not particularly
the absence of permanent dipoles in the gas molecules, useful in the pharmaceutical field. Not all atoms how-
interaction can occur through transiently induced ever, need to be ionized for plasma to gain its typical
dipoles (London forces). Note that in the literature the properties. So most plasma consist of ions, electrons,
expression ‘‘van der Waals force’’ is sometimes used and neutral molecules, which nevertheless are in an
to describe Keesom and London forces and sometimes activated state, e.g., in the form of radicals (molecules
specifically for London forces. containing one or more unpaired electrons).
The van der Waals equation is one model that It is also possible to create the plasma state from
takes into account the non-zero volume of the gas gases by electric discharge under reduced pressure,
molecules and the possible interactions between the leading to ‘‘cold plasma.’’ Cold plasma created in
gas molecules: this way has found medical applications 13 and, for
example, cold plasma from argon or oxygen has
nRT = (p + an2 /Vm
2
)(Vm − b) (7.24)
been used to irradiate polymer coats of tablets and
For one mol of gas the equation simplifies to granules.14 ,15 This plasma irradiation leads to the
emission of intense UV radiation, which can lead to
2
RT = (p + a/Vm )(Vm − b) (7.25) changes in the polymer structure, influencing, for
example, drug release kinetics from these tablets
where p is the pressure; T is the temperature; R is the
or creating gastro-retentive, floating drug delivery
ideal gas constant; V m is the molar volume; and n is
systems.16
the number of molecules.
The parameters a and b have to be empirically
determined for each gas. The parameter a appears
in the pressure term of the equation and relates to
Thermodynamics
intermolecular interactions, whereas the parameter b
Introduction
appears in the volume term of the equation and relates
to the fact that the gas molecules themselves occupy Thermodynamics rests upon three basic laws that
a certain volume of the gas. took over 500 years to establish. Although quantum
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224 | An Introduction to Pharmacy

mechanics has defined the limits of its scope, the the equation of state. Most pharmaceutically relevant
concepts embodied in the three laws have remained systems are extremely complicated, because there are
unchanged for over a century. Thus, thermodynam- typically many components; the properties of each
ics provides unassailable, certain answers. As such, must be specified for the system to be at equilibrium.
the great value, but also the main challenge, is using
the simple concepts to understand complicated phys-
The first law
ical and biological phenomena. There are many texts
available on the subject of thermodynamics ranging The first law of thermodynamics is a statement of the
from introductory to complex, rigorous treatments. principle of conservation of energy; energy may nei-
The approach here will involve the development of the ther be created nor be destroyed. It is mathematically
concepts with pharmaceutically relevant examples. written as
The purpose is to demonstrate how to make judicious
dE = δq − δW (7.27)
assumptions to allow use of the rigorous definitions in
thermodynamics to reveal the certainty in the complex where dE is the differential change in the internal
field of pharmaceutics. energy, δq is the differential change in the absorbed
To begin, the definitions of system, surroundings, heat, and δW is the differential change in the expended
universe, and boundaries are introduced. These, as work or work done.
well as all other definitions, must be clearly under- The change in internal energy of a system in going
stood, otherwise thermodynamics will not be properly from state A to state B is given by
used. A system is that part of the universe under  B
consideration and, as such, is separated from the sur- E = dE (7.28)
roundings or, equivalently, the rest of the universe. A
The focus of the analysis will center on how the prop- The internal energy is a state function. A change
erties of a system are altered through an interaction in the value of a state function depends only on
with the surroundings. Properties are those qualita- the initial and final state and does not depend on
tive characteristics (e.g., type of phase, which may be how the change in state was achieved. The symbol
solid, liquid, or gas) and quantitative characteristics d represents an exact differential. Another example
(e.g., temperature, pressure) that describe the system. of a state property is the temperature; that is, the
The interaction between the system and surroundings change in temperature only depends on the initial and
is controlled by the boundary and is revealed in the final temperatures and does not depend on how the
change in properties. temperature was changed (that is, the path followed).
When a sufficient number of properties of the A cyclic change in a system describes a series of
system have been specified with fixed values, then changes where the initial and final states have the
the system is at equilibrium. Certain systems at same values for the state properties; one may say,
equilibrium have a simple equation that provides a the system ‘‘comes to a full circle.’’ For all cyclic
relationship among the values of the properties. For processes, the change in all state properties is zero.
example, a system containing an ideal gas (one com- Finally, the first law provides only a relation for the
ponent) has the properties of pressure, P, volume, V, change in the internal energy and does not provide an
number of mols, n and temperature, T (K), related absolute value. Thus like temperature, a zero point
by: must be defined as well as a scale for a unit of energy,
which were arbitrary until the scientific community
PV = nRT (7.26)
reached a consensus.
where R is the gas law constant. Such a relationship is Although it seems too obvious to point out that if
referred to as an equation of state because it specifies the system has the same value of energy in the initial
the relationship among the quantitative properties and final state that the change in energy would be zero,
of a system in a definite state. Furthermore, if the there are quantities that may not be zero even when
system is at equilibrium, only three properties need a system undergoes a cyclic change. Two examples
to be specified, as the fourth may be calculated from are heat flow and work done, which in the first law
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Pharmaceutics | 225

are described by inexact differentials, and the unique where the subscript rev denotes that the heat flow
symbol δ is used. Neither the heat nor the work is a occurs in a reversible manner. By carrying out the
state function and thus, the integral of the differential integration, the change in entropy for a reversible,
depends on the path taken. Mathematically, they are isothermal change from state 1 to state 2 is given by
written as  2
 B
S = δqrev /T = qrev /T (7.32)
q= δq (7.29) 1
A

 With the introduction of entropy, the second law

B
W= δW (7.30) may be stated as follows: For any spontaneous process
A in an isolated system, there is an increase in the value
The work and heat may only be determined if more of entropy. Alternatively, the first and second laws
information is provided concerning how the change may be combined with the classic thermodynamic
in the state of the system was achieved. statement, ‘‘the energy of the universe is constant; the
entropy is increasing’’.
Entropy and the second law Historically, Carnot analyzed the efficiency of
such a theoretical cycle, which has come to be known
Although the first law provides the framework for cal- as the Carnot cycle. This can be found in most texts
culating the change in energy associated with chemical on thermodynamics, although it typically involves
reactions or physical changes in state, there is insuffi- isothermal and adiabatic processes in the context of
cient information to allow prediction of the likelihood what is known as a heat engine. Nevertheless, the
of whether the change will occur. Consider a system premise is that by permitting the flow of heat into a
composed of two parts that are at different temper- system, work may be done by the system. The second
atures, T 1 and T 2 , separated by an impermeable, law dictates that not all of the heat may be converted
adiabatic partition. When the partition is removed, into work, even if all changes occur in a reversible
heat will flow from the part at a higher temperature manner. In fact, the maximum work, W max , that may
to the part at a lower temperature. According to the be obtained is specified by the heat flow into the sys-
first law, the energy of the whole system, the sum of tem and the temperature difference over which the
parts one and two, has not changed.
heat engine is operating; that is,
Intuitively it is known that the above change will
occur regardless of the fact that the first law does Wmax = q1 (T1 − T2 )/T1 (7.33)
not provide a method of predicting the occurrence.
Such changes are described as spontaneous, for the where T 1 > T 2 . The proof of this equation can be
obvious reason that they occur without additional established by calculating the heat and work for each
stimulation. It should be noted that this spontaneous step and noting that not all of the heat energy may be
change involved an increase in the disorder or, if you converted into work. This can be seen from Table 7.3.
will, the randomness of the system. Thus, the sys- The heat flow into the system occurs with the second
tem initially was separated into two parts at different step. The efficiency of an engine ε, is given by the
temperatures, but after thermal contact, a uniform amount of work extracted divided by the heat flow
temperature was reached. The entropy, S, is the func- into the system:
tion that provides a quantitative description of the
randomness or disorder of the system and is fun- ε = Wtot /q1 (7.34)
damental for predicting the spontaneity of chemical
where W tot = W max for reversible changes. The effi-
reactions and physical changes. The entropy is a state
ciency is proportional to the difference in temperature
function that depends only on the initial and final
between the heat reservoirs. In addition, there is no
state of the system.
work done unless there is a difference in temperature
The definition of the entropy change is given by
between the heat reservoirs. Finally, 100% efficiency
the seemingly surprising form:
is obtained only when T 2 → 0, which as will be noted
dS = δqrev /T (7.31) from the third law, is impossible.
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226 | An Introduction to Pharmacy

Table 7.3 Values for the work and heat and the change in energy and enthalpy for
each step for the cyclic change described in text and illustrated in Fig. 7.21

Step 1 2 3 4 Total

W, J −4.16 1.69 4.16 −1.4 0.29

Q, J 0 5.85 0 −5.85 3.04

E, J 4.16 4.16 −4.16 −4.16 0

H, J 0 5.85 0 −2.74 0

can be found. The value from the internet is 47 mmHg.

Using the approach from above, the moles of water
that must undergo the phase change from a liquid at
B 2 C 310 K to a vapor at the same temperature is 37 mmHg
or (37 × 133 Pa mmHg =) 4921 Pa. The number of
Pressure

moles is found with the ideal gas law:

3
1
n/V = P/RT = (4921)/(8.314 × 310)
= 1.91 mol m−3 (7.35)
A D
4
or for a typical inhalation volume of 0.001 m3 , 1.91
× 10 –3 mol.
The entropy of vaporization, Svap , is given by
Volume
 
dS = δq/Tb (7.36)
Figure 7.21 Pressure given as a function of volume for an
ideal gas. The system undergoes a cyclic change beginning 
which may be determined from δq = qp = H,
and ending at point A following the paths given by the solid
but this is the value at the boiling point. We will
lines.
return to this point below, but for now, consider the
problem as occurring at the boiling point. The molar
The above analysis elucidates the connection heat of vaporization of water at the boiling point is
between entropy and heat flow. The second law 40.65 kJ mol−1 . Thus
provides the quantitative limit on the amount of work 
that can be done with a cyclic operation performed dS = Hvap /Tm
in a reversible manner.
S = 40650/373 = 109 J mol−1 K−1 (7.37)
Given the above background, the entropy changes
associated with several reversible processes may be In our problem, the number of moles was 1.91 × 10 –3
determined. Consider the vaporization of water in leading to the total entropy change of 0.208 J K−1 .
the context of the lung, which is known to carry The positive change in entropy confirms the intuition
out the important function of humidifying air. Let us concerning such an event: gases are in a state of more
assume that initially that the inhaled air contains no disorder than liquids, thus the entropy also is greater
water vapor, but is at 310 K, and the final state is in the vapor state in comparison to the liquid state.
air saturated with water at 310 K. To calculate the The discussion, thus far, has been limited to rever-
amount of water that must be evaporated to saturate sible processes that are strictly impossible to achieve
the air, the saturation vapor pressure of water in air in the laboratory (even though such a process may be
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Pharmaceutics | 227

approximated very closely). The question arises as to entropy, system plus surroundings, increases. The
what the entropy change is for an irreversible change. mathematical statement of this relationship is
Here the entropy change is given by 
Stot = 0 reversible process (7.46)
dS > δqirr /T (7.38)

Stot > 0 irreversible process (7.47)
Thus, all real processes may be written as

dS ≥ δq/T (7.39) The third law

This concept may be extended to determine the The third law of thermodynamics simply defines
condition of spontaneity. Consider a system that is the zero point of the entropy scale. The entropy
transformed irreversibly from state 1 to state 2 and of a pure, perfectly crystalline substance is zero at
absolute zero. Intuitively, a system that has perfect
then reversibly from state 2 back to state 1. The
three-dimensional order should have no entropy at
overall change is given by:
the lowest possible temperature. The defining of a
 State 2  State 2 zero for the entropy is unlike the other state func-
δqirr /T + δqrev /T < 0 (7.40)
State 1 State 1 tions introduced previously. Thus, the value of the
entropy, S, of a system in any state, in principle, may
 State 2  State 2 be calculated.
δqirr /T + dS < 0 (7.41) What would be the entropy of a crystalline solid
State 1 State 1
at 150 K, S150 ? This may be calculated as
which may be rearranged, with changing the limits of
integration, to yield S = S150 − S0 (7.48)
 State 2  State 2 
δqirr /T < dS (7.42) S = (Cp /T)dT − 0 (7.49)
State 1 State 1

or, equivalently, for infinitesimal changes, or:

S = S150 (7.50)
δqirr /T < dS (7.43)
If the heat capacity over the range of 0 to 150 K is
This is known as the Clausius inequality. For isolated
known, the value of the entropy may be calculated.
systems, where boundaries do not permit the passage
of energy or matter, δqirr = 0, the result is given
Free energy
dS > 0 (7.44)
The concept of free energy is probably the most useful
That is, for every spontaneous change in an isolated aspect of thermodynamics. The criteria for determin-
system there is an increase in the entropy. ing the spontaneity of a chemical reaction or phase
The second law may be generalized in another change were presented above; however, it involved
way. The total entropy for any process is given by the carrying out the change in an isolated system. One
sum of the entropy of the system and the surround- can imagine how inconvenient and often impossible it
ings; that is would be to apply such a constraint to the laboratory
setting. For this sake, additional state functions have
dStot = dSsys + dSsurr (7.45) been defined to allow prediction of the spontaneity of
a change in state. The rationale for the development
For reversible processes, the entropy change of other functions was to allow maximum flexibility
in a system is the negative of the entropy change in their application. The two functions introduced are
produced in the surroundings. The total entropy, Helmholtz free energy, A, and Gibbs free energy, G.
therefore, is zero. For irreversible processes, the total The functions for predicting spontaneity are
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228 | An Introduction to Pharmacy

1. Isolated system: dS > 0 well as facilitating their use to specific problems. The
2. Isothermal and isochoric system: dA < 0 four differential equations are
3. Isothermal and isobaric: dG < 0
dE = TdS − PdV (7.56)
4. Constant volume and entropy: dE < 0
dH = TdS + VdP (7.57)
Helmholtz free energy is defined as: dA = −SdT − PdV (7.58)

A ≡ E − TS (7.51) dG = −SdT + VdP (7.59)

These expressions represent the four fundamental

Helmholtz free energy is the energy available to do
equations of thermodynamics, which in reality are
pressure–volume work for reversible isothermal pro-
four ways of looking at one fundamental equation
cesses: a decrease in the Helmholtz free energy is equal
describing the conditions of spontaneity.
to the capacity of the system to do work. An alter-
Example: One mol of liquid water is vaporized
native view is that, for systems at constant volume
reversibly at 100◦ C and 1 atm pressure. The molar
and temperature, a change in state is spontaneous
heat of vaporization is 40.65 kJ mol−1 . Calculate qp ,
if, and only if, there is a decrease in the Helmholtz
H, E, A, G, and S.
free energy. Thus, with the introduction of A, the
Solution:
spontaneity of changes occurring at constant volume
The value of qp actually is given in the question,
and temperature may be predicted.
as the heat required to vaporize 1 mol of liquid is the
As most reactions carried out in the laboratory are
definition of the molar heat of vaporization; thus, qp
under conditions of constant pressure and tempera-
= 40.65 kJ. Recognizing that the pressure is constant,
ture, Gibbs free energy is the most useful function and
H = qp = 40.65 kJ. To calculate E, the work first
is defined as
must be determined. The work is given by

G ≡ E + PV − TS (7.52)
W = PdV = PV
which can be converted into a more usable form by an
W = P(Vg − V ) (7.60)
analogous method used with the Helmholtz function.
Taking the differential and applying the constraints However, the volume of the gas, V g , is much larger
of constant pressure and temperature yields than the volume of the liquid, V  , which implies that
the work is given by
dG = dE + PdV − TdS (7.53)
W ≈ PVg (7.61)
but dE = δq – δW = TdS – δW; thus, upon substitu-
tion, Assuming the gas is ideal, the work is

W = nRT
−dG = δW − PdV (7.54)
= (1 mol)(8.314 J mol−1 K−1 )(373 K) = 3100 J
A decrease in Gibbs free energy is equal to the
(7.62)
non-PV work done by the system or, equivalently,
From the above, E may be calculated from
dG = −δW(non-PV) (7.55)
E = q − w = 40650 − 3100 = 37550 J (7.63)
which also provides the conditions of a spontaneous
change under the constraints of constant temperature The change in entropy was determined above:
and pressure. A direct application of the relationship S = H/Tm = 40650/373 = 109 J K−1 (7.64)
between Gibbs free energy and non-PV work is used
in potentiometry. Helmholtz free energy is given by
These relationships for predicting spontaneity
A = E − TS = 40650 − (373) (109.0)
often are expressed in a differential form, which
presents the state functions in a concise manner as = −3100 J (7.65)
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Pharmaceutics | 229

which also may have been obtained by recognizing substance (the solute) and the dispersing medium
that (the solvent), the solution phase contains the same
chemical entity as found in the solid phase; thus,
A = −Wrev − 3100 cal (7.66) upon removal of the solvent, the solute is recovered
unchanged. One example would be sugar dissolved
Finally, the change in Gibbs free energy is determined
in water where, in the presence of sugar in excess of
from
its solubility, there is an equilibrium between sugar
G = E + PV − TS molecules in the solid phase with sugar molecules
in the solution phase. A second example would be
= 37550 + 3100 − (373) (109) = 0 cal (7.67)
dissolving silver chloride in water. Admittedly, the
solubility of this salt in water is low, but it is finite.
which, too, may have been obtained by recognizing
In this case the solvent contains silver and chloride
the absence of non-PV work.
ions, and the solid phase contains the same material.
Removal of the solvent yields the initial solute in
unchanged form.
Solutions and phase equilibria In the second type the solvent contains a com-
pound that is different from the one in the solid
Solutions and solubility phase. The difference between the compound in the
A solution is a chemically and physically homoge- solid phase and solution is due generally to some
neous mixture of two or more substances. The term chemical reaction that has occurred in the presence of
solution generally denotes a homogeneous mixture solvent. An example would be dissolving aspirin in an
that is liquid, even though it is possible to have homo- aqueous solvent containing some basic material capa-
geneous mixtures that are solid or gaseous. Thus, it is ble of reacting with the acid aspirin. Now the species
possible to have solutions of solids in liquids, liquids in solution would not only be undissociated aspirin,
in liquids, gases in liquids, gases in gases, and solids in but aspirin also as its anion, whereas the species in
solids. The first three of these are most important in the solid phase is aspirin in only its undissociated acid
pharmacy, and ensuing discussions will be concerned form. In this situation, if the solvent were removed,
primarily with them. part of the substance obtained (the salt of aspirin)
In pharmacy different kinds of liquid dosage forms would be different from what was present initially in
are used, and all consist of a dispersion of one or more the solid.
substances in a liquid phase. Depending on the size
of the dispersed particle, they are classified as true
Pharmaceutical solvents
solutions, colloidal solutions, or disperse systems. If
sugar is dissolved in water, it is supposed that the The discussion will focus now on solvents available
ultimate sugar particle is of molecular dimensions to pharmacists and on the properties of these sol-
and that a true solution is formed. On the other vents. Pharmacists must obtain an understanding of
hand, if very fine sand is mixed with water, a suspen- the possible differences in solubility of a given solute
sion of comparatively large particles, each consisting in various solvents because they are often called
of many molecules, is obtained. Between these two on to select a solvent that will dissolve the solute.
extremes lie the colloidal solutions, the dispersed par- Knowledge of the properties of solvents will allow the
ticles of which are larger than those of true solutions intelligent selection of suitable solvents.
but smaller than the particles present in suspensions. On the basis of the forces of interaction occurring
Colloidal solutions, in general, are considered to be in solvents, one may broadly classify solvents as one
thermodynamically stable. In this section only true of three types:
solutions will be discussed.
It is possible to classify broadly all solutions as 1. Polar solvents – those made up of strong dipo-
one of two types. In the first type, although there may lar molecules having hydrogen bonding (water or
be lesser or greater interaction between the dispersed hydrogen peroxide)
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230 | An Introduction to Pharmacy

2. Semipolar solvents – those also made up of strong due primarily to their poor solubility in aqueous
dipolar molecules but that do not form hydrogen medium. Recently, several strategies have been used
bonds (acetone or pentyl alcohol) to improve solubility profile of these drugs and include
3. Non-polar solvents – those made up of molecules the following:
having a small or no dipolar character (benzene,
vegetable oil, or mineral oil). 1. Use of buffers
2. Use of cosolvents
Naturally, there are many solvents that may fit into
3. Use of surfactants
more than one of these broad classes; for example,
4. Complexation
chloroform is a weak dipolar compound but generally
5. Solid dispersions.
is considered non-polar in character, and glycerin
could be considered a polar or semipolar solvent even
though it is capable of forming hydrogen bonds. Use of buffers
The idea behind the use of buffers to improve sol-
Colligative properties of solutions ubility is to create and maintain pH conditions in
a system that causes the drug to be in its ionized
Up to this point our concern has been with dissolving
state. The ionized fraction of a drug is much more
a solute in a solvent. Once the dissolution has been
soluble in water, due to its increased polarity relative
brought about, naturally the solution has a number
to the un-ionized fraction. Buffers can also help in
of properties that are different from that of the pure
solvent. Of very great importance are the colligative reducing the likelihood of drug precipitation when
properties that a solution possesses. drug solution is diluted in an aqueous medium. Con-
The colligative properties of a solution are those sistent with the principles of solubility changes with
that depend on the number of solute particles in pH, acidic drugs are formulated under relatively basic
solution, irrespective of whether these are molecules conditions while the opposite is true for the basic
or ions, large or small. Ideally, the effect of a solute drugs. Some examples of drugs that are formulated
particle of one species is considered to be the same as with buffer systems are Amikacin sulfate (pH 3.5 to
that of an entirely different kind of particle, at least in 5.5, citrate buffer) and Midazolam hydrochloride (pH
dilute solution. Practically, there may be differences 3).17 – 19 The drugs that make good candidates for use
that may become substantial as the concentration of of pH variation or buffers are the ones that have the
the solution is increased. ability to ionize within a pH range of 2 to 8.
The colligative properties that will be considered
are Use of co-solvents
A common way to increase drug solubility is through
1. Osmotic pressure the use of a water-miscible organic solvent. This strat-
2. Vapor-pressure lowering egy is based on the fact that poor solubility of drugs
3. Boiling-point elevation in water results from the great difference in polar-
4. Freezing-point depression. ity of the two components, water being of very high
polarity and the drug having low polarity. Addition
Of these four, all of which are related, osmotic
of a co-solvent with a polarity value of less than
pressure has the greatest direct importance in the
that of water reduces the difference between polar-
pharmaceutical sciences. It is the property that largely
ity of the drug and water co-solvent system, thereby
determines the physiological acceptability of a variety
improving solubility. Commonly used co-solvents for
of solutions used for therapeutic purposes.
this purpose are the hydrogen bonding organic sol-
vents such as ethyl alcohol, propylene glycol, and
Methods to increase solubility of poorly
glycerin.
soluble drugs
The polarity scale of solvents is defined by a
A large number of promising drug candidates do not property known as the dielectric constant. This value
make it to the market because of poor bioavailability, for water is 80, and for ethyl alcohol, propylene
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Pharmaceutics | 231

glycol, and glycerin, it is 24, 32, and 42, respec- insertion in the complexing agent. One requirement
tively. Most poorly soluble drugs have dielectric for the complexing agent in such systems is that it
constant values of less than 20. Examples of some has a non-polar core and a polar exterior. The most
parenteral solution that contain cosolvents include commonly used inclusion complexing molecules are
chlordiazepoxide (25% propylene glycol), diazepam cyclodextrins. The cyclic oligomers of glucose are
(10% ethyl alcohol and 40% propylene glycol), and relatively soluble in water and have cavities large
digoxin (10% ethyl alcohol and 40% propylene enough to accept non-polar portions of many drug
glycol). Non-polar and nonionizable drugs are good molecules. Cyclodextrins can consist of six, seven,
candidates for cosolvent systems.17 – 19 or eight sugar residues and are classified as α, β
and γ , respectively. Due to geometric considerations,
Use of Surfactants steroid molecules are very suitable for inclusion into
Surfactants are molecules with well defined polar and cyclodextrin complexes.
non-polar regions that allow them to aggregate in
solution to form micelles. Non-polar drugs can parti- Solid dispersions
tion into these micelles and be solubilized. Depending Solid dispersion refers to the dispersion of one
on the nature of the polar area, surfactants can be or more active ingredients in an inert carrier or
nonionic (e.g., polyethylene glycol), anionic (e.g., matrix at solid state, prepared by the melting
sodium dodecyl sulfate), cationic (e.g., trialkylammo- (fusion), solvent, or the melting-solvent method.
nium), and zwitterionic (e.g., glycine and proteins). It has also been defined as the product formed
Among these, the most commonly used ones are the by converting a fluid drug–carrier combination
anionic and nonionic surfactants. Since the process of to the solid state. The term co-precipitate or
solubilization occurs due to presence of micelles, gen- co-evaporate has also been used frequently when
erally high concentrations of surfactants are needed a solid dispersion is prepared by the solvent
to significantly improve drug solubility. One example method.
of surfactant based solution is Taxol (paclitaxel),
Classification of solid dispersions
an anti-cancer drug that is solubilized in a 50%
solution of Cremophor. Other examples include val- Solid dispersions can be classified as follows:
rubicin in 50% Cremophor, and cyclosporine in 65%
Cremophor.17 – 19 1. Simple eutectic mixtures
2. Solid solutions
Complexation 3. Glass solutions of suspensions
Complexation is the association between two or more 4. Compound or complex formation between the
molecules to form a noncovalent-based complex that drug and the carriers
has higher solubility than the drug itself. From the 5. Amorphous precipitations of drug in crystalline
solubility standpoint, complexes can be put into carrier.
two categories, the stacking complexes and inclusion
complexes. Stacking complexation is driven by asso- Simple eutectic mixtures
ciation of non-polar areas of the drug and complexing A simple eutectic mixture consists of two compounds
agent. This results in exclusion of the non-polar areas that are completely miscible in the liquid state but only
from contact with water, thereby reducing the total to a very limited extent in the solid state. A eutectic
energy of the system. This aggregation is favored by mixture of a sparingly water-soluble drug and a highly
large, planar, non-polar regions on the molecules. water-soluble carrier may be regarded thermodynam-
Stacking can be homogeneous or mixed, but results ically as an intimately blended physical mixture of its
in a clear solution. two crystalline components. These components are
Inclusion complexes are formed by insertion of assumed to crystallize simultaneously in very small
drug molecule into a cavity formed by the complexing particulate sizes. The increase in specific surface area,
agent. In this arrangement the non-polar area of the therefore, is mainly responsible for the increased rate
drug molecule is excluded from water, due to its of dissolution of a poorly water-soluble drug.
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232 | An Introduction to Pharmacy

Differential thermal analysis (DTA) of binary mix- chemical constituent or a group of chemically related
tures normally exhibits two endotherms, but a binary substances. Most medicinal agents require some
mixture of eutectic composition usually exhibits a degree of purification before being incorporated into
single major endotherm. In the case of a simple desirable dosage forms. Many times the analysis
eutectic system, the thaw points of binary mixtures of pharmaceutical preparations requires separation
of varying compositions are equal to the eutectic of the chief constituent from other formulation
temperature of the system. constituents before quantitative measurement can be
made.
Solid solutions
Although the problems of separation are the con-
A solid solution consists of a solid solute dissolved in cern chiefly of pharmaceutical manufacturers, at times
a solid solvent. The particle size in solid solution is they may be encountered by the pharmacist in the
reduced to molecular level. Successful solubilization prescription laboratory; hence, all pharmacy prac-
of itraconazole has been achieved using solid solution titioners should have knowledge of the underlying
techniques. Solid solutions of lower drug concentra- principles and the techniques employed in the basic
tions generally give faster dissolution rate, and drug processes of separation.
dissolution improves considerably with an increase in The processes of separation may be divided into
molecular weight of a water-soluble polymer, such as two general categories – simple and complex –
polyethylene glycol. depending on the complexity of the method used.
Glass solutions of suspensions Simple processes bring about separation of con-
stituents through a single mechanical manipulation.
A glass solution is a homogeneous system in which a
Processes in this category are limited usually to sep-
glassy or a vitreous form of the carrier solubilizes drug
arations of relatively simple mixtures or solutions.
molecules. PVP has been used as a carrier in several
Some examples of this type are the use of:
formulations. In its matrix form, PVP dissolved in
an organic solvent, undergoes a transition to a glassy
state upon evaporation of the solvent. • A separatory funnel or pipette to separate two
immiscible liquids such as water and ether
Compound or complex formation • A distillation process to separate two miscible liq-
between drug and carriers uids such as benzene and chloroform
This system is characterized by complexation of two • A garbling process to separate solids
components in a binary system during solid disper- • Centrifugation, filtration, and expression processes
sion preparation. The availability of a drug from the to separate solids from liquids.
complex is dependent on the solubility, dissociation
constant, and intrinsic absorption rate of the com- Complex processes usually require formation of a
plex. α, β and γ Cyclodextrins in combination with second phase by the addition of either a solid, liquid,
polyethylene glycol (PEG) 6000, have been used to or gas plus mechanical manipulation to bring about
formulate such systems. effective separation. One example is the separation
of aspirin (acetylsalicylic acid) from salicylic acid.
Amorphous precipitation In this mixture, salicylic acid is considered to be
Amorphous precipitation occurs when the drug pre- an impurity, and to separate the impurity from the
cipitates as an amorphous form in the inert carrier. desired constituent, a suitable solvent is added to
The high-energy state of the drug in this system gen- the mixture for the purpose of recrystallizing only
erally produces much greater dissolution rates than the acetylsalicylic acid. The contaminant remains in
the corresponding crystalline forms of the drug. solution and is removed in the filtrate during the
filtration process.
Separation methods Only selected processes involving separations are
covered here. Other methods are discussed under the
Separation may be defined as an operation that headings of Complex Formation, Colloidal Disper-
brings about isolation and/or purification of a single sions and Coarse Dispersions.
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Pharmaceutics | 233

Ionic solutions and electrolytic as therapeutic agents. Around 50% of drugs are
administered as salts.20 Salt formation is a simple
equilibria
way of modifying the properties of a drug having
ionizable functional groups in order to overcome
Electrolytes
some undesirable characteristic of the parent drug,
Electrolytes are substances containing free ions, thus normally poor solubility. This affords the opportunity
rendering the substance electrically conductive. The to modify other physicochemical characteristics, such
most typical electrolyte is an ionic solution typified by as melting point, hygroscopicity, chemical stability,
solutions of acids, bases, or salts. As most drugs are dissolution rate, solution pH, and crystal form;
weak acids or bases, it is essential to understand the and mechanical properties, such as hardness and
properties of ionic solutions. Colligative properties elasticity of the potential drug substance and to
are properties of solutions that depend on the number develop dosage forms with acceptable bioavailability,
of molecules in a given volume of solvent rather than stability, manufacturability, and patient compliance.
the weight concentration of the molecules. The col- Salts are formed when a compound that is ionized
ligative properties of solutions of electrolytes depend in solution forms a strong ionic interaction with an
on the total number of entities in solution, including oppositely charged compound leading to the precipi-
ions. In order to determine which species are present tation of the salt form. The counterions are attracted
in ionic solutions, it is mperative to understand ionic by intermolecular coulombic forces. These interac-
equilibria and their impact on subsequent drug activ- tions change the potential energy landscape and lead
ity. An understanding of these fundamental concepts to stronger interaction between the charged active
and an ability to manipulate and predict the sub- pharmaceutical ingredient and polar aqueous sol-
sequent drug properties is crucial in pharmaceutical vents, which can result in enhanced dissolution rates
disciplines. and higher apparent solubility on physiological time
scales, resulting in increased drug delivery rates in
vivo. For the salt to be dissolved the solvent must
Pharmaceutical significance overcome the crystal lattice energy of the solid and
pKa is one of the most important physicochemical create space for the solute. Thus, the solubility of the
properties of a molecule and the impact of pH on salt depends on its polarity, lipophilicity, ionization
drug systems is widespread. Both solubility and potential, and size. A salt’s solubility also depends on
lipophilicity are both governed by pKa ; therefore the properties of the solvent and solid, such as the
understanding and predication of absorption, crystal packing and the presence of solvates.
distribution, metabolism, and excretion (ADME) The advantages and disadvantages of salt forma-
behaviour is impacted. The metabolic profile is highly tion for manipulation of drug properties are summa-
influenced by the parent compound’s pKa which is rized in Table 7.4. A large number of different salt
also extremely relevant in metabolite identification. forms are potentially available for application as the
Phase II reactions, mechanism-based inhibition are counterion and the following criteria are desirable for
also influenced by pKa . Receptor binding can also be a particular salt form:
strongly influenced by pKa because most drugs are
ionized in physiological conditions. • High aqueous solubility, over a wide pH range,
depending on the intended pharmaceutical profile
Salt formation • High degree of crystallinity
When the first ‘‘drugs’’ or alkaloids were isolated • Low hygroscopicity, for consistent performance
from plant materials they were purified as well- • Optimal chemical and solid-state stability under
crystallising salts such as morphine hydrochloride, accelerated conditions.
atropine sulfate, codeine phosphate, quinine sulfate
and pilocarpine nitrate. In contrast to the free bases, A serious deficiency in any of these characteristics
the salts were found to be water soluble and also should exclude the salt for further development. Other
more stable, rendering them more suitable for use influential criteria are:
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234 | An Introduction to Pharmacy

Table 7.4 Advantages and disadvantages of salt formation (data from Kumar et al.21 )

Advantages

Altered solubility and dissolution rate

Controlled-release potential

Improved thermal, hydrolytic and photostability

Reduced hygroscopicity

Improved permeability

Improved organoleptic properties

Improved drug efficacy

Reduced pain on injection

Altered melting point resulting in improved milling and formulation properties

Ease of purification and handling

Improved compactability

Extended patent protection

Disadvantages

Only suitable for ionizable compounds

Decreased percentage of active content

Increased potential for formation of solvates and polymorphs

Reduced dissolution rate or solubility for hydrochloride salts in gastric fluid

Increased chance of poor solid-state stability at the microenvironment pH of the salt, e.g. precipitation of the free acid in the
gastrointestinal environment

Corrosiveness of salts, resulting in tableting problems

Possible dissociation of hydrochloride and hydrobromide salts, resulting in the release of hydrohalide gas or reaction with
excipients or process-related chemicals

Additional step in synthesis of medicinal product

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Pharmaceutics | 235

• Limited number of polymorphs concentration above which precipitation will occur.

• Ease of synthesis, handling and formulation devel- This equation can be rearranged to give
opment. S0
[H3 O+ ]p = Ka (7.70)
Cs − S0
The solubility product of a salt, Ksp , needs to be
taken into account when predicting the solubility of Taking logarithms gives
a salt in a particular environment that contains other Cs − S0
pHp = pKa + log (7.71)
salts with a common counterion. S0
In spite of the abundance of available counterions,
Thus, the pH below which precipitation occurs is a
few are used frequently. USP (2013) showed that salt
function of the amount of salt added initially, the pKa
forms (56.15%) are generally preferred over free acid
and the solubility of the free acid formed from the
or base forms of a drug (43.85%).20 Hydrochloride
salt.
(63%) and sodium (40%) salts remain the favourite
The analogous equation for salts of weak bases
counterions in salt formation with basic and acidic
and strong acids (such as pilocarpine hydrochloride,
drugs, respectively.21 Because of the low solubility of
cocaine hydrochloride, or codeine phosphate) is
many basic drugs, where pHmax (pH of maximum
solubility of the salt) is very low, most common car- S0
pHp = pKa + log (7.72)
boxylic acids do not form acceptable salts and it is Cs − S0
anticipated that the use of relatively strong counteri- in which pKa refers to the protonated form of the
ons will continue in the future. Similarly, 14 out of weak base.
19 salt forms of new chemical entities approved by For both acids and bases, when pH = pKa , [H3 O+ ]
the FDA from 1995 to 2006 are prepared with strong = Ka . If either is substituted the solution is as below,
alkalis such as NaOH and KOH, and this trend is 

also expected to continue in the future.22 H3 O+ + [H3 O+ ]

Cs = S0 (7.73)
If a salt, NaA, is added to water to give a concen- [H3 O+ ]
tration Cs , the following reactions occur: It can be seen that at 50% ionization, the solubility is
− H2 O always equal to twice the intrinsic solubility (S0 ).
Na+ A −−−→ Na+ + A−
A− + H2 O  HA + OH− Ionic liquids
Ionic liquids (ILs) are salt-like materials that are liq-
If the pH of the solution is lowered, more of the A−
uid below 100◦ C and whose melts are composed of
would be converted to the un-ionized acid, HA, in
discrete cations and anions, thus there is no molecu-
accordance with Le Chatelier’s principle. Eventually,
lar species present. Although they have been known
a pH will be obtained below which the amount of HA
for over a century, interest is increasing due to their
formed exceeds its intrinsic aqueous solubility, S0 ,
appealing solvent properties. They are miscible with
and the acid will precipitate from solution; this pH
water or organic solvents, their use can be classi-
can be designated as pHp . At this point, at which the
fied as process chemicals (e.g., solvents, separation
amount of HA formed just equals S0 , a mass balance
media) and performance chemicals (e.g., electrolytes,
on the total amount of drug in solution yields
lubricants) and they are useful solvents for extraction
Cs = [HA] + [A− ] = S0 + [A− ] (7.68) processes.
Other properties of ILs are that they have
Replacing [A− ] as a function of hydroniumion con- practically no vapor pressure and are reported to
centration gives have a wide window of electrochemical stability,
good electrical conductivity, high ionic mobility,
Ka Cs
Cs = S0 + (7.69) and excellent chemical stability. The third and most
[H3 O+ ]p + Ka
recent generation of ILs involve active pharmaceutical
where Ka is the ionization constant for the conjugate ingredients, which are being used to produce ILs with
acid, HA, and [H3 O+ ]p refers to the hydroniumion biological activity.23
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236 | An Introduction to Pharmacy

Drug stability and the effect of pH upon them, may be found under
One of the most diversified and fruitful areas of study the heading Colloidal Dispersions.
is the investigation of the effect of hydrogen-ion
concentration on the stability or, in more general Drug activity
terms, the reactivity of pharmaceutical systems. The Drugs that are weak acids or weak bases, and hence
evidence for enhanced stability of systems when these may exist in ionized or nonionized form (or a mixture
are maintained within a narrow range of pH, as of both), may be active in one form but not in the
well as of progressively decreasing stability as the other; often such drugs have an optimum pH range
pH departs from the optimum range, is abundant. for maximum activity. Thus, mandelic acid, benzoic
Stability (or instability) of a system may result from acid, or salicylic acid have pronounced antibacterial
gain or loss of a proton (hydrogen ion) by a substrate activity in their nonionized forms but have practi-
molecule (often accompanied by an electronic rear- cally no such activity in the equivalent ionized form.
rangement) that reduces (or increases) the reactivity Accordingly, these substances require an acidic envi-
of the molecule. Instability results when the substance ronment to function effectively as antibacterial agents.
desired to remain unchanged is converted to one or For example, sodium benzoate is effective as a preser-
more other, unwanted, substances. In aqueous solu- vative in 4% concentration at pH 7, in 0.06 to 0.1%
tion, instability may arise through the catalytic effect concentration at pH 3.5 to 4, and in 0.02 to 0.03%
of acids or bases: the former by transferring a proton concentration at pH 2.3 to 2.4. Other antibacterial
to the substrate molecule, the latter by accepting agents are active principally, if not entirely, in cationic
a proton. form. Included in this category are the acridines and
Specific illustrations of the effect of hydrogen- quaternary ammonium compounds.
ion concentration on the stability of medicinals are
myriad; only a few will be given here, these being
Drug absorption
chosen to show the importance of pH adjustment of
solutions that require sterilization. The degree of ionization and lipoid solubility of a
Morphine solutions are not decomposed during a drug are two important factors that determine the
60 minute exposure at a temperature of 100◦ C if the rate of absorption of drugs from the gastrointesti-
pH is less than 5.5; neutral and alkaline solutions, nal tract, and indeed their passage through cellular
however, are highly unstable. Minimum hydrolytic membranes generally. Drugs that are weak organic
decomposition of solutions of cocaine occurs in the acids or bases, and that in nonionized form are
pH range 2 to 5; in one study a solution of cocaine soluble in lipids, apparently are absorbed through
hydrochloride, initially at pH 5.7, remained stable cellular membranes by virtue of the lipoidal nature
during two months (although the pH dropped to 4.2 of the membranes. Completely ionized drugs, on the
in this time), whereas another solution buffered to other hand, are absorbed poorly, if at all. Rates of
about pH 6 underwent approximately 30% hydrol- absorption of a variety of drugs are related to their
ysis in the same time. Similarly, solutions of pro- ionization constants and in many cases may be pre-
caine hydrochloride containing some hydrochloric dicted quantitatively on the basis of this relationship.
acid showed no appreciable decomposition; when dis- Thus, not only the degree of the acidic or basic char-
solved in water alone, 5% of the procaine hydrochlo- acter of a drug, but also consequently the pH of
ride hydrolyzed, whereas when buffered to pH 6.5, the physiological medium (e.g., gastric or intestinal
from 19 to 35% underwent decomposition by hydrol- fluid, plasma, cerebrospinal fluid) in which a drug is
ysis. Solutions of thiamine hydrochloride may be dissolved or dispersed (because this pH determines
sterilized by autoclaving without appreciable decom- the extent to which the drug will be converted to
position if the pH is below 5; above this, thiamine ionic or nonionic form) become important parame-
hydrochloride is unstable. ters of drug absorption. Further information on drug
The stability of many disperse systems, and espe- absorption is given in Chapter 8 under the head-
cially of certain emulsions, is often pH dependent. ing Drug Absorption, Distribution, Metabolism and
Information concerning specific emulsion systems, Excretion.
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Pharmaceutics | 237

Tonicity, osmoticity, osmolality and In medicine, the term isotonic, meaning equal tone,
is commonly used interchangeably with iso-osmotic.
osmolarity
However, terms such as isotonic and tonicity should
be used only with reference to a physiological fluid.
Basic definitions
Iso-osmotic actually is a physical term that compares
If a solution is placed in contact with a membrane the osmotic pressure (or another colligative property,
that is permeable to molecules of the solvent, but such as freezing-point depression) of two liquids, nei-
not to molecules of the solute, the movement of sol- ther of which may be a physiological fluid, or which
vent through the membrane is called osmosis. Such may be a physiological fluid only under certain cir-
a membrane often is called semipermeable. As the cumstances. For example, a solution of boric acid that
several types of membranes of the body vary in their is iso-osmotic with both blood and lacrimal fluid is
permeability, it is well to note that they are selec- isotonic only with the lacrimal fluid. This solution
tively permeable. Most normal living-cell membranes causes hemolysis of red blood cells because molecules
maintain various solute concentration gradients. A of boric acid pass freely through the erythrocyte mem-
selectively permeable membrane may be defined either brane, regardless of concentration. Thus, isotonicity
as one that does not permit free, unhampered diffusion infers a sense of physiological compatibility where iso-
of all the solutes present or as one that maintains at osmoticity need not. As another example, a chemically
least one solute concentration gradient across itself. defined elemental diet or enteral nutritional fluid can
Osmosis, then, is the diffusion of water through a be iso-osmotic with the contents of the gastrointesti-
membrane that maintains at least one solute concen- nal tract but would not be considered a physiological
tration gradient across itself. fluid or suitable for parenteral use.
Assume that solution A is on one side of the A solution is isotonic with a living cell if there
membrane, and solution B of the same solute but is no net gain or loss of water by the cell, or no
of a higher concentration is on the other side; the other change in the cell, when it is in contact with
solvent will tend to pass into the more concentrated that solution. Physiological solutions with an osmotic
solution until equilibrium has been established. The pressure lower than that of body fluids, or of 0.9%
pressure required to prevent this movement is the sodium chloride solution, are referred to commonly
osmotic pressure. It is defined as the excess pressure, as being hypotonic. Physiological solutions having a
or pressure greater than that above the pure solvent, greater osmotic pressure are termed hypertonic.
that must be applied to solution B to prevent passage Such qualitative terms are of limited value, and it
of solvent through a perfect semipermeable membrane has become necessary to state osmotic properties in
from A to B. The concentration of a solution with quantitative terms. To do so, a term must be used that
respect to effect on osmotic pressure is related to will represent all the particles that may be present in
the number of particles (un-ionized molecules, ions, a given system. The term used is osmol: the weight, in
macromolecules, aggregates) of solute(s) in solution grams, of a solute, existing in a solution as molecules
and, thus, is affected by the degree of ionization or (and/or ions, macromolecules, aggregates, etc.), which
aggregation of the solute. See the Solutions and Phase is osmotically equivalent to a mole of an ideally
Equilibria section for a review of colligative properties behaving nonelectrolyte. Thus, the osmol weight of
of solutions. a nonelectrolyte, in a dilute solution, generally is
Body fluids, including blood and lacrimal fluid, equal to its gram molecular weight. A milliosmol,
normally have an osmotic pressure that often is abbreviated mOsm, is the weight stated in milligrams.
described as corresponding to that of a 0.9%w/v If one extrapolates this concept of relating an
solution of sodium chloride. The body also attempts osmol and a mole of a nonelectrolyte as being equiv-
to keep the osmotic pressure of the contents of the alent, then one also may define an osmol in the
gastrointestinal tract at about this level, but there following ways. It is the amount of solute that will
the normal range is much wider than that of most provide 1 Avogadro’s number (6.02 × 1023 ) of par-
body fluids. The 0.9%w/v sodium chloride solution ticles in solution, and it is the amount of solute that,
is said to be isoosmotic with physiological fluids. on dissolution in 1 kg of water, will result in an
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238 | An Introduction to Pharmacy

osmotic pressure increase of 17 000 torr at 0◦ C or blood pressure, water content, or blood sugar). To a
19 300 torr at 37◦ C. One mOsmol is 1/1000 of an great extent these effects occur within or between cells
osmol. For example, 1 mol of anhydrous glucose is and tissues where they cannot be measured. One of the
equal to 180 gram. One osmol of this nonelectrolyte is most troublesome problems in clinical medicine is the
also 180 gram. One mOsmol would be 180 mg. Thus, maintenance of adequate body fluids and proper bal-
180 mg of this solute dissolved in 1 kg of water will ance between extracellular and intracellular fluid vol-
produce an increase in osmotic pressure of 19.3 torr umes in seriously ill patients. It should be kept in mind,
at body temperature. however, that fluid and electrolyte abnormalities are
For a solution of an electrolyte such as sodium not diseases but are the manifestations of disease.
chloride, one molecule of sodium chloride represents The physiological mechanisms that control water
one sodium and one chloride ion. Hence, 1 mol will intake and output appear to respond primarily to
represent 2 osmol of sodium chloride theoretically. serum osmoticity. Renal regulation of output is influ-
Accordingly, 1 osmol NaCl = 58.5 g/2 or 29.25 g. enced by variation in rate of release of pituitary
This quantity represents the sum total of 6.02 × 1023 antidiuretic hormone (ADH) and other factors in
ions as the total number of particles. Ideal solutions response to changes in serum osmoticity. Osmotic
infer very dilute solutions or infinite dilution. changes also serve as a stimulus to moderate thirst.
However, as pH or concentration is increased, This mechanism is sufficiently sensitive to limit varia-
other factors enter. Strong electrolyte, interionic tions in osmoticity in the normal individual to less
attraction causes a decrease in their effect on colliga- than about 1%. Body fluid continually oscillates
tive properties. In addition, the charge of ions must around a narrow genetically determined set point
also follow an electrical gradient which operates to in the normal range of 280 to 295 mOsmol L−1 . An
intensify or reduce their colligative effect in vivo phys- increase of plasma osmoticity of 1% will stimulate
iological conditions. Body pH is actively maintained ADH release, resulting in a reduction of urine flow,
at differing values throughout the gastrointestinal and, at the same time, stimulate thirst that results
tract with more minor variations in other organs. A in increased water intake. Both the increased renal
combination of electrochemical gradient and chem- reabsorption of water (without solute) stimulated by
ical concentration maintains pH at different values circulating ADH and the increased water intake tend
across membranes, often forcing a change in state to lower serum osmoticity.
of organic acids or bases between ionized (multiple The transfer of water through the cell membrane
species) and un-ionized (one species) states. The body occurs so rapidly that any lack of osmotic equilib-
uses these systems for absorption of nutrition and rium between the two fluid compartments in any
medications but also excretion of waste products. given tissue usually is corrected within a few sec-
Therefore, it is very difficult and often impossible onds and, at most, within a minute or so. However,
to predict accurately the osmoticity of a solution. It this rapid transfer of water does not mean that com-
may be possible to do so for a dilute solution of a plete equilibration occurs between the extracellular
single pure and well-characterized solute entering a and intracellular compartments throughout the entire
similarly well defined environment, but not for most body within this same short period of time. The rea-
parenteral and enteral medicinal and/or nutritional son is that fluid usually enters the body through the
fluids; experimental determination is likely required gut and then must be transported by the circulatory
to predict behavior in vivo. system to all tissues before complete equilibration
can occur. In the normal person it may require 30
to 60 minutes to achieve reasonably good equili-
Therapeutic considerations
bration throughout the body after drinking water.
Generally it is accepted that osmotic effects have a Osmoticity is the property that largely determines the
major place in the maintenance of homeostasis (the physiological acceptability of a variety of solutions
state of equilibrium in the living body, with respect used for therapeutic and nutritional purposes.
to various functions and to the chemical composition Pharmaceutical and therapeutic consideration of
of the fluids and tissues, e.g., temperature, heart rate, osmotic effects has been, to a great extent, directed
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Pharmaceutics | 239

toward the side effects of ophthalmic and parenteral trap for ammonia migrating from the blood to the
medicinals due to abnormal osmoticity, and either colon. The conversion of ammonia of blood to the
to formulating to avoid the side effects or to find- ammonium ion in the colon ultimately is coupled
ing methods of administration to minimize them. with the osmotic effect and laxation, thus expelling
More recently this consideration has been extended undesirable levels of blood ammonia. This product
to total (central) parenteral nutrition, to enteral hyper- is employed to prevent and treat frontal systemic
alimentation (‘‘tube’’ feeding), and to concentrated- encephalopathy.
fluid infant formulas.24,25 Also, in recent years, the Osmotic laxation is observed with the oral or
importance of osmometry of serum and urine in the rectal use of glycerin and sorbitol. Epsom salt has
diagnosis of many pathological conditions has been been used in baths and compresses to reduce edema
recognized. associated with sprains. Another approach is the indi-
There are a number of examples of the direct rect application of the osmotic effect in therapy via
therapeutic effect of osmotic action, such as the intra- osmotic pump drug delivery systems.26
venous (IV) use of mannitol as a diuretic that is filtered
at the glomeruli and thus increases the osmotic pres-
Undesirable effects of abnormal
sure of tubular urine. Water must then be reabsorbed
osmoticity
against a higher osmotic gradient than otherwise,
so reabsorption is slower and diuresis is observed. Ophthalmic medication
The same fundamental principle applies to the IV It is generally accepted that ophthalmic preparations
administration of 30% urea used to affect intracranial intended for instillation into the cul-de-sac of the eye
pressure in the control of cerebral edema. Peritoneal should, if possible, be approximately isotonic to avoid
dialysis fluids tend to be somewhat hyperosmotic to irritation. It also has been stated that the abnormal
withdraw water and nitrogenous metabolites. Two tonicity of contact lens solutions can cause the lens
to 5% sodium chloride solutions or dispersions in to adhere to the eye and/or cause burning or dryness
an oleaginous base (Muro; Bausch and Lomb) and a and photophobia.
40% glucose ointment are used topically for corneal
edema. Ophthalgan (Wyeth-Ayerst) is ophthalmic Neonatal enteral and total parenteral
glycerin employed for its osmotic effect to clear medication
edematous cornea to facilitate an ophthalmoscopic Adult tolerances of osmoticity cannot be expected in
or gonioscopic examination. Glycerin solutions in pediatric and neonatal therapy. Paracetamol solutions
50% concentration (Osmoglyn; Alcon) and isosor- have an osmolality approaching 15,000 mOsm L−1
bide solution (Ismotic; Alcon) are oral osmotic agents with a target of less than 500 mOsmol/L suitable for
for reducing intraocular pressure. enternal feed. Modifications, or dilutions of these for-
The osmotic principle also applies to plasma mulations must be considered to prevent the risks
extenders, such as PVP and to saline laxatives, such as of pneumatosis intestinalis or hypernatremia,25 par-
magnesium sulfate, magnesium citrate solution, mag- ticularly in the cases of significant imbalance of
nesium hydroxide (via gastric neutralization), sodium ADH caused by existing trauma or acute diarrhea
sulfate, sodium phosphate, sodium biphosphate oral states.27,28
solution, and enema (Fleet). Because of the different fluid and protein
An interesting osmotic laxative that is a nonelec- requirements of neonates and pediatric patients, the
trolyte is a lactulose solution. Lactulose is a nonab- final concentration of glucose and amino acids are
sorbable disaccharide that is colon-specific, wherein often different from those of an adult. It is now
colonic bacteria degrade some of the disaccharide to expected that these variations are available to the
lactic and other simple organic acids. These, in total, clinician and that calculation or active measurement
lead to an osmotic effect and laxation. An extension of the osmolarity of a system should be made. Many
of this therapy is illustrated by Cephulac (Marion automated compounding systems are now capable
Merrell Dow) solution, which uses the acidification of calculation of the full bag osmolarity, using previ-
of the colon via lactulose degradation to serve as a ously recorded individual coefficients of variations for
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240 | An Introduction to Pharmacy

the individual components. Large validation cycles • Excessive infusion of hypotonic fluids may cause
allow these calculations to be clinically relied upon, swelling of red blood cells, hemolysis, and water
but pharmacists must take particular care with regard invasion of the body’s cells in general. When this
to the extemporaneous addition of compounds to is beyond the body’s tolerance for water, water
these systems, for these concentrated systems are not intoxication results, with convulsions and edema,
governed by the simpler calculations. such as pulmonary edema.

Hyperosmotic agents • Excessive infusion of isotonic fluids can cause an

increase in extracellular fluid volume, which can
Therapies directly applying osmotic gradients ther- result in circulatory overload.
apeutically are few. However, pediatric and mature
• Excessive infusion of hypertonic fluids leads to a
cystic fibrosis patients infrequently make use of salt wide variety of complications. For example, the
solutions in the range 295 to 700 mOsm L−1 for
sequence of events when the body is presented
their direct osmotic effect. Upon nebulization of these
with a large IV load of hypertonic fluid, rich in glu-
solutions, water movement is increased through the
cose, is as follows: hyperglycemia, glycosuria and
lungs’ transepithelial surface to dilute any mucus.
intracellular dehydration, osmotic diuresis, loss of
Higher osmolarities produce transepithelial move-
water and electrolytes, dehydration, and coma.
ment through tight junctions,29,30 further accelerating
tracheobronchial mucocillary clearance.31
One cause of osmotic diuresis is the infusion of
Diagnostic contrast agents
glucose at a rate faster than the ability of the patient
Radiopharmaceutical and tomography contrast to metabolize it (as greater than perhaps 400 to
agents demand a pharmaceutical concentration to be 500 mg kg−1 per hour for an adult on total parenteral
held in a specific area of interest to allow appropriate
nutrition). A heavy load of unmetabolizable glucose
imaging. This requirement can produce localized
increases the osmoticity of blood and acts as a
concentrations in the region of 600 mOsm L−1
diuretic; the increased solute load requires more fluid
resulting in tissue shrinkage and the potential for
for excretion, 10 to 20 mL of water being required to
resultant cell death.32 Since dilution of the agent is
excrete each gram of glucose. Solutions such as those
not possible until after treatment, reformulation with
for total parenteral nutrition should be administered
alternative agents could be considered.
by means of a metered constant-infusion apparatus
Parenteral medication over a lengthy period (usually more than 24 hours)
Osmoticity is of great importance in parenteral injec- to avoid sudden hyperosmotic glucose loads. Such
tions, its effects depending on such factors as the solutions may cause osmotic diuresis; if this occurs,
degree of deviation from tonicity, the concentration, water balance is likely to become negative because
the location of the injection, the volume injected, the of the increased urinary volume, and electrolyte
speed of the injection, and the rapidity of dilution and depletion may occur because of excretion of sodium
diffusion. When formulating hypotonic parenterals, and potassium secondary to the osmotic diuresis. If
they usually have tonicity adjusted by the addition such diuresis is marked, body weight falls abruptly
of glucose or sodium chloride. Hypertonic parenteral and signs of dehydration appear. Urine should be
drug solutions cannot be adjusted, but if prepared monitored for signs of osmotic diuresis, such as
from a dry powder, they may be reconstituted in a glycosuria and increased urine volume.
different solvent volume. Hypotonic and hypertonic If the IV injection rate of hypertonic solution is
solutions usually are administered slowly, in small too rapid, there may be catastrophic effects on the
volumes, or into a large vein such as the subclavian, circulatory and respiratory systems. Blood pressure
where dilution and distribution occur rapidly. Solu- may fall to dangerous levels, cardiac irregularities or
tions that differ from the serum in tonicity generally arrest may ensue, respiration may become shallow
cause tissue irritation, pain on injection, and elec- and irregular, and there may be heart failure and
trolyte shifts, the effect depending on the degree of pulmonary edema. Probably the precipitating factor
deviation from tonicity: is a bolus of concentrated solute suddenly reaching
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Pharmaceutics | 241

the myocardium and the chemoreceptors in the aortic Clinical applications

arch and carotid sinus.33 Although there are many issues with abnormal
Abrupt changes in serum osmoticity can lead osmoticity, most pharmacists are concerned with pre-
to cerebral hemorrhage. It has been shown experi- ventable adverse effects, such as thrombophlebitis and
mentally that rapid infusions of therapeutic doses pain at the injection site. The understanding of these
of hypertonic saline with osmotic loads produce a potential risks from hyperosmotic parenteral medi-
sudden rise in cerebrospinal fluid (CSF) pressure and cations has fine-tuned IV administration techniques.
venous pressure, followed by a precipitous fall in The site of administration – peripheral versus central
CSF pressure. This particularly may be conducive venous catheter – plays a significant role in determin-
to intracranial hemorrhage, for the rapid infusion ing the final concentration of parenteral medications
produces an increase in plasma volume and venous infused IV. Attention should be directed toward
pressure at the same time the CSF pressure is falling. establishing the optimal osmolarity of IV adminis-
During the CSF pressure rise, there is a drop in tered parenteral medications via the peripheral venous
hemoglobin and hematocrit, reflecting a marked route that will result in the least adverse effects.
increase in blood volume. Since the introduction of parenteral nutrition sup-
Hyperosmotic medications, such as sodium port, hyperosmoticity of these nutrition solutions
bicarbonate (osmolarity of 1560 at 1 mEq mL−1 ), remains a concern. The commonly accepted osmolar-
which are administered intravenously, should be ity of less than 900 mOsmol L−1 has been quoted for
diluted prior to use and should be injected slowly to safe peripheral administration of parenteral nutrition
allow dilution by the circulating blood. Rapid push solutions.35,36 All attempts should be made to pre-
injections may cause a significant increase in blood pare solutions with osmoticity close to that of serum
osmoticity.34 osmoticity or no greater than 900 mOsmol L−1 . This
Safety, therefore, demands that all IV injections, can be achieved by carefully selecting the diluent for
especially of highly osmotic solutions, be performed dilution and determining the final concentration of
slowly, usually being given preferably over a period the parenteral medication. Glucose 5% in Water for
not less than that required for a complete circulation Injection and Sodium Chloride 0.9% have been used
of the blood (1 minute). The exact danger point routinely as diluents. When comparing the two dilu-
varies with the state of the patient, the concentration ents, parenteral medications diluted with Glucose 5%
of the solution, the nature of the solute, and the rate in Water for Injection have a lower osmolarity than
of administration. do solutions diluted with Sodium Chloride 0.9% at
Hyperosmotic solutions also should not be dis- the same final concentration.
continued suddenly. In dogs, marked increase in Several studies have been conducted to deter-
levels of intracranial pressure have occurred when mine optimal final concentration of commonly used
hyperglycemia produced with glucose infusions was parenteral medications.37 – 39 The published final con-
suddenly reversed by stopping the infusion and admin- centrations for most parenteral medications are rec-
istering saline. It also has been shown that the CSF ommended for peripheral as well as central venous
pressure in humans rises during treatment of dia- catheter IV administration for patients with no spe-
betic ketoacidosis in association with a fall in the cial needs, such as fluid restriction. In the event that
plasma concentration of glucose and a fall in plasma fluid restriction is required or the recommended final
osmolality. These observations may be explained concentration is not achievable, the parenteral med-
by the different rates of decline in glucose content ication should be administered via a central venous
of the brain and of plasma. The concentration of catheter, by which immediate dilution and distribu-
glucose in the brain may fall more slowly than tion is achieved rapidly. This will minimize potential
in the plasma, causing a shift of fluid from the for phlebitis and pain at the injection site.
extracellular fluid space to the intracellular compart- Osmoticity issues associated with parenteral medi-
ment of the CNS, resulting in increased intracranial cations are also applicable to total parenteral nutrition
pressure. (TPN) solutions, especially via peripheral venous
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242 | An Introduction to Pharmacy

administration. Peripheral parenteral nutrition sup- value is nearly proportional to concentration. If a D

port remains an integral part of therapeutic options value is needed for a concentration of drug not listed
for hospitalized patients. The peripheral route of in Appendix A, a D value can be calculated from the
administration often is preferred for patients who appendix by direct proportion, using a D value closest
require short-term therapy or supplemental nutrition to the concentration of drug in the actual solution.
support. The reference solution for the freezing-point-
depression method is 0.9% sodium chloride, which
has a freezing-point depression of T f = 0.52◦ C.
Methods of adjusting tonicity
Using the three steps described above, the dexam-
There are several methods for adjusting the tonicity ethasone sodium phosphate solution in Example 1
of an aqueous solution, provided, of course, that the can be rendered isotonic as follows:
solution is hypotonic when the drug and additives
are dissolved. The most prominent of these methods
Example 1
are the freezing-point depression method, the sodium
chloride equivalent method, and the isotonic solution Dexamethasone Sodium Phosphate 0.1%
V-value method. The first two of these methods can
be used with a three-step problem-solving process, Purified Water qs 30 mL
based on sodium chloride.

1. Identify a reference solution and the associated Mft Isotonic Solution

tonicity parameter. Step 1 – Reference solution: 0.9% sodium chlo-
2. Determine the contribution of the drug(s) and ride.
additive(s) to the total tonicity. T f = 0.52◦ C
3. Determine the amount of sodium chloride needed D = 0.050◦ /0.5% (dexamethasone sodium phos-
by subtracting the contribution of the actual solu- phate)
tion from the reference solution. Step 2 – Contribution of drug.

0.050◦ ◦
The result of the third step also indicates whether the × 0.1% drug = 0.010 (7.74)
0.5% drug
actual solution is hypotonic, isotonic, or hypertonic.
If the actual solution contributes less to the total Step 3 – Reference solution – Actual solution.
tonicity than the reference solution, then the actual 0.52◦ – 0.01◦ = 0.51◦
solution is hypotonic. If, however, the actual solution Sodium chloride needed.
contributes a greater amount to tonicity than the 0.883 g NaCl
reference solution, the actual solution is hypertonic × 30 mL = 0.265 g NaCl (7.75)
100 mL
and can be adjusted to isotonicity only by dilution.
This may not be possible on therapeutic grounds.
0.9% NaCl
The amount of sodium chloride resulting in the × 30 mL = 0.265 g NaCl (7.76)
0.52◦
third step also can be converted into an amount of
other materials, such as glucose, to render the actual The above solution could be made isotonic with any
solution isotonic. appropriate material other than sodium chloride by
using the D value for that material. For example,
Freezing-point-depression method to make the solution isotonic with glucose with a D
The freezing-point method makes use of a D value, D = 0.091◦ /1%;
value (found in Appendix A) which has the units
5.60 g Dextrose
of degree centigrade/(x% drug). For example, in × 30 mL = 1.68 g Dextrose (7.77)
100 mL
Appendix A, dexamethasone sodium phosphate has
D values of 0.050◦ /(0.5% drug), 0.180◦ /(2.0% drug),
1% Dextrose ◦
0.52◦ /(6.75% drug), etc. It is apparent that the D × 0.51 = 5.60% Dextrose (7.78)
0.091◦
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Pharmaceutics | 243

in Appendix A, dexamethasone sodium phosphate

Example 2 has an E value of 0.18 g NaCl/g drug at 0.5% drug
concentration, 0.17 g NaCl/g drug at 1% drug concen-
Naphazoline HCl (N.HCl) 0.02%
tration and a value of 0.16 g NaCl/g drug at 2% drug.
Zinc Sulfate 0.25%
This slight variation in the sodium chloride equiva-
lent with concentration is due to changes in interionic
Purified Water qs 30 mL attraction at different concentration of drug; the E
value is not directly proportional to concentration, as
was the freezing-point depression.
Mft Isotonic solution The reference solution for the sodium chloride
Step 1 – Reference solution: 0.9% sodium chlo- equivalent method is 0.9% sodium chloride, as it was
ride. for the freezing-point-depression method.
T f = 0.52◦ C The dexamethasone sodium phosphate solution in
D = 0.14◦ /1% (naphazoline HCl) Example 1 can be rendered isotonic, using the sodium
D = 0.086◦ /1% (zinc sulfate) chloride equivalent method as follows:
Step 2 – Contribution of drugs.

0.086◦ ◦ Example 1
× 0.25% ZnSO4 = 0.022
1% ZnSO4
(7.79) Dexamethasone Sodium Phosphate 0.1%
◦
0.14 ◦
× 0.02% N.HCl = 0.003 Purified Water qs 30 mL
1% N.HCl
(7.80)
Mft Isotonic Solution
Step 3 – Reference solution – Actual solution.
Step 1 – Reference solution: 0.9% sodium chlo-
0.52◦ – 0.025◦ = 0.495◦
ride.
Sodium chloride needed.
0.9 g NaCl
0.857 g NaCl × 30 mL = 0.270 g NaCl (7.85)
× 30 mL = 0.257 g NaCl (7.81) 100 mL
100 mL
E = 0.18 g NaCl/g drug
0.9% NaCl ◦ Step 2 – Contribution of drug.
× 0.495 = 0.857% NaCl (7.82)
0.52◦
0.18 g NaCl 0.1 g drug
The above solution could be made isotonic with any × × 30 mL
1 g drug 100 mL
appropriate material, other than sodium chloride, by
= 0.0054 g NaCl (7.86)
using the D value for that material.
For example, to make the solution isotonic with
Step 3 – Reference solution – Actual solution.
glucose with a D value, D = 0.091◦ /1%;
0.270 g NaCl – 0.0054 g NaCl = 0.265 g NaCl
5.44 g Dextrose The above solution can be made isotonic with a
× 30 mL = 1.63 g Dextrose
100 mL material other than sodium chloride, such as glu-
(7.83) cose, by using the E value of that material. For
1% Dextrose ◦ example, to make the solution isotonic with glucose,
× 0.495 = 5.44% Dextrose
0.091◦ E = 0.16 g NaCl/g glucose, the amount of sodium
(7.84) chloride needed in Step 3, can be converted to glucose
as follows:
Sodium chloride equivalent method
A sodium chloride equivalent, E value, is defined as 1 g Dextrose
× 0.265 g NaCl = 1.66 g Dextrose
the weight of sodium chloride that will produce the 0.16 g NaCl
same osmotic effect as 1 g of the drug. For example, (7.87)
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244 | An Introduction to Pharmacy

prescribed volume. The basic principle underlying the

Example 2 use of V-values is to prepare an isotonic solution of
the prescribed drug and then dilute this solution to
Naphazoline HCl (N.HCl) 0.02%
final volume with a suitable isotonic vehicle.
The two solutions in the previous examples can
Zinc Sulfate 0.25%
be prepared as follows using the V-value method:
Purified Water qs 30 mL

Example 1

Mft Isotonic Solution Dexamethasone Sodium Phosphate 0.1%

Step 1 – Reference solution: 0.9% sodium chlo-
ride. Purified Water qs 30 mL

0.9 g NaCl
× 30mL = 0.270 g NaCl (7.88)
100 mL
Mft Isotonic Solution
E = 0.27 g NaCl/g N.HCl Step 1 – The V-value for dexamethasone sodium
E = 0.15 g NaCl/g ZnSO4 phosphate can be calculated from the sodium
Step 2 – Contribution of drugs. chloride equivalent, E, as outlined in the footnote in
Appendix B.
0.27 g NaCl 0.02 g N.HCl
× × 30 mL 100 mL Soln 0.17 g NaCl
1 g N.HCl 100mL × × 0.3 g drug
0.9 g NaCl 1 g drug
= 0.002 g NaCl (7.89)
0.15 g NaCl 0.25 g ZnSO4 = 5.67 mL Soln (7.92)
× × 30 mL
1 g ZnSO4 100mL for a dilute solution:
= 0.011 g NaCl (7.90) 5.67 mL Soln ∼ = 5.67 mL H2 O
where V = (5.67 mL H2 O)/(0.3 g drug)
0.002 g NaCl + 0.011 g NaCl = 0.013 g NaCl Step 2 – Amount of drug needed.
Step 3 – Reference solution − Actual solution.
0.1 g drug
0.270 g NaCl – 0.013 g NaCl = 0.257 g NaCl × 30 mL = 0.030 g drug (7.93)
100 mL
The above solution can be made isotonic with a
material other than sodium chloride, such as glu- Volume of water needed to prepare an isotonic solu-
cose, by using the E value of that material. For tion.
example, to make the solution isotonic with glucose, 5.67 mL H2 O
E = 0.16 g NaCl/g glucose, the amount of sodium × 0.030 g = 0.57 mL H2 O
0.3 g drug
chloride needed in Step 3 can be converted to glucose (7.94)
as follows:
Step 3 – To prepare the solution, dissolve 0.030 g
1 g Dextrose of drug in 0.57 mL water, and qs to volume with a suit-
× 0.257 g NaCl = 1.61 g Dextrose
0.16 g NaCl able isotonic vehicle, such as 0.9% sodium chloride
(7.91) solution, 5.51% glucose, or an isotonic phosphate
buffer.
Isotonic solution V-values
The V-value of a drug is the volume of water to be
Example 2
added to a specified weight of drug (0.3 g or 1.0 g,
depending on the table used) to prepare an isotonic Naphazoline HCl (N.HCl) 0.02%
solution. Appendix B gives such values for some com-
monly used drugs. The reason for providing data for Zinc Sulfate 0.25%
0.3 g of drug is for convenience in preparing 30 mL
Purified Water qs 30 mL
(approximately 1 fluid ounce) of solution, a commonly
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Pharmaceutics | 245

Chemical reactions
Mft Isotonic Solution
Step 1 – The V-value for naphazoline HCl can be A chemical reaction is said to have occurred when
calculated from the sodium chloride equivalent, E, as one or more molecules undergoes a process in which
outlined in the footnote in Appendix B; the V-value electrons are either lost or gained by an atom or
for zinc sulfate is taken directly from Appendix B. molecule, or the electrons go through a transition
process in which they are shared differently between
100 mL Soln 0.27 g NaCl atoms which result in the breaking or forming of
× × 0.3 g N.HCl
0.9 g NaCl 1 g N.HCl bonds. These result in the formation of one or more
= 9.00 mL Soln (7.95) new chemical species with different chemical struc-
tures and properties than that of the original starting
for a dilute solution:
material. Such chemical processes usually result in
9.00 mL Soln ∼ = 9.00 mL H2 O
changes in energy and/or degree of randomness in
where V = (9.00 mL H2 O)/(0.3 g N.HCl)
going from the initial to the final state which is the
V = 5.00 mL H2 O/0.3 g ZnSO4
basis for thermodynamics. Thermodynamic parame-
Step 2 – Amount of drugs needed.
ters, such as G, E, H, and S, are state functions
0.25 g ZnSO4 that only depend on the initial and final states of a
× 30 mL = 0.075 g ZnSO4
100 mL chemical process (usually defined as the state of the
(7.96)
reactants and products at certain temperatures, pres-
0.02 g N.HCl sures and physical states) and are independent of the
× 30 mL = 0.006 g N.HCl
100 mL pathway taken to get to the final state from the initial
(7.97)
state. Spontaneous reactions are said to occur when
Volume of water needed to prepare an isotonic solu- the reactants proceed to products when the energy
tion: contained within the products is less than the energy
5.00 mL H2 O contained in the reactants (i.e., G < 0) which usually
× 0.075 g ZnSO4 = 1.25 mL H2 O result in the release of heat (i.e., H < 0) and/or an
0.3 g ZnSO4
(7.98) increase in randomness of the chemical system (i.e.,
9.00 mL H2 O S > 0). However, it has been observed that in some
× 0.006 g drug = 0.18 mL H2 O cases, whereas some reactions are thermodynamically
0.3 g N.HCl
(7.99) favorable to proceed spontaneously, the conversion of
reactants to products may proceed at very slow rates
Step 3 – To prepare the solution, dissolve 0.006 g over relatively long periods of time. This serves to
of naphazoline HCl and 0.075 g zinc sulfate in point out that thermodynamics is essentially a snap-
1.43 mL water, and qs to volume with a suitable shot of the differences between the properties of the
isotonic vehicle, such as 0.9% sodium chloride product and reactant states of a chemical reaction
solution, 5.51% glucose, or an isotonic phosphate which provides no indication of the chemical pro-
buffer. cesses or the time that it took to go from reactant to
product state.
Chemical kinetics is the discipline that is con-
Chemical kinetics cerned with the mechanism by which a chemical
process gets to its final state from its initial state and
This section is intended as a general introduction the rate in which this reaction proceeds. Therefore,
to Chemical Kinetics. A comprehensive review chemical kinetics involves the study of rate of chemical
of experimental approaches and interpretation of change and the way in which this rate is influenced by
data can be found in several texts, such as the the conditions of the concentration of reactants, prod-
books by House, Epenson, and Houston, and the ucts, and other chemical species that may be present,
compilation of information relative to kinetic studies and by factors such as solvent, pressure, and temper-
on pharmaceuticals by Garrett.40 – 43 ature. From these studies, one or more mechanisms
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246 | An Introduction to Pharmacy

involving a series of elementary processes may be where D represent a reactant species that collides and
postulated to explain how the reactants are converted reacts with the excited species A* to produce the prod-
to products during a chemical process. uct species F. At other times, the excited electrons may
Applied to pharmaceutics, chemical kinetic infor- revert back to a lower energy level or even the original
mation permits a rational approach to the stabiliza- energy level through a release of electromagnetic
tion of drug products, and prediction of shelf life and radiation as shown by the elementary process
optimum storage conditions.
A∗ → A + hv

Reaction mechanism The other common method in which a reaction

can occur is when a transfer of energy occurs when
There are two basic ways in which chemical reactions
an atom or molecule collides with another atom,
can occur. One method involves the absorption of
molecule or even the wall of a container. For example,
electromagnetic radiation which excites certain elec-
an atom or molecule with a certain amount of kinetic
trons within an atom or molecule to a higher energy
and potential energy collides with a wall of a con-
state or even the ejection of the electron creating a free
tainer that is at a higher temperature than that of the
radical which is a very reactive chemical species. This
atom or molecule. The atom/molecule absorbs some
may be indicated by the elementary processes such as
of this thermal energy resulting in an increase in its
A + hv → A∗ kinetic energy, which causes it to increase its veloc-
ity, or, in the case of a molecule, may absorb enough
and energy to disrupt bonds within the molecule. A similar
process can occur when there is a collision between
A + hv → A• + e−
atoms/molecules where there may be a transfer of
where hv represents a quantum of electromagnetic energy. In such cases where the atoms/molecules col-
radiation absorbed by chemical species A, A* rep- lide and bounce off one another, one atom/molecule
resents the higher energy, excited state of chemical may increase its kinetic or potential energy at the cost
species A, A• represents the free radical of species A, of energy of the other atom/molecule. Such processes
and e− represents an electron. If the excited electrons can be represented by
were originally involved in a bond between atoms,
A + W → A∗ + W
then the bond may be weakened or broken which may
cause the molecule to dissociate into smaller molecules where W represents either a molecule or the wall
or possibly cause the molecule to internally rearrange of a container in which chemical species A has col-
its bonds as shown by the elementary processes lided creating a higher energy, activated species A*.
It should be noted that W in such cases has lost
A + hv → B + C
some of its energy upon such collisions. The higher
or energy atom/molecule may then go on to collide with
other atoms/molecules. If there is sufficient energy
A + hv → H between the colliding molecules/atoms and other con-
ditions, such as intermolecular orientation, are right,
where species B and C are the products of the intermolecular interactions may be sufficient to cause
disintegration of species A, and H is a resulting the colliding entities to ‘‘stick’’ together creating an
product caused by the rearrangement of species A intermediate species as indicated by the elementary
upon absorption of a quantum of electromagnetic process
energy. If an excited molecule collides with another
atom/molecule under the right conditions, a new A∗ + B → [A − −B]∗ → AB∗
bond may form creating a new molecule as shown by
the elementary process where [A– –B]* and AB* represent intermediate or
transition state species. During this process, either
A∗ + D → F a transfer of energy can occur before the entities
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Pharmaceutics | 247

separate creating an excited species, certain electrons where the uppercase letters represent chemical species
of the two entities can form a bond creating a new and the lowercase letters represent stoichiometric
chemical species, or the transition state entity can coefficients, the rate in which reactants go to prod-
break apart to form a new chemical species as shown ucts can be determined by following the rate of the
by the elementary processes disappearance of the reactants as a function of time.

AB∗ → A + B∗ Rate = −
d[A]
=−
d[B]
(7.100)
adt bdt
or The brackets denote concentration (usually molar
concentration unless otherwise indicated) and d rep-
AB∗ → C
resents the derivative function. The negative sign
or signifies that the concentration of the reactants is
decreasing, as the rate must always be positive as
AB∗ → D + F long as the reaction is progressing from reactants to
products.
Thus, when a chemical reaction does occur, it
The rate at which a reaction proceeds for the
may occur via a mechanism in a single reaction step,
reaction type shown above also can be determined by
known as an elementary process, or by a series of two
following the appearance of the products as a function
or more elementary processes which, when totaled,
of time.
will give the net chemical reaction. For example,
d[C] d[D]
Rate = + =+ (7.101)
Rxn 1 A∗ + B → AB∗ cdt ddt
Rxn 2 AB∗ → D + F∗ where the positive signs indicate that the concentra-
∗ tions of the products are increasing. Note that these
Rxn 3 F → 2G
two expressions for rate are only for the type of reac-
which when summed together gives tion where the reactants go irreversibly to products,
without going through any intermediates.
A∗ + B + AB∗ + F∗ → AB∗ + D + F∗ 2G
If [A]0 , [B]0 , [C]0 , and [D]0 represent the initial
However, because the transition state AB* and the concentration (i.e., t = 0) of each of the reactants and
activated molecule F* appear in both reactant and products, at some time t (i.e., t = t), the concentration
product sides of the reaction in the same stoichiomet- of A decreases by aX (i.e., [A]t = [A]0 – aX) and the
ric quantities, they can be treated as intermediates and concentration of B decreases by bX (i.e., [B]t = [B]0
removed from the reaction to give the net reaction – bX). Similarly, the concentrations of the products
C and D increase by cX and dX, respectively (i.e.,
A∗ + B → D + 2G [C]t = [C]0 + cX and [D]t =[D]0 + dX) after some
time t. Thus, upon normalization, the rate expressed
in equations (7.101) and (7.102) can be shown to
Reaction rate reduce to equation (7.103).
The rate of a reaction is the velocity with which a
dX
reactant or reactants undergoes a chemical change. Rate = + (7.102)
dt
Experimentally, the rate of a reaction must be deter-
mined by directly or indirectly following the change The law of mass action relates these experimen-
in the concentration of the reactants or products as a tally determined rates to the concentration of all of
function of time. When there is more than one reac- the reacting species. This law states that, at a given
tant, such changes need to be normalized according temperature, the rate of the reaction is at each instant
to the stoichiometry of the reaction. For a reaction of proportional to the product of the concentration of
the type each of the reacting species raised to a power equal
to the number of molecules of each of these species
aA + bB + . . . → cC + dD + . . . participating in the process. Accordingly, the law of
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248 | An Introduction to Pharmacy

mass action applied to the above reaction gives the It should be noted that unless the stoichiometric
following rate equation: coefficient of the reactant or product that is being
followed to determine the rate of the reaction is unity
Rate = k[A]n [B]m (7.103) (one), the rate of the reaction is not equivalent to the
change in the concentration of the chemical species
where the proportionality constant k (referred to as with respect to time. For the case where there is only
the specific rate constant or as the rate constant) one chemical reactant, which has a stoichiometric
should be independent of the concentrations of all coefficient that is greater than unity, authors of articles
chemical species at a given temperature. The expo- and textbooks on kinetics often base the reaction rate
nents, n and m, are known as the order of the reaction only on the disappearance of the reactant without
with respect to the components A and B, respectively; accounting for the stoichiometry. When this occurs,
their sum represents the overall order of the reaction. the resulting rate constant will be greater than the true
Equation (7.103) can be applied to each individual rate constant by a factor equal to the stoichiometric
elementary process which makes up a reaction. In such coefficient. Thus, care must be taken to determine
cases, the exponents of each of the reacting species how the rates of reactions were determined when
are equal to their stoichiometric coefficients for the comparing rate constants of a reaction.
balanced equation representing the processes. These
exponents indicate the number of molecules/atoms of
each reacting species that participate in a simultane- Drug stabilization
ous collision to form the reactants with the rate of the
process controlled by the specific rate constant, k, dur- Some drug decomposition reactions, such as pho-
ing that specific elementary process. It is interesting to tolytic and oxidative reactions, are relatively easy
note that statistically, collisions involving more than to avoid by protecting the components from light
two bodies are extremely rare and collisions involv- (photodecomposition) or exclusion of oxygen and by
ing more than three bodies are nearly impossible; the use of chain-terminating reagents or free-radical scav-
specific rate constants for these rare processes will be engers to minimize free-radical-mediated reactions.
very small and the reactions very slow. Solvolysis reactions, however, cannot be stopped
It is important to note that for a net chemical by such procedures, but several techniques may be
reaction, which is the sum of all of the elementary employed to retard reactions sufficiently to permit the
processes, there is no requirement that the order of formulation of a suitable drug product. The follow-
the reaction with respect to a chemical species be ing approaches may be useful in attempts to retard
identical to its stoichiometric coefficient indicated in solvolytic reactions.
the net chemical equation. This is because chemical
species that appeared as both reactants and prod-
ucts in the various elementary processes have been
Selection of optimum pH, buffer, and
removed to create a balanced net equation. Further,
solvent
it may be necessary for some elementary processes Consideration of the mechanism of the reaction and
to occur more than once in order to arrive at net the way in which the reaction rate is influenced by
balanced equation. Additionally, some elementary pH, buffer species, and solvent permits the selection
processes may be reversible (i.e., products revert to of the optimum conditions for drug stability. Often,
reactants) during an overall chemical reaction. There- however, ideal conditions for maximum stability may
fore, unlike for elementary processes in which the be unacceptable from the viewpoint of pharmaceuti-
species which enter into equation (7.103), can only be cally acceptable formulation or therapeutic efficacy;
reactants, equation (7.103) for a net chemical reaction thus, it may be necessary to prepare a formulation
can include products as well as reactants. However, with conditions less than optimum for drug stabil-
a proper rate equation for a net chemical equation ity. If a suitable compromise between conditions for
should not contain any chemical species that exists as maximum stability and conditions for a pharmaceu-
an intermediate during a chemical reaction. tically acceptable formulation cannot be achieved,
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Pharmaceutics | 249

techniques, such as those described below, may be suspensions degraded at a rate proportional to the
useful in retarding solvolysis reactions. low concentration of penicillin in solution. Because
the penicillin in solution was in equilibrium with
excess solid penicillin G procaine, the penicillin con-
Specific complexing agents
centration in solution was constant and the observed
The technique of stabilization by forming complexes order of reaction was apparently zero order.
in solution was introduced by Higuchi and Lachman9
who demonstrated that the rate of hydrolysis of the
Refrigeration
ester function of benzocaine was retarded significantly
in the presence of caffeine, a reagent with which the Storage below room temperature usually will retard
benzocaine formed a soluble complex. It was demon- solvolytic reactions. Storage in the frozen state gen-
strated further that, in these systems, the complexed erally is an effective means of retarding degradative
drug did not hydrolyze at all and that the observed reactions. Several antibiotics are sold as frozen solu-
rate of hydrolysis could be ascribed to the concen- tions in flexible plastic bags. An exception is sodium
tration of the free or uncomplexed drug that was in ampicillin dissolved in 5% dextrose solution, which
equilibrium with the drug complex. showed approximately 10% decomposition after 4 h
There are many recognized examples in which of storage at 5◦ C and more than 13% loss after
drug stabilization occurs by disrupting the kinetic storage for the same period in the frozen state at
mechanisms of degradation. Boric acid chelation −20◦ C.
of the catechol function of epinephrine stabilizes
epinephrine against attack by bisulfite and sulfite.
The complex of povidone (polyvinylpyrrolidone) and
Stability testing of pharmaceutical
iodine was used for many years as a topical antiseptic
products
because of its higher iodine concentration, slow If a product is to be marketed, it must be stable over
release of iodine from the complex, lower toxicity, relatively long storage times at room temperature or
and its ability to stabilize and protect the iodine from at the actual temperature at which it will be shipped
degradation before application. and stored prior to its ultimate use. Thus, the rate
of degradation may have to be studied over an unde-
sirably long period of time in order to determine the
Surfactants
product’s stability under normal storage conditions.
It has been demonstrated that the incorporation To avoid this undesirable delay in evaluating
of benzocaine into surfactant micelles could retard possible formulations, the manufacturer attempts to
significantly the rate of ester hydrolysis. Nonionic predict stability under conditions of room tempera-
and anionic surfactants retarded the hydroxide-ion- ture or actual storage conditions by using data for
catalyzed hydrolysis, but cationic surfactants some- the rate of decomposition obtained at several elevated
what increased the rate of hydroxide-ion-catalyzed temperatures. This is accomplished using an Arrhe-
hydrolysis. Similar observations have been reported nius plot to predict, from high-temperature data, the
for a number of drugs that are sufficiently lipophilic rate of product breakdown to be expected at actual
to be solubilized by surfactant micelles. lower temperature storage conditions.
Prediction based on data obtained at elevated
temperatures generally is satisfactory for solution
Suspensions
dosage forms. Success is more uncertain when non-
If the solubility of a labile drug is reduced and the homogeneous products are involved. Suspensions of
drug is prepared in a suspension form, the rate at drugs may not provide linear Arrhenius plots because
which the drug degrades will be related only to the often there is the possibility that the solid phase,
concentration of dissolved drug rather than to the which exists at elevated temperature, may not be
total concentration of drug in the product. Thus it the same solid phase that exists at room tempera-
has been demonstrated that penicillin G procaine ture. Such differences in the solubility of the several
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250 | An Introduction to Pharmacy

solid phases may invalidate the usual Arrhenius plots

due to a change in mechanism as the phase changes
with increase in temperature. These difficulties should
be anticipated when polymorphic crystal forms or
several different solvates are known to exist for a slope = –Ea /R

In k
specific solute. Also, when solid dosage forms (e.g.,
tablets) are subjected to high temperatures, changes
in the quantity of moisture in the product may greatly
influence the stability of the product.
Arrhenius plots also suffer limitations when
applied to reactions that have relatively low acti-
1/T (K–1)
vation energies and, therefore, are not accelerated
greatly by an increase in temperature. Where usually
Figure 7.22 Variation of the rate constant with reciprocal
it is desirable to determine drug stability by analyzing
absolute temperature, illustrating the Arrhenius equation.
samples for the amount of intact drug remaining (in
instances where there is very little drug decomposi-
tion and particularly when it is not convenient to
Cl NH3 H3N Cl
accelerate the reaction by increasing temperature)
Pt Pt
it sometimes is advantageous to determine initial Cl NH3 Cl NH3
reaction rates from the determination of the amount
Cisplatin Transplatin
of reaction product formed.
Using modern methods of analysis, such as high- Figure 7.23 A coordination complex is called a chelate if
performance liquid chromatography (HPLC), it is the same substrate (metal ion) binds with two or more sites on
often possible to measure the rate of formation of a ligand.
a degradation product. By using this technique, very
small amounts of degradation (less than 1% loss of
parent compound) can be detected, resulting in a more blies formed by combination of substrates, S, and
sensitive indication of product stability than can be ligands, L. Most often, complex (Sm Ln ) formation is
obtained by analyzing potency. a reversible process:
Because manufacturers are interested primarily
mS + nL  Sm Ln (7.104)
in the time required to produce just a few-percent
breakdown in their product, it is not uncommon to where m substrate molecules, associate with n ligand
employ terminology such as t0.90 or t0.95 , which is molecules to form a complex of m:n stoichiometry. In
the time required for the drug to decompose to 90 or this context, complex formation, complexation, bind-
95%, respectively, of original potency. ing, association, and chelation are often synonymous.
An Arrhenius-type plot, analogous to that illus- The substrate and ligand are kept together by rela-
trated in Fig. 7.22 can be obtained by plotting the tively strong coordinate covalent bonds or by weak
natural logarithm of the specific rate constants versus non-covalent forces such as hydrogen bonding, van
the reciprocal of absolute temperature. The rate con- der Waals forces, electrostatic interactions, dipole
stant at the temperature of interest can be determined forces, charge transfer, release of conformational
and applied to the appropriate kinetic model to deter- strain, or hydrophobic interactions. The complex for-
mine the time required for the product to decrease in
mation changes the physicochemical properties of its
potency to 90% of original potency.
constituents, both of the substrate and the ligand,
including their aqueous solubility, molar absorptiv-
Complex formation ity, NMR chemical shifts, adsorption to solid surfaces,
partitioning behavior, conductivity, chemical reactiv-
In chemistry and chemical processes the word com- ity and/or pKa values. By studying such properties,
plex usually refers to molecules or molecular assem- for example of the substrate as a function of the
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Pharmaceutics | 251

ligand concentration, the complex can be identified carboxylic acid function can be shown to interact
and quantitatively described. Furthermore, the meth- with the pyridine nitrogen.
ods of chemical kinetics and thermodynamics can be
applied to describe the formation and dissociation of
a complex. Although most frequently substrate and
Interfacial phenomena
ligand molecules are associated by weak chemical
Very often it is desirable or necessary in the devel-
forces, there are complexes where bonds are quite
opment of pharmaceutical dosage forms to produce
strong and formation of some metal complexes are
multiphasic dispersions by mixing together two or
virtually irreversible. Complexes are usually broadly
more ingredients that are not mutually miscible and
classified into two groups based on type of S–L bond-
capable of forming homogeneous solutions. Examples
ing involved, namely coordination complexes and
of such dispersions include
molecular complexes.
Coordination complexes consist of ionic sub-
• Suspensions (solid in liquid)
strates, most frequently transition metal ions, with
• Emulsions (liquid in liquid)
bases or, in other words, products of Lewis acid–base
• Foams (vapor in liquids).
reactions where the metal ion (an acid) accepts a pair
of electrons from the ligand (the base) to form a coor- Because these systems are not homogeneous and
dinate covalent bond. Examples of such complexes thermodynamically stable, over time they will show
are [Ag(NH3 )2 ]+ , [Co(NH3 )6 ]3+ and [Fe(CN)6 ]4– . some tendency to separate on standing. By doing so,
Other common types of coordination complexes are this produces the minimum possible surface area of
organometallic complexes that are complexes formed contact between phases. Thus, suspended particles
between organic groups and metal atoms such as agglomerate and sediment, emulsified droplets cream
vitamin B12 (a porphyrin containing a cobalt atom), and coalesce, and the bubbles dispersed in foams col-
and cluster complexes where the central metal ion lapse to produce unstable and nonuniform dosage
consists of a three-dimensional cell of several directly forms. One way to prevent or slow down this nat-
bonded metal ions such as triruthenium dodecacar- ural tendency for further phase separation is to add
bonyl (Ru3 (CO)12 ). materials that can accumulate at the interface to pro-
Molecular complexes consist of non-covalently vide some type of energy barrier to aggregation and
bound substrates and ligands. These include com- coalescence. Such materials are said to exhibit surface
plexes of relatively small substrates and ligands activity or to act as surface-active agents.
such as drug–cyclodextrin complexes, complexes
between small substrates and a large ligand such
Colloidal dispersions
as drug–protein complexes (e.g., plasma protein
binding) and complexes between large substrates and The British chemist Thomas Graham applied the term
a small ligand such as some protein–polyalcohol ‘‘colloid’’ (derived from the Greek word for glue)
complexes. Molecular complexes also include molec- about 1850 to polypeptides such as albumin and
ular dimers, ion-pairs, intramolecular interactions gelatin, to polysaccharides such as acacia, starch,
(such as base–base interactions in the DNA helix) and dextrin, and to inorganic compounds such as
and clathrate compounds (cage compounds) where gelatinous metal hydroxides and Prussian blue (fer-
a cage-like lattice of one type of molecules (e.g., ric ferrocyanide). Contemporary colloid and surface
hydroquinone molecule) entraps a second type of chemistry deals with an unusually wide variety of
molecules (e.g., methanol molecule). Pharmaceutical industrial and biological systems.
co-crystals can also be considered a type of molecular Within the field of pharmacy, the colloidal systems
complex with components subjected to hydrogen we commonly come across include some protein and
bonding and other forces in the crystal lattice. polymer solutions, micellar systems, liquid crystals
Examples of these types of molecular complexes and emulsions, suspensions, aerosols, foams and other
include isoniazid and 4-aminosalicylic acid where the drug delivery systems that fall within the colloidal size
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252 | An Introduction to Pharmacy

range. In some instances, what was formally referred An appreciable fraction of atoms, ions, or
to as colloidal systems have been replaced by the term molecules of colloidal particles are located in the
nanotechnology (structures that have one or more boundary layer between the particle and the disper-
dimension between approximately 1 and 100 nm). sion medium. The boundary layer between a particle
and air is commonly referred to as a surface, whereas
the boundary layer between a particle and a liquid
Colloidal systems and interfaces or solid is commonly referred to as an interface. The
ions or molecules within the particle and within the
Except for high-molecular-weight polymers, most medium are surrounded on all sides by similar ions
soluble substances can be prepared as either low- or molecules and have balanced force fields; however,
molecular-weight solutions, colloidal dispersions, or the ions or molecules at surfaces or interfaces
coarse suspensions, depending upon the choice of dis- are subjected to unbalanced forces of attraction.
persion medium and dispersion technique. Colloidal Consequently, a surface free-energy component is
dispersions consist of at least two phases: one or added to the total free energy of colloidal particles
more dispersed or internal phases, and a continuous and becomes important as the particles become
or external phase called the dispersion medium or smaller and a greater fraction of their atoms, ions,
vehicle. Colloidal dispersions are distinguished from or molecules are located in the surface or interfacial
solutions and coarse dispersions by the particle region. As a result, the solubility of very fine solid
size of the dispersed phase, not its composition. particles and the vapor pressure of very small
Whilst somewhat arbitrary, colloidal dispersions can liquid droplets are greater than the corresponding
be characterized as containing particles in the size values for coarse particles and drops of the same
range of between approximately 1 nm and 1 μm; materials.
however, a smaller size range of up to 500 nm is
also quoted. Thus, blood, cell membranes, micelles,
thinner nerve fibers, milk, rubber latex, fog, and beer Coarse dispersions
foam are colloidal systems. Some materials, such as
emulsions and suspensions of most organic drugs, are For the purpose of the present discussion, a dispersed
coarser than true colloidal systems but exhibit similar system, or dispersion, will be regarded as a two-phase
behavior. Even though serum albumin, acacia, and system in which one phase is distributed as parti-
povidone form true or molecular solutions in water, cles or droplets in the second, or continuous, phase.
the size of the individual solute molecules places such In these systems, the dispersed phase frequently is
solutions in the colloidal range (particle size >1 nm). referred to as the discontinuous or internal phase,
In general, there are several features that distin- and the continuous phase is called the external phase
guish colloidal dispersions from coarse suspensions or dispersion medium. Discussion will be restricted
and emulsions. Colloidal particles are usually too to those solid–liquid and liquid–liquid dispersions
small for visibility in a light microscope, because at that are of pharmaceutical significance, namely, sus-
least one of their dimensions measures 1 μm or less. pensions and emulsions. However, more complicated
They are, however, often visible in an ultramicro- phase systems (e.g., a combination of liquid and liquid
scope, and almost always in an electron microscope. crystalline phases) can exist in emulsions.
Conversely, coarse suspended particles are usually All dispersions may be classified into three groups
visible to the naked eye and always in a light micro- based of the size of the dispersed particles. One such
scope. In addition, colloidal particles, as opposed to group, colloidal dispersions, is where the size of the
coarse particles, pass through ordinary filter paper but dispersed particles is in the range of approximately
are retained by dialysis or ultrafiltration membranes. 1 nm to 0.5 μm. Molecular dispersions are the second
Also, unlike coarse particles, colloidal particles diffuse group in this classification. The third group, consisting
very slowly and undergo little or no sedimentation or of coarse dispersions in which the particle size exceeds
creaming. Brownian motion maintains the dispersion 0.5 μm, is the subject of this discussion. Knowledge
of the colloidal internal phases. of coarse dispersions is essential for the preparation
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Pharmaceutics | 253

of both pharmaceutical suspensions (solid–liquid dis- (pouring or spreading) suspension or emulsion in

persions) and emulsions (liquid–liquid dispersions). which dispersion of particles can be effected with
Table 7.5 contains examples of pharmaceutical minimum expenditure of energy.
suspensions and emulsions. Pharmaceutical course In preparing suspensions, particle–particle attrac-
dispersions are administered via several routes of tive forces need to be overcome by the high shearing
administration and include many different types of action of such devices as the colloid mill, or by use of
active ingredients. surface-active agents. The latter greatly facilitate wet-
ting of lyophobic powders and assist in the removal of
The dispersion step surface air that shearing alone may not remove; thus,
The pharmaceutical formulator is concerned primar- the clumping tendency of the particles is reduced.
ily with producing a smooth, uniform, easily flowing Moreover, lowering of the surface free energy by the

Table 7.5 Examples of pharmaceutical/cosmetic suspension and emulsion products

Suspensions Emulsions

Name Route of Name Route of

administration administration

Milk of Magnesia® (magnesium Oral Mineral Oil Oral

hydroxide)

Nystatin Oral Suspension, USP Oral Restasis® (cyclosporine ophthalmic Eye

emulsion)

Cortisporin® Ophthalmic and Otic Ear, eye Intralipid®,Liposyn® (intravenous Intravenous

suspensions (neomycin/ fat emulsion)
polymyxin, bacitracin, hydrocortisone)

Ibuprofen oral suspension, USP Oral Lipomul® Oral

Tobradex® (tobramycin, Eye Simethicone Emulsion, USP Oral,-manufacturing aid

dexamethasone)

Tussionex® Oral Propofol Injectable Emulsion, USP Intravenous

(chlorpheniramine/hydrocodone
sustained release)

Prednisolone Acetate Ophthalmic Eye Lubriderm® (emollient) Topical

Suspension, USP

NPH Insulin Subcutaneous Lidocaine/Prilocaine cream (EMLA®) Topical

Sterile Procaine Penicillin G Injectable Intramuscular Diazemuls® (diazepam) Intravenous

Suspension, USP

Griseofulvin Oral Suspension, USP Oral

Phenytoin Oral Suspension, USP Oral

Sulfamethoxazole/Trimethoprim Oral Oral

Suspension
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254 | An Introduction to Pharmacy

adsorption of these agents directly reduces the ther- where F is the increase in surface free energy in ergs,
modynamic driving force opposing dispersion of the A is the increase in surface area in cm2 , and γ is the
particles. interfacial tension in dyn cm−1 , between the dispersed
In emulsification, shear rates are frequently nec- particle or droplet and the dispersion medium. The
essary for dispersion of the internal phase into fine smaller F is, the more thermodynamically stable
droplets. The shear forces are opposed by forces oper- is the suspension of particles. A reduction in F is
ating to resist distortion and subsequent breakup effected often by the addition of a wetting agent which
of the droplets. Again surface-active agents help is adsorbed at the interface between the particle and
greatly by lowering interfacial tension, which is the the vehicle, thereby reducing the interfacial tension.
primary reversible component resisting droplet distor- This causes the particles to remain dispersed and
tion. Surface-active agents also may play an important settle relatively slowly. Unfortunately, in solid–liquid
role in determining whether an oil-in-water (O/W) or suspensions, the particles can form a hard cake at the
a water-in-oil (W/O) emulsion preferentially survives bottom of the container when they eventually settle.
the shearing action. Such a sediment, which can be extremely difficult to
Once the process of dispersion begins there devel- redisperse, can lead to dosing errors when the product
ops simultaneously a tendency for the system to is administered to the patient.
revert to an energetically more stable state, man-
ifested by flocculation, coalescence, sedimentation, Surface potential
crystal growth, and caking phenomena. If these phys- Both attractive and repulsive forces exist between
ical changes are not inhibited or controlled, successful particles in a liquid medium. The balance between
dispersions will not be achieved or will be lost during these opposing forces determines whether two par-
shelf-life. ticles approaching each other actually make contact
or are repulsed at a certain distance of separation.
Interfacial properties
Although much of the theoretical work on electrical
Because suspensions and emulsions are dispersions surface potentials has been carried out on lyophobic
of one phase within another, the process of disper- colloids, the theories developed in this area have been
sion creates a tremendous increase in interfacial area applied to suspensions and emulsions.
between the dispersed particles or droplets and the
dispersion medium. When considering the interfacial
properties of dispersed particles, two factors must be Suspensions
taken into account, regardless of whether the dis- A pharmaceutical suspension may be defined as a
persed phase is solid or liquid. The first relates to an coarse dispersion containing finely divided insoluble
increase in the free energy of the surface as the particle material suspended in a liquid medium. Because some
size is reduced and the specific surface increased. The
products occasionally are prepared in a dry form to
second deals with the presence of an electrical charge
be placed in suspension at the time of dispensing
on the surface of the dispersed particles.
by the addition of an appropriate liquid vehicle, this
definition is extended to include these products.
Surface free energy Suspension dosage forms are given by the oral
route, injected intramuscularly or subcutaneously,
When solid and liquid materials are reduced in size,
instilled intranasally, inhaled into the lungs, applied
they tend to agglomerate or stick together. This
to the skin as topical preparations, or used for oph-
clumping, which can occur either in an air or liq-
thalmic or otic purposes in the eye or ear, respectively.
uid medium, is an attempt by the particles to reduce
They are an important class of dosage form which can
the excess free energy of the system. The increase in
offer several advantages. Suspensions offer an alterna-
surface free energy is related to the increase in surface
tive oral dosage form for patients who cannot swallow
area produced when the mean particle size is reduced.
a tablet or capsule such as pediatric and geriatric
It may be expressed as
patients. Oral antibiotics, analgesic and antipyretic
F = γ A (7.105) drugs are commonly administered as suspensions to
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Pharmaceutics | 255

these groups of patients. Suspensions are often used The addition of a preferentially adsorbed ion
to deliver poorly water-soluble drugs which cannot whose charge is opposite in sign to that on the par-
be formulated as aqueous solutions. In early drug ticle leads to a progressive lowering of ζ . At some
development studies of potentially new drug candi- concentration of the added ion, the electrical forces
dates, suspension dosage forms are frequently used of repulsion are lowered sufficiently and the forces
to deliver drugs to animals, particularly when the of attraction predominate. Under these conditions the
drug is given orally. In addition, drugs that have an particles may approach each other more closely and
unpleasant taste may preferably be formulated as a form loose aggregates, termed flocs. Such a system is
suspension to reduce interaction of drug with taste said to be flocculated.
receptors in the mouth. Because suspended drug must Some workers restrict the term ‘‘flocculation’’ to
undergo a dissolution step prior to crossing biological the aggregation brought about by chemical bridging;
membranes, suspensions offer a way to provide sus- aggregation involving a reduction of repulsive poten-
tained release of drug by parenteral, topical, and oral tial at the double layer is referred to as coagulation.
routes of administration. Other workers regard flocculation as aggregation in
There are certain criteria that a well-formulated the secondary minimum of the potential energy curve
suspension should meet. The dispersed particles of two interacting particles and coagulation as aggre-
should be of such a size that they do not settle gation in the primary minimum. In the present chapter
rapidly in the container. However, in the event that the term flocculation is used for all aggregation pro-
sedimentation does occur, the sediment must not cesses, irrespective of mechanism.
form a hard cake. Rather, it should be capable of The continued addition of the flocculating agent
redispersion with a minimum of effort on the part can reverse the above process, if the zeta potential
of the patient. Finally, the product should be easy increases sufficiently in the opposite direction. Thus,
to pour, have a pleasant taste, and be resistant to the adsorption of anions onto positively charged,
microbial attack. deflocculated particles in suspension will lead to floc-
The three major concerns associated with suspen- culation. The addition of more anions eventually can
sions are: generate a net negative charge on the particles. When
this has achieved the required magnitude, defloccula-
tion may occur again. The only difference from the
1. Ensuring adequate dispersion of the particles in
starting system is that the net charge on the parti-
the vehicle
cles in their deflocculated state is negative rather than
2. Minimizing settling of the dispersed particles
positive. Some of the major differences between sus-
3. Preventing caking of these particles when a sedi-
pensions of flocculated and deflocculated particles are
ment forms.
presented in Table 7.6.

Much of the following discussion will deal with the Flocculation kinetics
factors that influence these processes and the ways in The rate at which flocculation occurs is a considera-
which settling and caking can be minimized. tion in the stability of suspended dispersions. Whether
flocculation is judged to be rapid or slow depends on
Flocculation and deflocculation the presence of a repulsive barrier between adjacent
Zeta potential, ζ , is a measurable indication of particles. In the absence of such a barrier, and for a
the potential existing at the surface of a particle. monodispersed system, rapid flocculation occurs at a
When ζ is relatively high (25 mV or more), the rate given by the Smoluchowski equation.
repulsive forces between two particles exceed the
δN/δt = −4 π DRN2 (7.106)
attractive London forces. Accordingly, the particles
are dispersed and are said to be deflocculated. Even where δN/δt is the disappearance rate of particles per
when brought close together by random motion or mL, R is the distance between the centers of the two
agitation, deflocculated particles resist collision due particles in contact, N is the number of particles per
to their high surface potential. mL, and D is the diffusion coefficient. Under these
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256 | An Introduction to Pharmacy

Table 7.6 Relative properties of flocculated and deflocculated particles in suspension

Deflocculated Flocculated

1. Particles exist in suspension as separate entities. 1. Particles form loose aggregates.

2. Rate of sedimentation is slow, as each particle settles 2. Rate of sedimentation is high, as particles settle as a floc, which is a
separately and particle size is minimal. collection of particles.

3. A sediment is formed slowly. 3. A sediment is formed rapidly.

4. The sediment eventually becomes very closely packed, due 4. The sediment is packed loosely and possesses a scaffold-like
to weight of upper layers of sedimenting material. Repulsive structure. Particles do not bond tightly to each other and a hard,
forces between particles are overcome and a hard cake is dense cake does not form. The sediment is easy to redisperse, so as to
formed that is difficult, if not impossible, to redisperse. reform the original suspension.

5. The suspension has a pleasing appearance, as the 5. The suspension is somewhat unsightly, due to rapid sedimentation
suspended material remains suspended for a relatively long and the presence of an obvious, clear supernatant region. This can be
time. The supernate also remains cloudy, even when settling minimized if the volume of sediment is made large. Ideally, volume of
is apparent. sediment should encompass the volume of the suspension.

conditions the rate is proportional to the square of many months and even years, even though they are
the particle concentration. The presence or absence thermodynamically unstable.
of an energy barrier is influenced strongly by the type In recent years, it has been recognized that com-
and concentration of any electrolyte present. When an plex multiple-phase combinations can exist in emul-
energy barrier does exist between adjacent particles, sions. Thus, liquid crystalline phases and gel structures
the flocculation rate likely will be much smaller than can form from the combination of the basic three-
predicted by equation (7.106). component mixture of water, oil, and surfactant
(emulsifying agent). Often, these structures confer
significant stability to the emulsion and therefore are
Emulsions
to be desired. Such multiple-phase emulsions and their
An emulsion is a dispersed system containing at least stability have been reviewed by Eccleston.41
two immiscible liquid phases. The majority of conven- Emulsions are widely used in pharmacy and
tional emulsions in pharmaceutical use have dispersed medicine, and emulsified materials can possess
particles ranging in diameter from 0.1 to 100 μm. As advantages not observed in formulations in other
with suspensions, emulsions are thermodynamically dosage forms. For example, certain medicinal agents
unstable as a result of the excess free energy associ- that have an objectionable taste have been made more
ated with the surface of the droplets. The dispersed palatable for oral administration when formulated
droplets, therefore, strive to come together and reduce in an emulsion. The principles of emulsification
the surface area. In addition to this flocculation effect, have been applied extensively in the formulation
also observed with suspensions, the dispersed par- of dermatological creams and lotions. Intravenous
ticles can coalesce, or fuse, and this can result in emulsions of contrast media have been developed to
the eventual destruction of the emulsion. To mini- assist the physician in undertaking X-ray examina-
mize this effect, a third component, the emulsifying tions of the body organs while exposing the patient
agent, is added to the system to improve its sta- to the minimum of radiation. Considerable attention
bility. The choice of emulsifying agent is critical to has been directed towards the use of sterile, stable
the preparation of an emulsion possessing optimum intravenous emulsions containing fat, carbohydrate,
stability. The efficiency of present-day emulsifiers per- and vitamins all in one preparation. Such products
mits the preparation of emulsions that are stable for are administered to patients unable to assimilate these
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Pharmaceutics | 257

vital materials by the normal oral route. Emulsions F is the force acting upon each of these materials of
are also used to deliver nutrients via the enteral mass m, and a is the acceleration of the center of mass
route in the form of nutritional supplements. More of each material. Since F is proportional to m, a is the
recently, emulsions have been used to deliver poorly same for each of these materials. Consequently, these
water-soluble drugs, such as general anesthetics and three bodies fall toward the table in exactly the same
anti-cancer compounds, via the intravenous route. manner. Their material differences do not become
Emulsions offer potential in the design of apparent until they reach the tabletop. At that point,
systems capable of giving controlled rates of drug the pencil rebounds somewhat, the plasticine stays
release and affording protection to drugs susceptible put, and the water spreads over the tabletop and,
to oxidation or hydrolysis. There is still a need on reaching the edge, flows off. These very different
for well-characterized dermatologic products with outcomes, which mechanics is unable to explain, are
reproducible properties, regardless of whether the focus of rheology.
these products are antibacterial, sustained-release, The ubiquity of rheological phenomena in phar-
protective, or emollient lotions, creams, or ointments. macy is evident in the levigation or mixing of oint-
In addition, emulsions may provide a useful way to ments on slabs, the use of a mortar and pestle to
deliver poorly water-soluble drugs via enteral and prepare suspensions and emulsions, the flow of emul-
parenteral routes. The principle of emulsification is sions through colloid mills and pumps, the use of
also involved in an increasing number of aerosol roller mills for compacting powders or processing
products. ointments, and the mechanical properties of glass or
The pharmacist must be familiar with the types of plastic containers and of rubber or polymeric clo-
emulsions and the properties and theories underlying sures. Squeezing ointments, creams, or toothpaste
their preparation and stability. from a collapsible tube, spreading lotion on the skin,
or spraying liquids from atomizers or aerosol cans
all involve rheological phenomena. The fluidity of
Rheology solutions to be injected by syringe or infused intra-
venously, the flexibility of tubing used in catheters,
Rheology is the branch of physics that deals with and the strength of sutures and ligatures are impor-
deformation, including flow, of matter. Although this tant rheological properties. Drug release from dosage
definition was proposed in 1929, the recognition of forms and delivery systems is often controlled or mod-
rheological phenomena dates back to antiquity.44 The ulated by the rheological properties of the formulation
earliest application of rheology (ca. 1600 BC) is asso- matrix. Diffusion, a process occurring at the molec-
ciated with the Egyptian Amenemhet, who made a ular level, is governed, in part, by the rheological
7◦ correction to the drainage angle of a water clock behavior of the molecule’s environment. Rheologi-
in order to account for the temperature-dependent cal principles govern the circulation of blood and
variation in water flow during the course of a day. lymph through capillaries and large vessels, the flow
Archimedes’s claim (ca. 250 BC) ‘‘Give me but one of mucus, the transit of the luminal contents through
firm spot on which to stand, and I will move the the gastrointestinal tract, the bending of bones, the
earth.’’ was based on the application of solid mechan- stretching of cartilage, and the contraction of muscles.
ics, the oldest branch of the physical sciences.45 The centrality of rheological behavior to many
Reiner46 describes a simple mechanical experi- unit operations in pharmaceutical manufacturing,
ment in which he lets three different materials – a to drug product functionality and stability, and to
pencil, a ball of plasticine, and a known mass of patient or consumer use of dosage forms and delivery
water – fall from some height onto the surface of a systems necessitates a thorough understanding of rhe-
table. Newton’s second law tells us that F = ma, where ology and the measurement of rheological behavior.
 hemolytic effects of certain medicinals in aqueous solution
Appendix A: sodium chloride equivalents, freezing-point depressions, and

258
|
0.5 % 1% 2% 3% 5% Iso-osmotic concentrationa

An Introduction to Pharmacy
E D E D E D E D E D % E D H pH

Acetrizoate methylglucamine 0.09 0.08 0.08 0.08 0.08 12.12 0.07 0 7.1

Acetrizoate sodium 0.10 0.027 0.10 0.055 0.10 0.109 0.10 0.163 0.10 0.273 9.64 0.09 0.52 0 6.9†

Acetylcysteine 0.20 0.055 0.20 0.113 0.20 0.227 0.20 0.341 4.58 0.20 0.52 100* 2.0

Adrenaline HCl 4.24 68 4.5

Alphaprodine HCl 0.19 0.053 0.19 0.105 0.18 0.212 0.18 0.315 4.98 0.18 0.52 100 5.3

Alum (potassium) 0.18 0.15 0.15 6.35 0.14 24* 3.4

Amantadine HCl 0.31 0.090 0.310 0.180 0.31 0.354 2.95 0.31 0.52 91 5.7

Aminoacetic acid 0.42 0.119 0.41 0.235 0.41 0.47 2.20 0.41 0.52 0* 6.2

Aminohippuric acid 0.13 0.035 0.13 0.075

Aminophylline 0.098c

Ammonium carbonate 0.70 0.202 0.70 0.405 1.29 0.70 0.52 97 7.7

Remington_Pharmacy
Ammonium chloride 1.12 0.8 1.12 0.52 93 5.0

Ammonium lactate 0.33 0.093 0.33 0.185 0.33 0.37 2.76 0.33 0.52 98 5.9

Ammonium nitrate 0.69 0.200 0.69 0.400 1.30 0.69 0.52 91 5.3

c07.tex V1 - 04/08/2013
Ammonium phosphate, dibasic 0.58 0.165 0.55 0.315 1.76 0.51 0.52 0 7.9

(continued overleaf)

8:44 P.M. Page 258

 0.5 % 1% 2% 3% 5% Iso-osmotic concentrationa

E D E D E D E D E D % E D H pH

Ammonium sulfate 0.55 0.158 0.55 0.315 1.68 0.54 0.52 0 5.3

Amobarbital sodium 0.25 0.143c 0.25 3.6 0.25 0.52 0 9.3

d-Amphetamine HCl 2.64 98 5.7

Amphetamine phosphate 0.34 0.20 0.27 0.47 3.47 0.26 0.52 0 4.5

Amphetamine sulfate 0.22 0.129c 0.21 0.36 4.23 0.21 0.52 0 5.9

Amprotropine phosphate 5.90 0 4.2

Amylcaine HCl 0.22 0.19 4.98 0.18 100 5.6

Anileridine HCl 0.19 0.052 0.19 0.104 0.19 0.212 0.18 0.316 0.18 0.509 5.13 0.18 0.52 12 2.6

Antazoline phosphate 6.05 90 4.0

Antimony potassium tartrate 0.18 0.13 0.10

Antipyrine 0.17 0.10 0.14 0.24 0.14 0.40 6.81 0.13 0.52 100 6.1

Remington_Pharmacy
Apomorphine HCl 0.14 0.080c

Arginine glutamate 0.17 0.048 0.17 0.097 0.17 0.195 0.17 0.292 0.17 0.487 5.37 0.17 0.52 0 6.9

Ascorbic acid 0.105c 5.05 0.52b 100* 2.2

Pharmaceutics

c07.tex V1 - 04/08/2013
Atropine methylbromide 0.14 0.13 0.13 7.03 0.13

Atropine methylnitrate 6.52 0 5.2

Atropine sulfate 0.13 0.075 0.11 0.19 0.11 0.32 8.85 0.10 0.52 0 5.0

|
Bacitracin 0.05 0.03 0.04 0.07 0.04 0.12

259

8:44 P.M. Page 259

(continued overleaf)
 260
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0.5 % 1% 2% 3% 5% Iso-osmotic concentrationa

An Introduction to Pharmacy
E D E D E D E D E D % E D H pH

Barbital sodium 0.30 0.171c 0.29 0.50 3.12 0.29 0.52 0 9.8

Benzalkonium chloride 0.16 0.14 0.13

Benztropine mesylate 0.26 0.073 0.21 0.115 0.15 0.170 0.12 0.203 0.09 0.242

Benzyl alcohol 0.17 0.09c 0.15

Bethanechol chloride 0.50 0.140 0.39 0.225 0.32 0.368 0.30 0.512 3.05 0.30 0 6.0

Bismuth potassium tartrate 0.09 0.06 0.05

Bismuth sodium tartrate 0.13 0.12 0.11 8.91 0.10 0 6.1

Boric acid 0.50 0.288c 1.9 0.47 0.52 100 4.6

Brompheniramine maleate 0.10 0.026 0.09 0.05 0.08 0.084

Bupivacaine HCl 0.17 0.048 0.17 0.096 0.17 0.193 0.17 0.29 0.17 0.484 5.38 0.17 0.52 83 6.8

Butabarbital sodium 0.27 0.078 0.27 0.155 0.27 0.313 0.27 0.47 3.33 0.27 0.52 0 6.8

Remington_Pharmacy
Butacaine sulfate 0.20 0.12 0.13 0.23 0.10 0.29

Caffeine and sodium benzoate 0.26 0.15 0.23 0.40 3.92 0.23 0.52 0 7.0

Caffeine and sodium salicylate 0.12 0.12 0.17 0.295 0.16 0.46 5.77 0.16 0.52 0 6.8

c07.tex V1 - 04/08/2013
Calcium aminosalicylate 4.80 0 6.0

Calcium chloride 0.51 0.298c 1.70 0.53 0.52 0 5.6

(continued overleaf)

8:44 P.M. Page 260

 0.5 % 1% 2% 3% 5% Iso-osmotic concentrationa

E D E D E D E D E D % E D H pH

Calcium chloride (6H2 O) 0.35 0.20 2.5 0.36 0.52 0 5.7

Calcium chloride, anhydrous 0.68 0.39 1.3 0.69 0.52 0 5.6

Calcium disodium edetate 0.21 0.061 0.21 0.120 0.21 0.240 0.20 0.357 4.50 0.20 0.52 0 6.1

Calcium gluconate 0.16 0.091c 0.14 0.24

Calcium lactate 0.23 0.13 0.12 0.36 4.5 0.20 0.52 0 6.7

Calcium lactobionate 0.08 0.022 0.08 0.043 0.08 0.085 0.07 0.126 0.07 0.197

Calcium levulinate 0.27 0.16 0.25 0.43 3.58 0 7.2

Calcium pantothenate 0.129 5.50 0 7.4

Camphor 0.12d

Capreomycin sulfate 0.04 0.011 0.04 0.02 0.04 0.042 0.04 0.063 0.04 0.106

Carbachol 0.205c 2.82 0 5.9

Remington_Pharmacy
Carbenicillin sodium 0.20 0.059 0.20 0.118 0.20 0.236 0.20 0.355 4.40 0.20 0.52 0 6.6

Carboxymethylcellulose sodium 0.03 0.007 0.03 0.017 0.145

Cephaloridine 0.09 0.023 0.07 0.041 0.06 0.074 0.06 0.106 0.05

Pharmaceutics

c07.tex V1 - 04/08/2013
Chloramine-T 4.10 100* 9.1

Chloramphenicol 0.06d

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Chloramphenicol sodium succinate 0.14 0.038 0.14 0.078 0.14 0.154 0.13 0.230 0.13 0.382 6.83 0.13 0.52 partial 6.1

Chlordiazepoxide HCl 0.24 0.068 0.22 0.125 0.19 0.220 0.18 0.315 0.17 0.487 5.50 0.16 0.52 66 2.7

Chlorobutanol (hydrated) 0.24 0.14

Chloroprocaine HCl 0.20 0.054 0.20 0.108 0.18 0.21

Chloroquine phosphate 0.14 0.039 0.14 0.082 0.14 0.162 0.14 0.242 0.13 0.379 7.15 0.13 0.52 0 4.3

Chloroquine sulfate 0.10 0.028 0.09 0.050 0.08 0.090 0.07 0.127 0.07 0.195

Chlorpheniramine maleate 0.17 0.048 0.15 0.085 0.14 0.165 0.13 0.22 0.09 0.265

Chlortetracycline HCl 0.10 0.030 0.10 0.061 0.10 0.121

Chlortetracycline sulfate 0.13 0.08 0.10 0.17

Citric acid 0.18 0.10 0.17 0.295 0.16 0.46 5.52 0.16 0.52 100* 1.8

Clindamycin phosphate 0.08 0.022 0.08 0.046 0.08 0.095 0.08 0.144 0.08 0.242 10.73 0.08 0.52 58* 6.8

Remington_Pharmacy
Cocaine HCl 0.16 0.090c 0.15 0.26 0.14 0.40 6.33 0.14 0.52 47 4.4

Codeine phosphate 0.14 0.080c 0.13 0.23 0.13 0.38 7.29 0.12 0.52 0 4.4

Colistimethate sodium 0.15 0.045 0.15 0.085 0.15 0.170 0.15 0.253 0.14 0.411 6.73 0.13 0.52 0 7.6

c07.tex V1 - 04/08/2013
Cupric sulfate 0.18 0.100c 0.15 0.14 6.85 0.13 trace* 3.9

Cyclizine HCl 0.20 0.060

Cyclophosphamide 0.10 0.031 0.10 0.061 0.10 0.125

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Cytarabine 0.11 0.034 0.11 0.066 0.11 0.134 0.11 0.198 0.11 0.317 8.92 0.10 0.52 0 8.0

Deferoxamine mesylate 0.09 0.023 0.09 0.047 0.09 -0.093 0.09 0.142 0.09 0.241

Demecarium bromide 0.14 0.038 0.12 0.069 0.10 0.108 0.08 0.139 0.07 0.192

Dexamethasone sodium phosphate 0.18 0.050 0.17 0.095 0.16 0.18 0.15 0.260 0.14 0.410 6.75 0.13 0.52 0 8.9

Dextroamphetamine HCl 0.34 0.097 0.34 0.196 0.34 0.392 2.64 0.34 0.52

Dextroamphetamine phosphate 0.25 0.14 0.25 0.44 3.62 0.25 0.52 0 4.7

Dextroamphetamine sulfate 0.24 0.069 0.23 0.134 0.22 0.259 0.22 0.380 4.16 0.22 0.52 0 5.9

Dextrose 0.16 0.091c 0.16 0.28 0.16 0.46 5.51 0.16 0.52 0 5.9

Dextrose (anhydrous) 0.18 0.101c 0.18 0.31 5.05 0.18 0.52 0 6.0

Diatrizoate sodium 0.10 0.025 0.09 0.049 0.09 0.098 0.09 0.149 0.09 0.248 10.55 0.09 0.52 0 7.9

Dibucaine HCl 0.074c

Remington_Pharmacy
Dicloxacillin sodium (1 H2 O) 0.10 0.030 0.10 0.061 0.10 0.122 0.10 0.182

Diethanolamine 0.31 0.089 0.31 0.177 0.31 0.358 2.90 0.31 0.52 100 11.3

Dihydrostreptomycin sulfate 0.06 0.03 0.05 0.09 0.05 0.14 19.4 0.05 0.52 0 6.1

Pharmaceutics

c07.tex V1 - 04/08/2013
Dimethpyrindene maleate 0.13 0.039 0.12 0.07 0.11 0.12

Dimethyl sulfoxide 0.42 0.122 0.42 0.245 0.42 0.480 2.16 0.42 0.52 100 7.6

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Diperodon HCl 0.15 0.045 0.14 0.079 0.13 0.141

Diphenhydramine HCl 0.161c 5.70 88* 5.5

Diphenidol HCl 0.16 0.045 0.16 0.09 0.16 0.180

Doxapram HCl 0.12 0.035 0.12 0.070 0.12 0.140 0.12 0.210

Doxycycline hyclate 0.12 0.035 0.12 0.072 0.12 0.134 0.11 0.186 0.09 0.264

Dyphylline 0.10 0.025 0.10 0.052 0.09 0.104 0.09 0.155 0.08 0.245

Echothiophate iodide 0.16 0.045 0.16 0.090 0.16 0.179

Edetate disodium 0.24 0.070 0.23 0.132 0.22 0.248 0.21 0.360 4.44 0.20 0.52 0 4.7

Edetate trisodium monohydrate 0.29 0.079 0.29 0.158 0.28 0.316 0.27 0.472 3.31 0.27 0.52 0 8.0

Emetine HCl 0.058c 0.17 0.29

Ephedrine HCl 0.30 0.165c 0.28 3.2 0.28 96 5.9

Remington_Pharmacy
Ephedrine sulfate 0.23 0.13 0.20 0.35 4.54 0.20 0.52 0 5.7

Epinephrine bitartrate 0.18 0.104 0.16 0.28 0.16 0.462 5.7 0.16 0.52 100* 3.4

Epinephrine hydrochloride 0.29 0.16b 0.26 3.47 0.26

c07.tex V1 - 04/08/2013
Ergonovine maleate 0.089c

Erythromycin lactobionate 0.08 0.020 0.07 0.040 0.07 0.078 0.07 0.115 0.06 0.187

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Ethyl alcohol 1.39 100 6.0

Ethylenediamine 0.253c 2.08 100* 11.4

Ethylmorphine HCl 0.16 0.088c 0.15 0.26 0.15 0.43 6.18 0.15 0.52 38 4.7

Eucatropine HCl 0.11d

Ferric ammonium citrate (green) 6.83 0 5.2

Floxuridine 0.14 0.040 0.13 0.076 0.13 0.147 0.12 0.213 0.12 0.335 8.47 0.12 0.52 3* 4.5

Fluorescein sodium 0.31 0.181c 0.27 0.47 3.34 0.27 0.52 0 8.7

Fluphenazine 2-HCl 0.14 0.041 0.14 0.082 0.12 0.145 0.09 0.155

D-Fructose 5.05 0* 5.9

Furtrethonium iodide 0.24 0.070 0.24 0.133 0.22 0.250 0.21 0.360 4.44 0.20 0.52 0 5.4

Galactose 4.92 0 5.9

Remington_Pharmacy
Gentamicin sulfate 0.05 0.015 0.05 0.030 0.05 0.060 0.05 0.093 0.05 0.153

D-Glucuronic acid 5.02 48* 1.6

Glycerin 0.203c 2.6 100 5.9

Pharmaceutics

c07.tex V1 - 04/08/2013
Glycopyrrolate 0.15 0.042 0.15 0.084 0.15 0.166 0.14 0.242 0.13 0.381 7.22 0.12 0.52 92* 4.0

Gold sodium thiomalate 0.10 0.032 0.10 0.061 0.10 0.111 0.09 0.159 0.09 0.250

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Hetacillin potassium 0.17 0.048 0.17 0.095 0.17 0.190 0.17 0.284 0.17 0.474 5.50 0.17 0.52 0 6.3

Hexafluorenium bromide 0.12 0.033 0.11 0.065

Hexamethonium tartrate 0.16 0.045 0.16 0.089 0.16 0.181 0.16 0.271 0.16 0.456 5.68 0.16 0.52

Hexamethylene sodium acetaminosalicylate 0.18 0.049 0.18 0.099 0.17 0.199 0.17 0.297 0.16 0.485 5.48 0.16 0.52 0* 4.0

Hexobarbital sodium 0.15c

Hexylcaine HCl 4.30 100 4.8

Histamine 2HCl 0.40 0.115 0.40 0.233 0.40 0.466 2.24 0.40 0.52 79* 3.7

Histamine phosphate 0.149c 4.10 0 4.6

Histidine HCl 3.45 40 3.9

Holocaine HCl 0.20 0.12

Homatropine hydrobromide 0.17 0.097c 0.16 0.28 0.16 0.46 5.67 0.16 0.52 92 5.0

Remington_Pharmacy
Homatropine methylbromide 0.19 0.11 0.15 0.26 0.13 0.38

4-Homosulfanilamide HCl 3.69 0 4.9

Hyaluronidase 0.01 0.004 0.01 0.007 0.01 0.013 0.01 0.02 0.01 0.033

c07.tex V1 - 04/08/2013
Hydromorphone HCl 6.39 64 5.6

Hydroxyamphetamine HBr 0.15d 3.71 92 5.0

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8-Hydroxyquinoline sulfate 9.75 59* 2.5

Hydroxystilbamidine isethionate 0.20 0.06 0.16 0.090 0.12 0.137 0.10 0.17 0.07 0.216

Hyoscyamine hydrobromide 6.53 68 5.9

Imipramine HCl 0.20 0.058 0.20 0.110 0.13 0.143

Indigotindisulfonate sodium 0.30 0.085 0.30 0.172

Intracaine HCl 4.97 85 5.0

Iodophthalein sodium 0.07c 9.58 100 9.4

Isometheptene mucate 0.18 0.048 0.18 0.095 0.18 0.196 0.18 0.302 4.95 0.18 0.52 0 6.2

Isoproterenol sulfate 0.14 0.039 0.14 0.078 0.14 0.156 0.14 0.234 0.14 0.389 6.65 0.14 0.52 trace 4.5

Kanamycin sulfate 0.08 0.021 0.07 0.041 0.07 0.083 0.07 0.125 0.07 0.210

Lactic acid 0.239c 2.30 100* 2.1

Remington_Pharmacy
Lactose 0.07 0.040c 0.08 0.09 9.75 0.09 0* 5.8

Levallorphan tartrate 0.13 0.036 0.13 0.073 0.13 0.143 0.12 0.210 0.12 0.329 9.40 0.10 0.52 59* 6.9

Levorphanol tartrate 0.12 0.033 0.12 0.067 0.12 0.136 0.12 0.203

Pharmaceutics

c07.tex V1 - 04/08/2013
Lidocaine HCl 0.13c 4.42 85 4.3

Lircomycin HCl 0.16 0.045 0.16 0.090 0.15 0.170 0.14 0.247 0.14 0.40 6.60 0.14 0.52 0 4.5

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Lobeline HCl 0.090*

Lyapolate sodium 0.10 0.025 0.09 0.051 0.09 0.103 0.09 0.157 0.09 0.263 9.96 0.09 0.52 0 6.5+

Magnesium chloride 0.45 2.02 0.45 0 6.3

Magnesium sulfate 0.17 0.094c 0.15 0.26 0.15 0.43 6.3 0.14 0.52 0 6.2

Magnesium sulfate, anhydrous 0.34 0.093 0.32 0.184 0.30 0.345 0.29 0.495 3.18 0.28 0.52 0 7.0

Mannitol 0.098c 5.07 0* 6.2

Maphenide HCl 0.27 0.075 0.27 0.153 0.27 0.303 0.26 0.448 3.55 0.25 0.52

Menadiol sodium diphosphate 4.36 0 8.2

Menadione sodium bisulfite 0.12d 5.07 0 5.3

Menthol

Meperidine HCl 0.125c 4.80 98 5.0

Remington_Pharmacy
Mepivacaine HCl 0.21 0.060 0.21 0.116 0.20 0.230 0.20 0.342 4.60 0.20 0.52 45 4.5

Merbromin 0.08b

Mercuric cyanide 0.15 0.06* 0.14 0.13

c07.tex V1 - 04/08/2013
Mersalyl

Mesoridazine besylate 0.10 0.024 0.07 0.04 0.05 0.058 0.04 0.071 0.03 0.087

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Metaraminol bitartrate 0.20 0.06 0.20 0.112 0.19 0.21 0.18 0.308 0.17 0.505 5.17 0.17 0.52 59 3.8

Methacholine chloride 0.184c 3.21 0 4.5

Methadone HCl 0.101c 8.59 100* 5.0

Methamphetamine HCl 0.213c 2.75 97 5.9

Methdilazine HCl 0.12 0.035 0.10 0.056 0.08 0.08 0.06 0.093 0.04 0.112

Methenamine 0.23 0.24 3.68 0.25 100 8.4

Methiodal sodium 0.24 0.068 0.24 0.136 0.24 0.274 0.24 0.41 3.81 0.24 0.52 0 5.9

Methitural sodium 0.26 0.074 0.25 0.142 0.24 0.275 0.23 0.407 3.85 0.23 0.52 78 9.8

Methocarbamol 0.10 0.03 0.10 0.06

Methotrimeprazine HCl 0.12 0.034 0.10 0.060 0.07 0.077 0.06 0.094 0.04 0.125

Methoxyphenamine HCl 0.26 0.075 0.26 0.150 0.26 0.300 0.26 0.450 3.47 0.26 0.52 96 5.4

Remington_Pharmacy
p-Methylaminoethanol-phenol tartrate 0.18 0.048 0.17 0.095 0.16 0.19 0.16 0.282 0.16 0.453 5.83 0.16 0.52 0 6.2

Methyldopate HCl 0.21 0.063 0.21 0.122 0.21 0.244 0.21 0.365 4.28 0.21 0.52 partial 3.0

Methylergonovine maleate 0.10 0.028 0.10 0.056

Pharmaceutics

c07.tex V1 - 04/08/2013
N-Methylglucamine 0.20 0.057 0.20 0.111 0.18 0.214 0.18 0.315 0.18 0.517 5.02 0.18 0.52 4 11.3

Methylphenidate HCl 0.22 0.065 0.22 0.127 0.22 0.258 0.22 0.388 4.07 0.22 0.52 66 4.3

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Methylprednisolone sodium succinate 0.10 0.025 0.09 0.051 0.09 0.102 0.08 0.143 0.07 0.20

Minocycline HCl 0.10 0.030 0.10 0.058 0.09 0.107 0.08 0.146

Monoethanolamine 0.53 0.154 0.53 0.306 1.70 0.53 0.52 100 11.4

Morphine HCl 0.15 0.086c 0.14

Morphine sulfate 0.14 0.079c 0.11 0.19 0.09 0.26

Nalorphine HCl 0.24 0.07 0.21 0.121 0.18 0.210 0.17 0.288 0.15 0.434 6.36 0.14 0.52 63 4.1

Naloxone HCl 0.14 0.042 0.14 0.083 0.14 0.158 0.13 0.230 0.13 0.367 8.07 0.11 0.52 35 5.2

Naphazoline HCl 0.27 0.14d 0.24 3.99 0.22 100 5.3

Neoarsphenamine 2.32 17 7.80

Neomycin sulfate 0.11 0.063c 0.09 0.16 0.08 0.232

Neostigmine bromide 0.22 0.127c 0.19 4.98 0 4.6

Remington_Pharmacy
Neostigmine methylsulfate 0.20 0.115c 0.18 0.17 5.22 0.17

Nicotinamide 0.26 0.148c 0.21 0.36 4.49 0.20 0.52 100 7.0

Nicotinic acid 0.25 0.144c

c07.tex V1 - 04/08/2013
Nikethamide 0.100c 5.94 100 6.9

Novobiocin sodium 0.12 0.033 0.10 0.057 0.07 0.073

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Oleandomycin phosphate 0.08 0.017 0.08 0.038 0.08 0.084 0.08 0.129 0.08 0.255 10.82 0.08 0.52 0 5.0

Orphenadrine citrate 0.13 0.037 0.13 0.074 0.13 0.144 0.12 0.204 0.10 0.285

Oxophenarsine HCl .67 trace* 2.3

Oxymetazoline HCl 0.22 0.063 0.22 0.124 0.20 0.232 0.19 0.335 4.92 0.18 0.52 86 5.7

Oxyquinoline sulfate 0.24 0.068 0.21 0.113 0.16 0.182 0.14 0.236 0.11 0.315

D-Pantothenyl alcohol 0.20 0.053 0.18 0.100 0.17 0.193 0.17 0.283 0.16 0.468 5.60 0.16 0.52 92 6.8

Papaverine HCl 0.10 0.061c

Paraldehyde 0.25 0.071 0.25 0.142 0.25 0.288 0.25 0.430 3.65 0.25 0.52 97 5.3

Pargyline HCl 0.30 0.083 0.29 0.165 0.29 0.327 0.28 0.491 3.18 0.28 0.52 91 3.8

Penicillin G, potassium 0.18 0.102c 0.17 0.29 0.16 0.46 5.48 0.16 0.52 0 6.2

Penicillin G, procaine 0.06d

Remington_Pharmacy
Penicillin G, sodium 0.18 0.100c 0.16 0.28 0.16 0.46 5.90 18 5.2

Pentazocine lactate 0.15 0.042 0.15 0.085 0.15 0.169 0.15 0.253 0.15 0.42

Pentobarbital sodium 0.145c 4.07 0 9.9

Pharmaceutics

c07.tex V1 - 04/08/2013
Pentolinium tartrate 0.09d 5.95 55* 3.4

Phenacaine HCl 0.09

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Pheniramine maleate 0.09d

Phenobarbital sodium 0.24 0.135c 0.23 0.40 3.95 0.23 0.52 0 9.2

Phenol 0.35 0.20 2.8 0.32 0.52 0* 5.6

Phentolamine mesylate 0.18 0.052 0.17 0.096 0.16 0.173 0.14 0.244 0.13 0.364 8.23 0.11 0.52 83 3.5

Phenylephrine HCl 0.32 0.184c 0.30 3.0 0.30 0 4.5

Phenylephrine tartrate 5.90 58* 5.4

Phenylethyl alcohol 0.25 0.070 0.25 0.141 0.25 0.283

Phenylpropanolamine HCl 0.38 0.219c 2.6 0.35 95 5.3

Physostigmine salicylate 0.16 0.090c

Physostigmine sulfate 0.074c

Pilocarpine HCl 0.24 0.138c 0.22 0.38 4.08 0.22 0.52 89 4.0

Remington_Pharmacy
Pilocarpine nitrate 0.23 0.132c 0.20 0.35 4.84 0.20 0.52 88 3.9

Piperocaine HCl 0.12d 5.22 65 5.7

Polyethylene glycol 300 0.12 0.034 0.12 0.069 0.12 0.141 0.12 0.216 0.13 0.378 6.73 0.13 0.52 53 3.8

c07.tex V1 - 04/08/2013
Polyethylene glycol 400 0.08 0.022 0.08 0.047 0.09 0.098 0.09 0.153 0.09 0.272 8.50 0.11 0.52 0 4.4

Polyethylene glycol 1500 0.06 0.015 0.06 0.036 0.07 0.078 0.07 0.120 0.07 0.215 10.00 0.09 0.52 4 4.1

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Polyethylene glycol 1540 0.02 0.005 0.02 0.012 0.02 0.028 0.03 0.047 0.03 0.094

Polyethylene glycol 4000 0.02 0.004 0.02 0.008 0.02 0.02 0.020 0.033 0.02 0.067

Polymyxin B sulfate 0.09 0.052 0.06 0.10 0.04 0.12

Polysorbate 80 0.02 0.005 0.02 0.010 0.02 0.02 0.020 0.032 0.02 0.055

Polyvinyl alcohol (99% hydrol) 0.02 0.004 0.02 0.008 0.02 0.020 0.02 0.035 0.03 0.075

Polyvinylpyrrolidone 0.01 0.003 0.010 0.006 0.01 0.01 0.01 0.017 0.01 0.035

Potassium acetate 0.59 0.172 0.59 0.342 1.53 0.59 0.52 0 7.6

Potassium chlorate 1.88 0 6.9

Potassium chloride 0.76 0.439c 1.19 0.76 0.52 0 5.9

Potassium iodide 0.34 0.196c 2.59 0.34 0.52 0 7.0

Potassium nitrate 0.56 0.324c 1.62 0.56 0 5.9

Remington_Pharmacy
Potassium phosphate 0.46 0.27 2.08 0.43 0.52 0 8.4

Potassium phosphate, monobasic 0.44 0.25 2.18 0.41 0.52 0 4.4

Potassium sulfate 0.44 2.11 0.43 0 6.6

Pharmaceutics

c07.tex V1 - 04/08/2013
Pralidoxime chloride 0.32 0.092 0.32 0.183 0.32 0.364 2.87 0.32 0.52 0 4.6

Prilocaine HCl 0.22 0.062 0.22 0.125 0.22 0.250 0.22 0.375 4.18 0.22 0.52 45 4.6

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Procainamide HCl 0.22 0.13 0.19 0.33 0.17 0.49

Procaine HCl 0.21 0.122c 0.19 0.33 0.18 5.05 0.18 0.52 91 5.6

Prochlorperazine edisylate 0.08 0.020 0.06 0.033 0.05 0.048 0.03 0.056 0.02 0.065

Promazine HCl 0.18 0.050 0.13 0.077 0.09 0.102 0.07 0.112 0.05 0.137

Proparacaine HCl 0.16 0.044 0.15 0.086 0.15 0.169 0.14 0.247 0.13 0.380 7.46 0.12 0.52

Propiomazine HCl 0.18 0.050 0.15 0.084 0.12 0.133 0.10 0.165 0.08 0.215

Propoxycaine HCl 6.40 16 5.3

Propylene glycol 2.00 100 5.5

Pyrathiazine HCl 0.22 0.065 0.17 0.095 0.11 0.123 0.08 0.140 0.06 0.17

Pyridostigmine bromide 0.22 0.062 0.22 0.125 0.22 0.250 0.22 0.377 4.13 0.22 0.52 0 7.2

Pyridoxine HCl 3.05 31* 3.2

Remington_Pharmacy
Quinacrine methanesulfonate 0.06c

Quinine bisulfate 0.09 0.05 0.09 0.16

Quinine dihydrochloride 0.23 0.130c 0.19 0.33 0.18 5.07 0.18 0.52 trace* 2.5

c07.tex V1 - 04/08/2013
Quinine hydrochloride 0.14 0.077c 0.11 0.19

Quinine and urea HCl 0.23 0.13 0.21 0.36 4.50 0.20 0.52 64 2.9

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Resorcinol 0.161c 3.30 96 5.0

Rolitetracycline 0.11 0.032 0.11 0.064 0.10 0.113 0.09 0.158 0.07 0.204

Rose Bengal 0.08 0.02 0.07 0.04 0.07 0.083 0.07 0.124 0.07 0.198 14.9 0.06 0.52

Rose Bengal B 0.08 0.022 0.08 0.044 0.08 0.087 0.08 0.131 0.08 0.218

Scopolamine HBr 0.12 0.07 0.12 0.21 0.12 0.35 7.85 0.11 0.52 8 4.8

Scopolamine methylnitrate 0.16 0.14 0.13 6.95 0.13 0 6.0

Secobarbital sodium 0.24 0.14 0.23 0.40 3.9 0.23 0.52 trace 9.8

Silver nitrate 0.33 0.190c 2.74 0.33 0.52 0* 5.0

Silver protein, mild 0.17 0.10 0.17 0.29 0.16 0.46 5.51 0.16 0.52 0 9.0

Silver protein, strong 0.06d

Sodium acetate 0.46 0.267 2.0 0.45 0.52

Remington_Pharmacy
Sodium acetazolamide 0.24 0.068 0.23 0.135 0.23 0.271 0.23 0.406 3.85 0.23 0.52

Sodium aminosalicylate 0.170c 3.27 0 7.3

Sodium ampicillin 0.16 0.045 0.16 0.090 0.16 0.181 0.16 0.072 0.16 0.451 5.78 0.16 0.52 0 8.5

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Sodium ascorbate 3.00 0 6.9

Sodium benzoate 0.40 0.230c 2.25 0.40 0.52 0 7.5

(continued overleaf)

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An Introduction to Pharmacy
E D E D E D E D E D % E D H pH

Sodium bicarbonate 0.65 0.375 1.39 0.65 0.52 0 8.3

Sodium biphosphate (H2 O) 0.40 0.23 2.45 0.37 0.52 0 4.1

Sodium biphosphate (2H2 O) 0.36 2.77 0.32 0 4.0

Sodium bismuth thioglycollate 0.20 0.055 0.19 0.107 0.18 0.208 0.18 0.303 0.17 0.493 5.29 0 8.3

Sodium bisulfite 0.61 0.35 1.5 0.61 0.52 0* 3.0

Sodium borate 0.42 0.241c 2.6 0.35 0.52 0 9.2

Sodium bromide 1.60 0 6.1

0.32 0.28 3.3 0.27 0 8.0

Sodium carbonate, monohydrated 0.60 0.346 1.56 0.58 0.52 100 11.1

Sodium cephalothin 0.18 0.05 0.17 0.095 0.16 0.179 0.15 0.259 0.14 0.400 6.80 0.13 0.52 partial 8.5

Sodium chloride 1.00 0.576c 1.00 1.73 1.00 2.88 0.9 1.00 0.52 0 6.7

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Sodium citrate 0.31 0.178c 0.30 0.52 3.02 0.30 0 7.8

Sodium colistimethate 0.16 0.045 0.15 0.087 0.14 0.161 0.14 0.235 0.13 0.383 6.85 0.13 0.52 0 8.4

Sodium hypophosphite 1.60 0 7.3

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Sodium iodide 0.39 0.222c 2.37 0.38 0.52 0 6.9

Sodium iodohippurate 5.92 0 7.3

(continued overleaf)

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 0.5 % 1% 2% 3% 5% Iso-osmotic concentrationa

E D E D E D E D E D % E D H pH

Sodium lactate 1.72 0 6.5

Sodium lauryl sulfate 0.10 0.029 0.08 0.046 0.07 0.068 0.05 0.086

Sodium mercaptomerin 5.30 0 8.4

Sodium metabisulfite 0.67 0.386c 1.38 0.65 0.52 5* 4.5

Sodium methicillin 0.18 0.050 0.18 0.099 0.17 0.192 0.16 0.281 0.15 0.445 6.00 0.15 0.52 0 5.8

Sodium nafcillin 0.14 0.039 0.14 0.078 0.14 0.158 0.13 0.219 0.10 0.285

Sodium nitrate 0.68 1.36 0.66 0 6.0

Sodium nitrite 0.84 0.480c 1.08 0.83 0* 8.5

Sodium oxacillin 0.18 0.050 0.17 0.095 0.16 0.177 0.15 0.257 0.14 0.408 6.64 0.14 0.52 0 6.0

Sodium phenylbutazone 0.19 0.054 0.18 0.104 0.17 0.202 0.17 0.298 0.17 0.488 5.34 0.17 0.52

Sodium phosphate 0.29 0.168 0.27 0.47 3.33 0.27 0.52 0 9.2

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Sodium phosphate, dibasic (2H2 O) 0.42 0.24 2.23 0.40 0.52 0 9.2

Sodium phosphate, dibasic (12H2 O) 0.22 0.21 4.45 0.20 0 9.2

Sodium propionate 0.61 0.35 1.47 0.61 0.52 0 7.8

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Sodium salicylate 0.36 0.210c 2.53 0.36 0.52 0 6.7

Sodium succinate 0.32 0.092 0.32 0.184 0.31 0.361 2.90 0.31 0.52 0 8.5

(continued overleaf)

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E D E D E D E D E D % E D H pH

Sodium sulfate, anhydrous 0.58 0.34 1.61 0.56 0.52 0 6.2

Sodium sulfite, exsiccated 0.65 0.38 1.45 0 9.6

Sodium sulfobromophthalein 0.07 0.019 0.06 0.034 0.05 0.060 0.05 0.084 0.04 0.123

Sodium tartrate 0.33 0.098 0.33 0.193 0.33 0.385 2.72 0.33 0.52 0 7.3

Sodium thiosulfate 0.31 0.181c 2.98 0.30 0.52 0 7.4

Sodium warfarin 0.18 0.049 0.17 0.095 0.16 0.181 0.15 0.264 0.15 0.430 6.10 0.15 0.52 0 8.1

Sorbitol (A H2 O) 5.48 0 5.9

Sparteine sulfate 0.10 0.03 0.10 0.056 0.10 0.111 0.10 0.167 0.10 0.277 9.46 0.10 0.52 19* 3.5

Spectinomycin HCl 0.16 0.045 0.16 0.092 0.16 0.185 0.16 0.280 0.16 0.460 5.66 0.16 0.52 3 4.4

Streptomycin HCl 0.17 0.10c 0.16 0.16

Streptomycin sulfate 0.07 0.036c 0.06 0.10 0.06 0.17

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Sucrose 0.08 0.047c 0.09 0.16 0.09 0.26 9.25 0.10 0.52 0 6.4

Sulfacetamide sodium 0.23 0.132c 0.23 0.40 3.85 0.23 0.52 0 8.7

Sulfadiazine sodium 0.24 0.14 0.24 0.38 4.24 0.21 0.52 0 9.5

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Sulfamerazine sodium 0.23 0.13 0.21 0.36 4.53 0.20 0.52 0 9.8

Sulfapyridine sodium 0.23 0.13 0.21 0.36 4.55 0.20 0.52 5 10.4

Sulfathiazole sodium 0.22 0.13 0.20 0.35 4.82 0.19 0.52 0 9.9

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Tartaric acid 0.143c 3.90 75* 1.7

(continued overleaf)
 0.5 % 1% 2% 3% 5% Iso-osmotic concentrationa

E D E D E D E D E D % E D H pH

Tetracaine HCl 0.18 0.109c 0.15 0.26 0.12 0.35

Tetracycline HCl 0.14 0.081c 0.10

Tetrahydrozoline HCl 4.10 60* 6.7

Theophylline 0.02*

Theophylline sodium glycinate 2.94 0 8.9

Thiamine HCl 0.139c 4.24 87* 3.0

Thiethylperazine maleate 0.10 0.030 0.09 0.050 0.08 0.089 0.07 0.119 0.05 0.153

Thiopental sodium 0.155c 3.50 74 10.3

Thiopropazate diHCl 0.20 0.053 0.16 0.090 0.12 0.137 0.10 0.170 0.08 0.222

Thioridazine HCl 0.06 0.015 0.05 0.025 0.04 0.042 0.03 0.055 0.03 0.075

Thiotepa 0.16 0.045 0.16 0.090 0.16 0.182 0.16 0.278 0.16 0.460 5.67 0.16 0.52 10* 8.2

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Tridihexethyl chloride 0.16 0.047 0.16 0.096 0.16 0.191 0.16 0.28 0.16 0.463 5.62 0.16 0.52 97 5.4

Triethanolamine 0.20 0.058 0.21 0.121 0.22 0.252 0.22 0.383 4.05 0.22 0.52 100 10.7

Trifluoperazine 2HCl 0.18 0.052 0.18 0.100 0.13 0.144

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Triflupromazine HCl 0.10 0.031 0.09 0.051 0.05 0.061 0.04 0.073 0.03 0.092

Trimeprazine tartrate 0.10 0.023 0.06 0.035 0.04 0.045 0.03 0.052 0.02 0.061

Trimethadione 0.23 0.069 0.23 0.133 0.22 0.257 0.22 0.378 4.22 0.21 0.52 100 6.0

|
Trimethobenzamide HCl 0.12 0.033 0.10 0.062 0.10 0.108 0.09 0.153 0.08 0.232

279

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(continued overleaf)
 Iso-osmotic concentrationa

280
0.5 % 1% 2% 3% 5%

E D E D E D E D E D % E D H pH

|
An Introduction to Pharmacy
Tripelennamine HCl 0.13d 5.50 100 6.3

Tromethamine 0.26 0.074 0.26 0.15 0.26 0.30 0.26 0.45 3.45 0.26 0.52 0 10.2

Tropicamide 0.10 0.03 0.09 0.050

Trypan blue 0.26 0.075 0.26 0.150

Tryparsamide 0.11c

Tubocurarine chloride 0.076c

Urea 0.59 0.34 1.63 0.55 0.52 100 6.6

Urethan 0.18b 2.93 100 6.3

Uridine 0.12 0.035 0.12 0.069 0.12 0.138 0.12 0.208 0.12 0.333 8.18 0.11 0.52 0* 6.1

Valethamate bromide 0.16 0.044 0.15 0.085 0.15 0.168 0.14 0.238 0.11 0.324

Vancomycin sulfate 0.06 0.015 0.05 0.028 0.04 0.049 0.04 0.066 0.04 0.098

Viomycin sulfate 0.08 0.05 0.07 0.12 0.07 0.20

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Xylometazoline HCl 0.22 0.065 0.21 0.121 0.20 0.232 0.20 0.342 4.68 0.19 0.52 88 5.0

Zinc phenolsulfonate 5.40 0* 5.4

Zinc sulfate 0.15 0.086c 0.13 0.23 0.12 0.35 7.65 0.12

c07.tex V1 - 04/08/2013
0.52

a The unmarked values were taken from Hammarlund et al.26 – 29 and Sapp et al.30
b Adapted from Lund et al.25
c Adapted from British Pharmaceutical Codex.31
d Obtained from several sources.

E, sodium chloride equivalents; D, freezing-point depression, ◦ C; H, hemolysis, %, at the concentration that is isoosmotic with 0.9% NaCl, based on freezing-point determination or equivalent test; pH,

8:44 P.M. Page 280

approximate pH of solution studied for hemolytic action; *, change in appearance of erythrocytes and/or solution30 – 32 ; † pH determined after addition of blood.
Note: See also Budavari S, ed. Merck Index, 11th edn, Rahway, NJ: Merck, 1988: MISC 79–103.
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Pharmaceutics | 281

Appendix B: isotonic solution values33

Drug (0.3 g) Water needed for Drug (0.3 g) Water needed for Drug (0.3 g) Water needed for
isotonicity (mL) isotonicity (mL) isotonicity (mL)

Alcohol 21.7 Epinephrine 6.0 Silver nitrate 11.0

bitartrate

Ammonium chloride 37.3 Epinephrine 9.7 Silver protein, mild 5.7

hydrochloride

Amobarbital sodium 8.3 Ethylmorphine 5.3 Sodium acetate 15.3

hydrochloride

Amphetamine 11.3 Fluorescein sodium 10.3 Sodium bicarbonate 21.7

phosphate

Amphetamine sulfate 7.3 Glycerin 11.7 Sodium 15.3

biphosphate,
anhydrous

Antipyrine 5.7 Holocaine 6.7 Sodium 13.3

hydrochloride biphosphate

Apomorphine 4.7 Homatropine 5.7 Sodium bisulfite 20.3

hydrochloride hydrobromide

Ascorbic acid 6.0 Homatropine 6.3 Sodium borate 14.0

methylbromide

Atropine 4.7 Hyoscyamine sulfate 4.7 Sodium iodide 13.0

methylbromide

Atropine sulfate 4.3 Neomycin sulfate 3.7 Sodium 22.3

metabisulfite

Bacitracin 1.7 Oxytetracycline 4.3 Sodium nitrate 22.7

hydrochloride

Barbital sodium 10.0 Penicillin G, 6.0 Sodium phosphate 9.7

potassium

Bismuth potassium 3.0 Penicillin G, sodium 6.0 Sodium propionate 20.3

tartrate

Boric acid 16.7 Pentobarbital 8.3 Sodium sulfite, 21.7

sodium exsiccated

Butacaine sulfate 6.7 Phenobarbital 8.0 Sodium thiosulfate 10.3

sodium

Caffeine and sodium 8.7 Physostigmine 5.3 Streptomycin 2.3

benzoate salicylate sulfate

Calcium chloride 17.0 Pilocarpine 8.0 Secobarbital sodium 8.0

hydrochloride
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282 | An Introduction to Pharmacy

Drug (0.3 g) Water needed for Drug (0.3 g) Water needed for Drug (0.3 g) Water needed for
isotonicity (mL) isotonicity (mL) isotonicity (mL)

Calcium chloride (6 H2 O) 11.7 Pilocarpine nitrate 7.7 Sulfacetamide 7.7

sodium

Chlorobutanol 8.0 Piperocaine 7.0 Sulfadiazine sodium 8.0

(hydrated) hydrochloride

Chlortetracycline sulfate 4.3 Polymyxin B sulfate 3.0 Sulfamerazine 7.7

sodium

Cocaine hydrochloride 5.3 Potassium chloride 25.3 Sulfapyridine 7.7

sodium

Cupric sulfate 6.0 Potassium nitrate 18.7 Sulfathiazole 7.3

sodium

Dextrose, anhydrous 6.0 Potassium 14.7 Tetracaine 6.0

phosphate, hydrochloride
monobasic

Dibucaine 4.3 Procainamide 7.3 Tetracycline 4.7

hydrochloride hydrochloride hydrochloride

Dihydrostreptomycin 2.0 Procaine 7.0 Viomycin sulfate 2.7

sulfate hydrochloride

Ephedrine 10.0 Scopolamine 4.0 Zinc chloride 20.3

hydrochloride hydrobromide

Ephedrine sulfate 7.7 Scopolamine 5.3 Zinc sulfate 5.0

methylnitrate

This table of isotonic solution values above shows for dilute solution
volumes in mL of water to be added to 300 mg
of the specified drug in sterile water to produce an 6.33 mL soln ∼
= 6.33 mL water
isotonic solution. The addition of an isotonic vehicle ∴ V = 6.33 mL water/0.3 g drug.
(commonly referred to as diluting solution) to make
30 mL yields a 1% solution. Solutions prepared as
directed above are iso-osmotic with 0.9% sodium References
chloride solution but may not be isotonic with blood
(see Appendix A for hemolysis data). 1. Spilker B. Guide to Drug Development: A Comprehen-
sive Review and Assessment. Philadelphia: Lippincott
The V values for drugs that do not appear in Williams & Wilkins, 2009.
the table above but are listed in Appendix A can be 2. Ott L, Longnecker M. An Introduction to Statistical
calculated from the sodium chloride equivalent for Methods and Data Analysis. Belmont: Brooks/Cole,
1% drug. 2010.
3. Chieng N et al. Effect of milling conditions on the solid-
Example: Calculate the V value for anileridine state conversion of rantidine hydrochloride form 1. Int
HCl (Appendix A defines E = 0.19). J Pharm 2006; 327: 36–44.
4. Murdande SB et al. Aqueous solubility of crystalline and
100 ml Soln 0.19 g NaCl amorphous drugs: Challenges in measurement. Pharm
× ×0.3 g drug = 6.33 mL Soln Dev Technol 2011; 16: 187–200.
0.9 NaCl 1 g drug
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5. Herman J, Visavarungroj N, Remon JP. Instability 24. Kaminski MV. Enteral hyperalimentation. Surg
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35. Payne-James JJ et al. First choice for total parenteral
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Pharm Tech 2008; 3: 22. Dekker, 1992: 137–188.
22. Serajuddin AT M. Salt formation to improve drug sol- 45. Doraiswamy D. The origins of rheology: a short histor-
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8
Pharmacokinetics and
pharmacodynamics

Basic pharmacokinetics and pharmacodynamics 285 Principles of immunology 296

Drug action and effect 288 Pharmacogenomics 296

Drug absorption, distribution, metabolism, and Pharmacokinetics/Pharmacodynamics in drug

excretion 291 development 301

Clinical pharmacokinetics and pharmacodynamics 296 References 302

Basic pharmacokinetics and

pharmacodynamics 20

The goal of pharmacotherapy is to provide optimal

drug therapy in the treatment or prevention of disease. 15

A major barrier to the achievement of this goal is the

Number of subjects

large variability in the pharmacological effect that is

observed following drug administration (Fig 8.1).1 10
The ability to implement drug therapy in a safe and
rational manner necessitates an understanding of the
factors that cause this variability. One of the most
5
important factors is the concentration of drug that is
achieved at the site of action.

0
The critical nature of the concentration 10–14 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 >54
Depression of blood glucose
versus effect relationship (expressed as percent of control)

The quantitative response to a drug depends highly on

Figure 8.1 Decrease in blood glucose in 97 subjects 30 min
the concentration of drug at the site of action. In most
after an intravenous dose of 1 g of tolbutamide. Note the large
situations one cannot quantify drug concentration variability observed after the equivalent dose was
at the actual site of action. Rather, drug concentra- administered in this group. (Data from Swerdloff RS et al.
tions are measured in an easily accessible site that is Influence of age on the intravenous tolbutamide response
believed to be in equilibrium with the site of action test. Diabetes 1967; 16: 161–170.)
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286 | An Introduction to Pharmacy

Patient A Patient B Patient C 8

2

Number of patients
Pain score

1
4

0.2 0.5 0.8 0.2 0.5 0.8 0.2 0.5 0.8

Pethidine (meperidine) concentration (µg/mL) 0
0 100 200 300 400 500 600 700
6–Mercaptopurine concentration (ng/mL)
Figure 8.2 Blood meperidine concentration-response
curves for three individual patients, illustrating a typical range Figure 8.3 Distribution of peak 6-mercaptopurine
in interpatient responses. (From Austin KL, Stapleton JV, concentrations achieved in a group of 20 patients receiving an
Mather LE. Relationship between blood meperidine oral dose of 1 mg/m2 . (Data from Sulh H et al. Pharmacokinetic
concentrations and analgesic response: a preliminary report. determinants of 6-mercaptopurine myelotoxicity and
Anesthesiology 1980; 53: 460–66.) therepeutic failure in children with acute lymphoblastic
leukemia. Clin Pharmacol Ther 1986; 40: 604–609.)

A basic understanding of the factors that control

(e.g., blood or one of its components). Figure 8.22 drug concentration at the site of action is important
provides a good illustration of a drug whose phar- for the optimal use of drugs. This is the area of study
macological effect is particularly sensitive to changes referred to as pharmacokinetics, which is the study
in blood concentration. Numerous studies have been of the time course of drug absorption, distribution,
published that substantiate the critical nature of the metabolism, and elimination.
concentration–effect relationship for a wide variety
of drugs.
Drug concentration versus time profile
It is recognized now that drug therapy may be
optimized by designing regimens that account for the Blood (or its components, plasma or serum) represents
concentration of a drug necessary to achieve a desired the most frequently sampled fluid used to characterize
pharmacological response. However, there is often the pharmacokinetics of drugs. Drug concentration
significant difficulty in achieving such target concen- in the blood is the sum of several processes (Fig.
trations. In particular, it often is observed that if a 8.4).4 Initially visual characterization of the processes
fixed dose of a drug is administered to a group of indi- controlling the concentration of drug in the blood
viduals, the drug concentration measured in plasma can be made by constructing a drug concentration
can vary widely. For example, the peak concentra- versus time profile (i.e., a plot of drug concentration
tion of 6-mercaptopurine achieved in a group of 20 in the blood versus time). As can be seen from Fig.
patients who received a standard 1 mg/m2 dose is 8.5, several useful pieces of information can be derived
shown in Fig. 8.3.3 The concentrations ranged from from such a profile. For example, the time at which the
0 to 660 ng/mL. Taken together, this suggests that peak concentration occurs can be approximated and
variability in drug concentration is a major source of the peak concentration quantified. If the minimum
variability in drug effect, and there may be a signif- concentration needed to maintain a desired effect is
icant degree of variability among individuals in the known, the onset and duration of effect also can
drug concentrations produced by a given dose of drug. be approximated. While useful information can be
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Pharmacokinetics and pharmacodynamics | 287

Drug in
dosage
form Lipoid barriers

Metabolizing enzymes
Release
Peripheral
Drug compartment
particles (tissue)
in body
fluid

Dissolution Distribution
IV
Drug IM
in Central
solution GI compartment
Biologic effect
Liver Free Protein
drug bound Compensatory
drug mechanisms

Aborption Metabolism Excretion Reabsorption Site of action Observed response

Gastrointestinal Activation Urinary Renal, tubular Enzyme systems Therapeutic
percutaneous deactivation biliary enterohepatic or “receptors” toxic
subcutaneous polarization pulmonary in specific
intramuscular salivary organs
ocular, nasal
pulmonary
sublingual, etc

Figure 8.4 Diagram illustrating the factors that influence onset, duration, and intensity of drug effects. Note that the drug must
dissolve before being absorbed and that it passes across many lipoid barriers and some metabolizing systems before reaching
the site of action. (From Barr WH. Principles of biopharmaceutics. Am J Pharm Educ 1968; 32: 958–959.)

effective use of drugs. This higher degree of accu-

100
racy necessitates the development of mathematical
models for describing the time course of absorption,
80 distribution, metabolism, and elimination.
Concentration (mg/L)

60
Pharmacokinetic models
40 One of the primary objectives of pharmacokinetic
models is to develop a quantitative method to describe
the relationship of drug concentration, or amount in
20
the body, as a function of time. The complexity of the
pharmacokinetic model will vary with the route of
0 administration, the extent and duration of distribu-
0 1 2 3 4 5 6
Time (hours)
tion into various body fluids and tissues, the processes
of elimination, and the intended application of the
Figure 8.5 Hypothetical plot of drug-concentration data pharmacokinetic model. Often, numerous potential
after oral administration of a drug. mathematical models exist for a particular drug. In
such cases, the simplest model that will adequately
drawn casually from a simple graph as depicted in Fig. and accurately describe the pharmacokinetics of the
8.5, a more rigorous description of the pharmacoki- drug is the model that should be chosen.
netics of a drug is necessary to achieve the accuracy There are a wide variety of potential uses for
in dosage regimen design required for the safe and pharmacokinetic models, which include:
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288 | An Introduction to Pharmacy

1. Prediction of drug concentration in blood/plasma disease, and many others. Drugs can aid in diagnosis,
or tissue. treatment, replenishment, prevention, as well as many
2. Calculation of a dosage regimen. other applications.
3. Quantitative assessment of the effect of disease on Drug discovery and development are complex
drug disposition. phenomena that involve the collective contributions
4. Elucidation of the mechanism of disease-induced of many scientific specialists. After a new potential
alterations in drug disposition. drug substance has undergone definitive chemical
5. Determination of the mechanism for drug–drug and physical characterization, the basic pharmacol-
interactions. ogy, or the nature and mechanism of action of the
6. Prediction of drug concentration versus effect rela- drug on the biologic system, must be determined.
tionships. The drug’s effects, or multiple effects, as well as its
selectivity, dose, potency and efficacy, dose–effect
There are three primary types of pharmacokinetic relationships, dose–intensity of effect relationships,
models: compartmental, noncompartmental, and dose–frequency of response relationships, and varia-
physiological. tions in response and responsiveness must be ascer-
Compartmental models describe the pharmacoki- tained. Additional studies on how the new drug
netics of drug disposition by grouping body tissues works investigate drug receptors and receptor theory,
that are kinetically indistinguishable and describe the occupation and other theories, mechanisms of drug
transfer of drug between body tissues in terms of rate action, types of targets for drug action, receptor bind-
constants. ing, receptor structure and function, voltage-sensitive
Noncompartmental models describe the phar- channels, ligand-activated ion channels, G protein-
macokinetics of drug disposition using time- and coupled receptors, tyrosine kinase-linked receptors,
concentration-averaged parameters. intracellular receptors that control DNA transcrip-
Physiological models attempt to describe drug dis- tion, enzyme inhibition, and receptor regulation.
position in terms of realistic physiological parameters, The word drug imposes an action–effect con-
such as blood flow and tissue-partition coefficients. text within which the properties of a substance are
described. The description must include the pertinent
properties of the recipient of the drug. Thus, when a
Drug action and effect drug is defined as an analgesic, it is implied that the
recipient reacts to a noxious stimulus in a certain way,
A drug is an agent intended for use in the diagnosis, called pain. (Studies indicate that pain is not simply
mitigation, treatment, cure, or prevention of disease the perception of a certain kind of stimulus but rather,
in humans or other animals. One of the most remark- a reaction to the perception of a variety of kinds of
able qualities of drugs is the great diversity of their stimuli or stimulus patterns.) Both because the per-
actions and effects on the body, which enables their tinent properties are locked into the complex and
selective use in the treatment of a wide range of condi- somewhat imprecise biological context and because
tions involving virtually every body organ, tissue, and the types of possible response are many, descriptions
cell. Some drugs selectively stimulate or depress the of the properties of drugs tend to emphasize the qual-
cardiac muscle, the central nervous system (CNS), or itative features of the effects they elicit. Thus, a drug
the gastrointestinal (GI) tract. Mydriatic drugs dilate may be described as having analgesic, vasodepressor,
the pupil of the eye, whereas miotic drugs constrict convulsant, antibacterial, or other properties. How-
or decrease pupillary size. Some drugs can induce ever, the description of a drug does not end with the
vomiting, whereas others prevent vomiting. Diuretic enumeration of the responses it may elicit. Certain
drugs increase the flow of urine, whereas other drugs intrinsic properties of the drug-recipient system can
decrease it. Laxatives evacuate the bowel; other drugs be described in quantitative terms and are essential to
cause constipation. The diverse effects of drugs in the full description of the drug and to the validation
the body include the treatment of infections, cancer, of the drug for specific uses. In the following section,
cardiovascular disease, asthma, glaucoma, Alzheimer Definitions and Concepts, certain general terms are
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Pharmacokinetics and pharmacodynamics | 289

defined in qualitative language; the subsequent section in the liver not only may lower serum cholesterol,
lays the foundation for an appreciation of some of the impair nerve myelination and function, and alter the
quantitative aspects of pharmacodynamics. condition of the skin (as a consequence of cholesterol
deficiency), but also may affect digestive functions
(because of a deficiency in bile acids) and alter adreno-
Definitions and concepts cortical and sexual hormonal balance.
The vocabulary that is unique to the field of pharma- Although a single action can give rise to multi-
cology is relatively small; the general vocabulary is ple effects, most drugs exert multiple actions. The
that of the biological sciences and chemistry. Never- various actions may be related, as for example,
theless, there are a few definitions that are important the sympathomimetic effects of phenylephrine that
to the proper understanding of pharmacology. It is accrue to its structural similarity to norepinephrine
necessary to differentiate among action, effect, selec- and its ability to exert sympathetic responses, or the
tivity, dose, potency, and efficacy. actions may be unrelated, as with the actions of mor-
phine to interfere with the release of acetylcholine
Action versus effect from certain autonomic nerves, block some actions
The effect of a drug is an alteration of function of of 5-hydroxytryptamine (serotonin), and release his-
the structure or process upon which the drug acts. It tamine. Many drugs bring about immunological (i.e.,
is common to use the term action as a synonym for allergic or hypersensitivity) responses that bear no
effect. However, action precedes effect. Action is the relation to the other pharmacodynamic actions of the
alteration of condition that brings about the effect. drug.
The final effect of a drug may be far removed from
its site of action. For example, the diuresis subsequent Selectivity
to the ingestion of ethanol does not result from an Although most drugs have the potential to elicit
action on the kidney but, rather, from a depression multiple effects, one effect is generally more readily
of activity in the region of the hypothalamus, which elicitable than another. This differential responsive-
regulates the release of antidiuretic hormone from the ness is called selectivity. It usually is considered to be
posterior pituitary gland. The alteration of hypotha- a property of the drug, but it is also a property of the
lamic function is, of course, also an effect of the drug, constitution and biodynamics of the recipient subject
as is each subsequent change in the chain of events or patient.
leading to diuresis. The action of ethanol was exerted Selectivity may come about in any of several ways.
only at the initial step, with each subsequent effect The subcellular structure (receptor) with which a drug
becoming then the action to a following step. combines to initiate one response may have a higher
affinity for the drug than that for some other action.
Multiple effects Atropine, for example, has a much higher affinity
No known drug is capable of exerting a single for muscarinic receptors that subserve the function
effect, although a number are known that appear of sweating than it does for the nicotinic receptors
to have a single mechanism of action. Multiple effects that subserve voluntary neuromuscular transmission,
may derive from a single mechanism of action. For so that suppression of sweating can be achieved with
example, the inhibition of acetylcholinesterase by only a tiny fraction of the dose necessary to cause
physostigmine will elicit an effect at every site where paralysis of the skeletal muscles. A drug may be
acetylcholine is produced, is potentially active, and distributed unevenly, so that it reaches a higher con-
is hydrolyzed by cholinesterase. Thus, physostigmine centration at one site than throughout the tissues
elicits a constellation of effects. generally; for example, chloroquine is much more
A drug also can cause multiple effects at several effective against hepatic than intestinal (colonic) ame-
different sites by a single action at only one site, pro- biasis because it reaches a much higher concentration
viding that the function initially altered at the site of in the liver than in the wall of the colon. An affected
action ramifies to control other functions at distant function may be much more critical to, or have less
sites. Thus, a drug that suppresses steroid synthesis reserve in, one organ than in another, so that a drug
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290 | An Introduction to Pharmacy

will be predisposed to elicit an effect at the more the inactivation and elimination of the drugs may not
critical site. Some inhibitors of dopa decarboxylase be developed fully in the infant.
(also known as 5-hydroxytryptophan decarboxylase) The patient’s nutritional status, his or her men-
depress the synthesis of histamine more than that of tal outlook, the presence of pain or discomfort, the
either norepinephrine or 5-hydroxytryptamine (sero- severity of the condition being treated, the presence
tonin), even though histidine decarboxylase is less of secondary disease or pathology, and genetic factors
sensitive to the drug, simply because histidine decar- as well as many other factors affect the dose of a drug
boxylase is the only step and, hence, is rate-limiting necessary to achieve a given therapeutic response or to
in the biosynthesis of histamine. Dopa decarboxy- cause an untoward effect. Even two apparently well-
lase does not become rate limiting in the synthesis of matched normal persons may require widely different
either norepinephrine or 5-hydroxytryptamine until doses for the same intensity of effect. Furthermore,
the enzyme is nearly completely inhibited. Another a drug is not always employed for the same effect
example of the determination of selectivity by the and, therefore, is not always given in the same dose.
critical balance of the affected function is that of the For example, the dose of a progestin necessary for
mercurial diuretic drugs. An inhibition of only 1% in an oral contraceptive effect is considerably different
the tubular resorption of glomerular filtrate usually from that necessary to prevent spontaneous abortion,
will double urine flow, because 99% of the glomerular and the dose of an estrogen used for the treatment of
filtrate normally is resorbed. Aside from the question menopausal symptoms is much lower than that used
of the possible concentration of diuretics in the urine, for the treatment of prostatic carcinoma.
a drug-induced reduction of 1% in sulfhydryl enzyme The wise physician knows that the dose of a drug
activity in tissues other than the kidney usually is is not a rigid quantity, but, rather, that which is
not accompanied by an observable change in func- necessary and can be tolerated, and he or she individ-
tion. Selectivity also can be determined by the pattern ualizes the regimen accordingly. The wise pharmacist
of distribution of inactivating or activating enzymes also recognizes that official or manufacturer’s recom-
among the tissues and by other factors. mended doses sometimes are quite narrowly defined
and should serve only as a useful guide rather than as
an absolute.
Dose
Even the uninitiated person knows that the dose of Potency and efficacy
a drug is the amount administered. However, the The potency of a drug is the reciprocal of dose. Thus,
appropriate dose of a drug is not some unvarying it will have the units of persons/unit weight of drug or
quantity, a fact sometimes overlooked by pharma- body weight/unit weight of drug, for example. Potency
cists, official committees, and physicians. The practice generally has little utility other than to provide a
of pharmacy is entrapped in a system of fixed-dose means of comparing the relative activities of drugs in
formulations, so that fine adjustments in dosage often a series; relative potency, relative to some prototypic
are difficult to achieve. Fortunately, a rather wide member of the series, is a parameter commonly used
latitude in dosages usually is allowable. It is obvious among pharmacologists and in the pharmaceutical
that the size of the recipient individual should have a industry.
bearing upon the dose, and the physician may elect to Whether a given drug is more potent than
administer the drug on a body-weight or surface-area another has little bearing on its clinical usefulness,
basis rather than as a fixed dose. Usually, however, as long as the potency is not so low that the size of
a fixed dose is given to all adults, unless the adult is the dose is physically unmanageable or the cost of
exceptionally large or small. The dose for infants and treatment is higher than with an equivalent drug.
children often is determined by one of several formu- A drug that is less potent but more selective is the
las that take into account age or weight, depending one to be preferred. Promotional arguments in favor
on the age group of the child and the type of action of a more potent drug, therefore, are irrelevant to
exerted by the drug. Infants are relatively more sensi- the important considerations that should govern the
tive to many drugs, often because systems involved in choice of a drug. However, drugs of the same class
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Pharmacokinetics and pharmacodynamics | 291

sometimes differ in the maximum intensity of effect; to a class of drugs and the differences among the
that is some drugs of the class may be less efficacious members of that class.
than others, regardless of how large a dose is used. To have the desired action, a drug must achieve
Efficacy connotes the property of a drug to achieve absorption and transport to the appropriate tissue
the desired response, and maximum efficacy denotes or organ, penetrate to the responding cell surface
the maximum achievable effect. Even huge doses of or subcellular structure, and elicit a response or alter
codeine often cannot achieve the relief from severe ongoing processes. The drug may be distributed simul-
pain that relatively small doses of morphine can; thus, taneously or sequentially to a number of tissues, be
codeine is said to have a lower maximum efficacy than bound or stored, be metabolized to inactive or active
morphine. Efficacy is one of the primary determinants products, or be excreted. The basic entry, movement,
of which drug is chosen. and disposition of drugs and metabolites within the
body are summarized in Fig. 8.6. Each of the processes
or events depicted relates importantly to therapeu-
Drug absorption, distribution, tic and toxic effects of a drug and to the mode of
metabolism, and excretion administration, and drug design must take each into
account. The extent to which all the components of
Introduction absorption, distribution, metabolism (biotransforma-
Drugs differ widely in their pharmacodynamic effects tion), and elimination apply varies enormously with
and clinical applications, as well as in penetration, the drug or xenobiotic (the latter being a term widely
absorption, and usual route of administration. They used to refer to not only drugs but any chemical not
also differ in their distribution among the body tis- part of the normal biochemistry and physiology of the
sues, and in disposition and mode of termination of body) and the dose (level of exposure), and to some
action. Certain general principles that help explain extent is subject to interindividual variation, the latter
the differences have both pharmaceutical and ther- often arising from genetic and disease state influences.
apeutic implications. These principles facilitate an Pharmacokinetics is the science that treats the rate
understanding of both the features that are common and extent of absorption, rates of distribution among

IN

Absorption :
Major = alimentary tract (enteral)
Other = respiratory tract, skin

Target organ
(drug action)

Non-target Blood:
organs = free drug
(drug = bound IN Parenteral
sequestration) drug
(albumin)
Metabolism :
Major = liver

Excretion :
Major = kidney

OUT

Figure 8.6 Interrelationship of the major components of drug entry, distribution, metabolism, and elimination within the body.
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292 | An Introduction to Pharmacy

body compartments, rate of elimination, and related are, for example, differences between the membrane
phenomena. Next we will consider the physiological of the endoplasmic reticulum and the plasma mem-
bases of the processes. brane, even though the membranes are co-extensive.
The membrane surface facing the cytoplasm is rich
in phosphatidylethanolamine and phosphatidylserine,
Structure and properties of while the surface facing the outside is rich in phos-
membranes phatidylcholine and sphingomyelin. Oligosaccharide
In almost all stages of absorption, distribution, chains linked to lipids (glycolipids), and oligo- and
metabolism (biotransformation), and elimination, a polysaccharide chains attahed to proteins (glycopro-
drug must pass through several to many biological teins) are confined to non-cytosolic facing surfaces.
membranes during the processes. Since membranes Sugar moieties attached to the outer proteins are most
are traversed in all of these events, a brief description often attached to the asparagine residue. These sugar
of biological membranes and membrane processes moieties are important to both cellular and immuno-
is in order, as well as the relationship of the logical recognition and adhesion, and they have other
physicochemical properties of a drug molecule to functions as well. Where membranes are double, the
penetration and transport. inner and outer layers differ considerably; the inner
Numerous sophisticated techniques have estab- and outer membranes of mitochondria have strikingly
lished the nature of the plasma, mitochondrial, different compositions and properties.
nuclear, and other cell membranes. The description The cell membrane appears to be perforated by
of the plasma membrane that follows is much over- water-filled pores of various sizes, varying from about
simplified, but it will suffice to provide a background 4 to 10 Å, most of which are about 7 Å. Probably
for an understanding of drug penetration into and all major ion (water-filled) channels penetrate the
through membranes. The cell membrane has been large protein assemblies that traverse the membrane.
characterized as a bimolecular layer of lipid material Through these pores pass inorganic ions and small
entrained between two parallel monomolecular layers organic molecules. Among the common inorganic
of protein. However, rather than forming a contin- ions, because sodium ions are more hydrated than
uous layer, the protein layer comprises ‘‘islands’’ potassium and chloride ions, they are larger and do
sporadically scattered over the surfaces. For many not pass as freely through the pores as do potassium
proteins, much of the protein is below the surface and chloride. Ion (ion plus water) movement can be
and within the fatty bilayer. The lipid bilayer can be by diffusion down a chemical concentration gradient.
envisaged as a somewhat orderly, lamellar array of However, movement of ions through the pores can be
phospholipid molecules associated tail-to-tail, each controlled by counterion transport, or expenditure of
tail being an alkyl chain or steroid group, and the intracellular energy – adenosine triphosphate (ATP)
heads being polar groups. The disorder that does hydrolysis – by so-called ABC transporters. Vascular
exist is the result of the different degrees of saturation endothelium appears to have pores at least as large
of the fatty acids and the interspersed cholesterol as 40 Å, but these seem to be interstitial passages
molecules that break up the close packing of the rather than transmembrane pores. Lipid molecules
fatty acid tails. Cholesterol maintains the mechanical small enough to pass through the cell membrane
stability of cell membranes, is a determinant of pores may do so, but they have a higher probability
membrane fluidity, and – with relevance to drug of entering into the lipid layer (since pores constitute
passage across membranes – decreases permeability less than 1% of the cell surface upon which the
to water-soluble molecules. Moreover, the lamellar drug molecule impinges); from there these molecules
portion is penetrated by large globular proteins with will equilibrate chemically with the interior of the
a highly hydrophobic interior (like the lipid layers), cell. Other proteins may be confined to one or the
and by some fibrous proteins as well. other surface and not traverse the membrane. Often
The plasma membrane is asymmetrical. The lipid proteins on the inner surface protein are linked to
composition varies from cell type to cell type and per- intracellular structural proteins that contribute to cell
haps from site to site on the same membrane. There shape.
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Pharmacokinetics and pharmacodynamics | 293

Diffusion and transport different sizes and probably with varying thickness
and composition, both D and x probably vary from
Transport is the movement of a drug from one place
place to place. Nevertheless, some mean values can be
to another within the body. The drug may diffuse
assumed. It is customary to combine the membrane
freely in uncombined form with a kinetic energy
factors into a single constant, called a permeability
appropriate to its thermal environment, or it may
constant or coefficient, P, so that P = D/x, and A
move in combination with extracellular or cellular
in the equation above has unit value. The rate of
constituents, sometimes in connection with energy-
net transport (diffusion) across the membrane then
yielding processes that allow the molecule or complex
becomes:
to overcome barriers to simple diffusion.
dQ/dt = P(C1 − C2 )
Simple nonionic diffusion and passive transport
Molecules in solution move in a purely random fash- As diffusion continues, C1 approaches C2 , and
ion, provided they are not charged and moving in an the net rate, dQ/dt, approaches zero in exponential
electrical gradient. Such random movement is called fashion, characteristic of a first-order process. Equi-
diffusion; if the molecule is uncharged, it is called non- librium is defined as that state in which C1 = C2 . The
ionic diffusion. In a population of drug molecules, the equilibrium is, of course, dynamic, with equal num-
probability that during unit time any drug molecule bers of molecules being transported in each direction
will move across a boundary is directly proportional during unit time. If water also is moving through the
to the number of molecules adjoining that boundary membrane, it may either facilitate the movement of
and, therefore, to the drug concentration. Except at drug or impede it, according to the relative directions
dilutions so extreme that only a few molecules are of movement of water and drug; this effect of water
present, the actual rate of movement (molecules per movement is called solvent drag.
unit time) is directly proportional to the probability of Ionic or electrochemical diffusion
movement and, therefore, to the concentration. Once
If a drug is ionized, the transport properties are mod-
molecules have passed through the boundary to the
ified. The probability of penetrating the membrane is
opposite side, their random motion may cause some
still a function of concentration, but it is also a func-
to return and others to continue to move farther away
tion of the potential difference or electrical gradient
from the boundary. The rate of return is likewise pro-
across the membrane. A cationic drug molecule will
portional to the concentration on the opposite side
be repelled from the positive charge on the outside of
of the boundary. It follows that, although molecules
the membrane, and only those molecules with a high
are moving in both directions, there will be a net
kinetic energy will pass through the ion barrier. If the
movement from the region of higher to that of
cation is polyvalent, it may not penetrate at all.
lower concentration, and the net transfer will be
Once inside the membrane, a cation will be simul-
proportional to the concentration differential. If the
taneously attracted to the negative charge on the
boundary is a membrane, which has both substance
intracellular surface of the membrane and repelled by
and dimension, the rate of movement is also directly
the outer surface; it is said to be moving along the
proportional to the permeability and inversely pro-
electrical gradient. If it is also moving from a higher
portional to the thickness. These factors combine into
toward a lower concentration, it is said to be mov-
Fick’s law of diffusion:
ing along its electrochemical gradient, which is the
dQ/dt = DA(C1 − C2 )/x sum of the influences of the electrical field and the
concentration differential across the membrane.
where Q is the net quantity of drug transferred across Once inside the cell, cations will tend to be kept
the membrane, t is time, C1 is the concentration on inside by the attractive negative charge on the interior
one side and C2 that on the other, x is the thick- of the cell, and the intracellular concentration of drug
ness of the membrane, A is the area, and D is the will increase until – by sheer numbers of accumulated
diffusion coefficient, related to permeability. Since a drug particles – the rate of outward diffusion or mass
biological membrane is heterogeneous, with pores of escape equals that of inward transport. At this point
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294 | An Introduction to Pharmacy

electrochemical equilibrium is said to have occurred. 5. The transport rate approaches an asymptote (i.e.,
At electrochemical equilibrium at body temperature saturates) as concentration increases.
(37◦ C), ionized drug molecules will be distributed
according to the Nernst equation: Characteristics 3, 4, and 5 are in common with those
of carrier-mediated facilitated diffusion.
± log CO /CI = ZE/61
Many drugs are secreted by active transport from
where CO is the molar extracellular and Ci the intra- the renal tubules into urine, from liver cells into
cellular concentration, Z is the number of charges bile or blood, from intestinal cells into the lumen
per molecule, and E is the membrane potential in of the GI tract, or from the cerebrospinal fluid into
millivolts. Log CO /Ci is positive when the molecule is blood, but the role of active transport of drugs in the
negatively charged and negative when the molecule is distribution into most body compartments and tissues
positively charged. has been less extensively documented, although it is
now an active area of research. Active transport is
Facilitated diffusion often required for the movement of drug metabolites,
entities that generally have less lipid solubility than
Sometimes a substance moves more rapidly through
the parent drug, across cell membranes.
a biological membrane than can be accounted for
by the process of simple diffusion. This accelerated
Pinocytosis and exocytosis
movement is termed facilitated diffusion. It is due to
the presence of a special molecule within the mem- Many (perhaps all) cells are capable of a type of
brane, called a carrier, with which the transported phagocytosis called pinocytosis. The cell membrane
substance combines. There is considered to be greater has been observed to invaginate into a sac-like struc-
permeability to the carrier–drug complex than to the ture containing extracellular materials and then pinch
drug alone, so that the transport rate is enhanced. off the sac at the membrane, so that the sac remains
After the complex has traversed the membrane, it as a vesicle or vacuole within the interior of the cell.
dissociates. For the carrier process to be continuous, Because metabolic activity is required and because an
either the carrier must return to the original side extracellular substance can be transported against an
of the membrane to be used again, or it must con- electrochemical gradient, pinocytosis shows some of
stantly be produced on one side and eliminated on the the same characteristics as active transport. However,
other. Many characteristics of facilitated diffusion, pinocytosis is relatively slow and inefficient compared
formerly attributed to ion carriers, can be explained with most active transport, except in GI absorption,
by ion exchange. Facilitated diffusion only transports where for some xenobiotics pinocytosis may be of
a molecule along its electrochemical gradient. some importance.
It is not known to what extent pinocytosis con-
Active transport tributes to the transport of most drugs, but many
Active transport can be defined as energy-dependent macromolecules and even larger particles can be
movement of a substance through a biological mem- absorbed by the gut. Exocytosis is the reverse of
brane against an electrochemical gradient. It is char- pinocytosis. Granules, vacuoles, or other organelles
acterized as follows: within the cell move to the cell membrane, fuse with it,
and extrude their contents into the interstitial space.

1. The substance is transported from a region of

lower to one of higher electrochemical activity.
Physicochemical factors in
2. Metabolic poisons (that most often reduce ATP
penetration
concentrations) interfere with transport.
3. The transport system shows a requirement for spe- Drugs and other substances may traverse the mem-
cific chemical structures. brane primarily either through the pores, or by move-
4. Closely related chemicals are competitive for the ment into the membrane lipids and subsequent dif-
transport system. fusion from the membrane into the cytosol or other
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Pharmacokinetics and pharmacodynamics | 295

fluid on the far side of the membrane. The physico- the skin appears to be lower than that for the perme-
chemical prerequisites differ according to which route ation of the cell membrane, perhaps being as low as
is taken. To pass through the pores, the diameter of unity.
the molecule must be smaller than the pore, but the
Dipolarity, polarity, and nonionic diffusion
molecule can be longer than the pore diameter. The
probability that a long, thin molecule will be suitably The partition coefficient of a drug depends upon the
oriented, however, is low unless there is also bulk polarity and the size of the molecule. Drugs with a
flow, and therefore transmembrane passage of such high dipole moment, even though nonionized, have
molecules is slow. low lipid solubility and hence penetrate poorly. An
Water-soluble molecules with low lipid solubility example of a highly dipolar substance with a low par-
are usually thought to pass through the membrane tition coefficient, which does not penetrate into cells,
mainly via the pores. If there is a membrane carrier or is sulfisoxazole. Sulfadiazine is somewhat less dipo-
active-transport system, a low solubility of the drug lar, has a chloroform-to-water partition coefficient
in membrane lipids is no impediment to penetration, ten times that of sulfisoxazole, and readily penetrates
because the drug–carrier complex is assumed to have cells. Ionization not only greatly diminishes lipid sol-
an appropriate solubility, and energy from an active- ubility but also may impede passage through charged
transport system enables the drug to penetrate the membranes.
energy barrier imposed by the lipids. Actually, the It is often stated that ionized molecules do not pen-
lipids are not an important energy barrier; rather, etrate membranes, except for ions of small diameter.
the barrier is the force of attraction of the solvent This is not necessarily true because of the presence of
water for its dipolar-to-polar solute, so that it is membrane carriers for some ions that effectively shield
difficult for the solute to leave the water and enter the or neutralize the charge (formation of ion pairs). The
renal tubular transport systems, which transport such
lipid.
obligate ions as tetraethylammonium, probably form
Drugs with a high solubility in the membrane
ion pairs. Furthermore, if an ionized molecule has a
lipids pass easily through the membrane. Even when
large non-polar moiety such that appreciable lipid sol-
their dimensions are small enough to permit pas-
ubility is imparted to the molecule despite the charge,
sage through pores, lipid-soluble drugs primarily pass
the drug may penetrate, though usually at a slow
through the membrane lipids, not only because chem-
rate. Nevertheless, when a drug is a weak acid or
ical partition favors the lipid phase but also because,
base, the nonionized form, with a favorable partition
as mentioned previously, the surface area occupied by
coefficient, passes through a biological membrane so
pores is only a small fraction of the total membrane
much more readily than the ionized form that for all
area.
practical purposes, only the nonionized form is said to
Lipid solubility and partition coefficients pass through the membrane. This has become known
as the principle of nonionic diffusion.
Over a century ago, the importance of lipid solubility
in the penetration and absorption of drugs was being
investigated. Eventually it was recognized that more
Absorption of drugs
important than lipid solubility was the lipid-to-water Absorption is the process of movement of a drug
partition (or distribution) coefficient; in other words, a from the site of application into the extracellular com-
high lipid solubility does not favor penetration unless partment of the body. Inasmuch as there is a great
the water solubility is low enough so that the drug is similarity among the various membranes through
not entrained in the aqueous phase. When the water which a drug may pass to gain access to the extracel-
solubility of a substance is so low that a significant lular fluid, it might be expected that the particular site
concentration in water or extracellular fluid cannot of application (or route) would make little difference
be achieved, absorption may be negligible despite a to the successful absorption of the drug. Actually it
favorable partition coefficient. Hence, such substances makes a great deal of difference; many factors, other
as mineral oil or petrolatum are virtually unabsorbed. than the structure and composition of the membrane,
The optimal partition coefficient for permeation of determine the ease with which a drug is absorbed.
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296 | An Introduction to Pharmacy

Clinical pharmacokinetics and A basic knowledge of pharmacokinetics provides

guidance to the clinician when selecting a drug prod-
pharmacodynamics
uct, dosing regimen, the anticipated onset of drug
effect, and determining an appropriate sampling strat-
Clinical pharmacokinetics is the discipline in which
egy if drug concentrations are to be obtained.
basic pharmacokinetic principles are applied to the
development of rational dosage regimens. The con-
cepts of pharmacokinetics are placed into perspective
with the development of individualized drug dosage
Principles of immunology
regimens. The clinical significance of drug absorption,
Physical barriers, such as the skin and mucosal mem-
distribution, and elimination and influence of disease
branes, represent the first line of protection against
states on these processes are emphasized. Examples
antigen and pathogen intrusion into the body. Once
are given of the ways pharmacokinetic principles can
the foreign particle has transversed these barriers,
be applied in the calculation and adjustment of dosage
a complex and coordinated response is activated
regimens designed to fit the pharmacokinetic and
in an effort to maintain tissue sterility and restore
pharmacodynamic properties of drugs and specific
homeostasis. These activities are often compared to
disease states that alter drug disposition. The princi-
ples of therapeutic drug monitoring and the rational a military response towards a foreign incursion, in
use of this clinical science in the management of which the defensive response employs a diverse reper-
patients also are discussed. toire of assets to dispatch any threat. Similarly, the
The application of pharmacokinetic principles to immune system is equipped with a vast array of
patient care can aid the clinician in making rational humoral and cellular mechanisms, used to maintain
drug use decisions. However, knowing the relation- physiological homeostasis.
ship between the time course of drug concentration
and the pharmacologic effect is critical to the applica-
tion of pharmacokinetic principles and the interpreta- Pharmacogenomics
tion of plasma drug concentrations in the patient care Introduction
setting.
As a general rule traditional pharmacokinetic Pharmacogenomics is the science of optimizing phar-
research is an intensive study of a limited number maceutical therapeutic outcomes for an individual
of subjects resulting in very precise pharmacokinetic based upon their genetic information. The term ‘‘phar-
and pharmacodynamic parameter estimates. Clini- macogenomics’’ is often used synonymously with the
cal pharmacokinetics, on the other hand, is usually more general phrase ‘‘personalized medicine’’. Person-
limited to very few and sometimes no plasma drug alized medicine, however, is a very broad model that
concentrations, requiring the clinician to make an includes environmental factors, enhanced detection of
educated guess about key elements of drug disposi- disease, and determining a person’s predisposition to
tion and the drug use process. In the research setting disease. Pharmacogenomics, or the genetic predeter-
it is common to obtain ten or more samples for drug mination of reactions to pharmaceuticals, is therefore
concentration measurements within a single dosing only one aspect of personalized medicine.
interval. In the clinical setting it is uncommon to The goal of pharmacogenomics is to provide a
obtain more than two or three samples for a patient genetic roadmap for both clinician and patient leading
during a hospitalization or within a year for ambula- to the most appropriate medications for the treatment
tory care patients. of disease. The ideal outcome is to optimize the ben-
Therefore, understanding the usual manner in efits of a drug while minimizing its adverse effects.
which drugs are absorbed, distributed, and elimi- Responses to the therapeutic and adverse effects of
nated, as well as the known factors that alter drug a drug are highly variable. Every patient does not
disposition and which of these elements is most likely exhibit untoward adverse responses, nor do individu-
to be altered in the individual patient, is key to the als who experience drug effects exhibit a response to
clinician’s ability to effectively use pharmacokinetics. the same degree. It is understood that a proportion
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Pharmacokinetics and pharmacodynamics | 297

of adverse responses may be dose-related, but despite Pharmacogenomics data add a new factor to give a
standardized drug dosing by body mass, age, sex, and more complete picture of the patient. A pharmacist
health condition, there still remains large interindi- who knows how patients will metabolize certain
vidual variation in drug response. Much, if not all, of medications can predict adverse effects and influence
this unpredictability is a product of the genetic pro- medication selection recommendations. As the field
file of the patient. The science of pharmacogenomics, of pharmacogenomics grows, the pharmacist can
therefore, is one tool that is being used to reduce or play a vital role in individualized medicine. This role
eliminate the unpredictable nature of drug therapy. In may be more nontraditional, such as a consultant;
doing so, drug treatments will result in fewer adverse alternatively, community pharmacists might provide
events and decrease the overall costs of healthcare. a service to their patients right at the pharmacy.
A key expectation of pharmacogenomics is to These new roles may require additional training and
remove the trial-and-error method of finding the best education5 but will lead to better patient outcomes.
drug treatment for a particular condition. Clinicians
and their patients often try a variety of drugs and
dosages, individually or in combination, to effect a History of pharmacogenomics
desired therapeutic outcome. This method is both
Clinical observations of inherited differences in
inefficient and ineffective. Considerable time is wasted
the effects of drugs were first documented in the
searching for that one drug, or combination of drugs,
1950s6 – 18 and led to the early development of the
that will produce the best result. Then when the drug is
field of pharmacogenetics. As a result of the successful
found, the most efficacious dose must be determined.
sequencing of the entire human genome and the
The financial cost of this method is surely higher than
development of genome-wide analysis techniques,
knowing ahead of time, through genetic testing, what
pharmacogenetics has been redefined by a broad
drugs and dosages would be most effective for an
spectrum of academia and industry, giving rise to
individual with a particular condition or disease.
pharmacogenomics. The goal of pharmacogenomics
Many pharmaceutical companies are sponsoring
is to elucidate the inherited basis for interindividual
the development of companion diagnostics. These
differences in drug response, using genome-wide
are diagnostic tests developed alongside of drugs in
approaches to identify the genetic polymorphisms
clinical trials to provide a means of screening patients
that determine an individual’s response to specific
who would be most responsive to the treatment and
medications. In addition to conventional targeted
not experience potentially severe side-effects of these
genetic studies to identify functional variants, the field
drugs. The use of pharmacogenomic testing in this
includes such diverse areas as RNA-based microarray
manner, therefore, may reduce the overall cost of
analysis and genome-wide DNA analysis to identify
drug development by reducing the number of failed
the major genetic sites (loci) associated with altered
drugs. New formulations that show a lack of efficacy
drug effects.
in the general population may be saved from the trash
Because a key principle in the practice of phar-
heap by identifying specific subpopulations that may
macotherapy is the optimization of drug treatment
be helped by a new drug.
through the identification of those patient-specific
variables that affect the likelihood of a clinical
Pharmacogenomics and the pharmacist response or toxicity, this section will focus on the
examination of the genetic basis of differences in
As pharmacists become more involved in medication
drug response.
therapy management services, the role of pharmaco-
genomics will be increasingly significant. As the
medication experts of the medical team, pharmacists The human genome
have a unique opportunity to improve patient care.
How well a medication works for a particular The human genome project
patient is based on many factors – environment, sex, In 1990 the Human Genome Project was officially ini-
race, health of the patient, and other medications.5 tiated in the United States under the direction of the
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298 | An Introduction to Pharmacy

National Institutes of Health and the US Department capable of causing disease or altering response to drug
of Energy with a 15-year, $3 billion plan for complet- treatment if their function is altered significantly.
ing the genome sequence of humans. This enormous Because pharmacogenomics relies on the genetic
multinational effort was undertaken by a number of basis of an individual in predicting drug variability,
public and private laboratories, known collectively as certain aspects of pharmacogenomics responses are
the International Human Genome Sequencing Con- inherited. Depending on the type of genetic varia-
sortium (IHGSC). The IHGSC first announced a draft tion (discussed under Types of Genetic Variations),
sequence of the human genome in 2000, and by April certain responses would follow classical Mendelian
of 2003, the entire 3.1 gigabases that make up the models of inheritance. In fact, it has been proposed
human genome were essentially complete.9,10 In other that genetics may account for 20 to 95% of vari-
words, more than 99% of what can be done with cur- ability in drug response and effects.15 There are now
rent technology was done, and virtually all of the several examples where interindividual differences in
bases were identified in their proper order. Political drug response have been traced to heritable genetic
leaders from the United States, Britain, China, France, variations (genetic polymorphisms) in genes encod-
Germany, and Japan issued a joint proclamation hon- ing drug-metabolizing enzymes, drug transporters, or
oring their scientists who worked on the project, drug targets.16,17 While it is clearly important to iden-
tify environmental factors that influence the effect of
hailing their work as one of the most significant
medications, inherited determinants of drug response
scientific breakthroughs of modern times.
remain stable for an individual’s lifetime and can
While much is now known about the structure
affect agents across number of different drug classes;
of the human genome, many mysteries remain. It
moreover, the effects can be profound.
is known, for instance, that less than 2% of the
human genome consists of sequences that actually Variation in the human genome
encode proteins, while over 50% represents repeti-
One characteristic of the human genome with med-
tive sequences of several types, whose function is less
ical and social relevance is that, on average, two
well understood.9 Moreover, it is still not known
unrelated persons share over 99.9% of their DNA
precisely how many genes the human genome con-
sequences.14 However, given that more than 3 billion
tains. Data indicate that the human genome includes
base pairs constitute the human genome, this means
approximately 30,000 to 35,000 genes – a num-
that the DNA sequences of two unrelated individuals
ber that is substantially smaller than was previously
differ at millions of bases. Because a person’s geno-
thought.9 Only about half these genes have rec-
type represents the blending of parental genotypes,
ognizable DNA-sequence patterns, or motifs, that
we are each thus heterozygous at about 3 million
suggest their possible function. Furthermore, while genetic loci. Many efforts are currently under way,
it was once dogma that one gene encodes one pro- in both the academic and commercial sectors, to
tein, it now appears that, through the mechanism catalogue these variants – commonly referred to as
of alternative splicing, more than 100,000 different single-nucleotide polymorphisms (SNPs) – and to cor-
proteins can be derived from these 30,000 to 35,000 relate these specific genotypic variations with specific
genes.10 In addition to alternative splicing, a num- phenotypic variations relevant to health.
ber of ‘‘epigenetic’’ phenomena, such as methylation, The Single Nucleotide Polymorphism (SNP) Con-
phosphorylation, and histone modification, can alter sortium was established in 1999 as a collaboration of
the effect of a gene.11 – 13 Furthermore, a complex several companies and institutions within the larger
array of molecular signals allows specific genes to be IHGSC to produce a public resource of genetic varia-
‘‘turned on’’ (expressed) or ‘‘turned off’’ in specific tion in the human genome. SNPs, as the name implies,
tissues and at specific times. It is widely accepted that are single-nucleotide changes in the DNA sequence
every human gene contains inherited genetic variants that are present in the genome, and therefore rep-
or mutations.14 Mutations known to cause disease resent inheritable genetic variations. More than 1.4
have been identified in approximately 1000 genes. million SNPs were identified in the initial sequenc-
However, it is likely that nearly all human genes are ing of the human genome,14 with over 60,000 of
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Pharmacokinetics and pharmacodynamics | 299

these in the regions encoding the proteins, and it instrumental in efforts to use genomic medicine to
is anticipated that 10 million common SNPs will individualize healthcare.
ultimately be identified. Some of these SNPs have
already been associated with significant changes in Types of genetic variations
the metabolism or effects of medications, and are There are several categories of genetic variation cur-
beginning to make their way into clinical medicine as rently known to influence an individual’s response to
important molecular diagnostic tools.16 – 18 Because a drug. Three categories of genetic variation believed
most drug effects are determined by the complex inter- to impact pharmacogenomics that are sufficiently
play of gene products that influence both the phar- described in literature today are: point mutations
macokinetics and pharmacodynamics of medications, in genes, or SNPs; copy number variation; and epige-
pharmacogenomics is increasingly focused on poly- nomic variation. These three genetic-variation criteria
genic determinants of drug effects, including inherited are considered in addition to the known conditions
difference in drug targets (e.g., receptors) and drug classified as ‘‘genetic diseases’’ that include insertions
disposition (e.g., metabolizing enzymes, transporters). or deletions of large portions of chromosomes or
The human genes involved in many pharmacogenetic genes, or chromosomal duplication or chromosomal
traits have now been identified, their molecular mech- deletions.
anisms detailed, and their clinical importance more Point mutations or SNPs both refer to a change
clearly defined. In some cases, SNP–phenotype corre- in a single DNA base in the sequence. The difference
lations occur as a direct result of the influence of the between a point mutation and a SNP is based upon
the frequency at which it is found in the population. If
SNP on health. However, more commonly, the SNP is
a point mutation is found at a frequency greater than
merely a marker of biological diversity that happens
or equal to 1% in the general population, it is called a
to correlate with health because of its proximity to
SNP. When a DNA base change is found in less than
the genetic factor that is the actual cause of the clin-
1% in the population, it is termed a point mutation.
ical phenotype.19 In this sense, the term ‘‘proximity’’
Depending on the location and substation of the point
is only a rough measure of physical closeness. More
mutations or SNPs, they result in different effects. One
specifically, proximity means that, as genetic material
type of result is a missense mutation, where a single
has passed through 5000 generations from our com-
DNA base change results in the encoding of a dif-
mon ancestral pool, recombination between the SNP
ferent amino acid. Because there is some redundancy
and the actual genetic factor has occurred only rarely.
of the three-base sequence codon for amino acids,
In genetic terminology, the SNP and the actual genetic
some single DNA base changes do not result in the
factor are said to be in linkage disequilibrium.20,21
encoding of a different amino acid. These mutations
As an extension of the current efforts to that do not result in amino acid changes are called
catalogue individual SNPs and correlate them to ‘‘silent mutations.’’ Other single DNA base changes
phenotype, efforts are being made to map and can result in more dramatic changes, such as the
use haplotypes.19 – 21 Whereas a SNP represents a change from encoding a particular amino acid to a
single-base variant, a haplotype represents a con- ‘‘stop’’ codon, which causes the termination of the
siderably longer sequence of nucleotides (averaging protein instead of producing an amino acid. These
about 25,000 bases), that tend to be inherited types of mutations are called ‘‘nonsense mutations’’
together.20 – 22 SNPs and haplotypes will be the key and can produce proteins that have altered or no
to the association studies (i.e., studies of affected functionality. Another type of genetic change is the
persons and control subjects) necessary to identify frameshift mutation, which changes the way the cell’s
the genetic factors in complex, common diseases, transcription machinery reads the sequence of the
just as family studies have been important to the gene downstream from the site of the mutation, often
identification of the genes involved in monogenic leading to a premature stop codon.
conditions. Also, until whole-genome sequencing of However, most variants in the human genome
individual patients becomes feasible clinically, the sequence have no apparent phenotypic effect, such
identification of SNPs and haplotypes will prove as the silent mutations, which replace one base with
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300 | An Introduction to Pharmacy

another yet still encode the same amino acid. Also, result of the subtlety of their phenotypic effects, some
some mutations may not alter or affect the encoded examples include mutations in the genes that cause
protein if the altered codon substitutes an amino such neurological disorders as Huntington disease and
acid for another similar one that produces little to spinocerebellar ataxia, which appear to lead to neu-
no change in the function of the protein. These are ropathological abnormalities by producing proteins
referred to as ‘‘conservative mutations.’’ In contrast, with abnormally improved function.32,33 Gain-of-
‘‘nonconservative mutations’’ replace an amino acid function mutations are often dominantly inherited,
with a very different one and are more likely to because a single copy of the mutant gene is sufficient
affect the phenotype or functioning of the protein. to alter function.
Protein structure, or three-dimensional structure, is Although it was previously assumed that muta-
affected by its particular amino acid sequence. Three- tions in the approximately 98.5% of the genome
dimensional structural changes can alter a protein that does not code for proteins do not affect the
receptor’s recognition of a hormone or signaling lig- phenotype, several examples of noncoding mutations
and, whereas proteins with enzymatic function can with important phenotypic implications have changed
be altered such that the rate at which it processes a this perception. Indeed, while the vast majority of
substrate is impacted. these ‘‘noncoding’’ mutations do not affect protein
Although genetic mutations can result in altered function, other ‘‘regulatory mutations’’ may ulti-
protein function by a variety of means, the most mately prove as important in the variability of drug
common is loss of function. Loss-of-function muta- metabolism and etiology of common diseases as the
tions alter the phenotype of the affected individual coding-region variants. Such regulatory mutations act
by decreasing the quantity or the functional activity by altering the expression of a gene and therefore
of a protein. Typically, loss-of-function mutations are the amount of its protein product. For instance, a
the most easily identified as a result of their ‘‘all- regulatory mutation could lead to the loss of expres-
or-none’’ phenotypic outcome. Therefore, examples sion of a gene, to unexpected expression in a tissue
of heritable genetic changes involving loss of func- in which it is usually silent, or to a change in the
tion are plentiful. For instance, mutations in the time at which it is expressed. Examples of regula-
glucose-6-phosphate dehydrogenase (G6PD) gene on tory mutations associated with disease include those
the X chromosome decrease the functional activity in the flanking region of the FMR1 gene (causing
of the enzyme, leading to acute hemolytic anemia fragile X syndrome),34 a regulatory site of the type I
if a male (who would have only one copy of the collagen gene (increasing the risk of osteoporosis),35
X chromosome) with the mutation is exposed to and an intronic regulatory site of the calpain-10 gene
certain drugs, including sulfonamides, primaquine, (increasing the risk of type 2 diabetes mellitus).36
and nitrofurantoins.23 Furthermore, because genes For the past several decades, pharmacogenomics has
involved in metabolism do not exist merely to han- largely been focused on drug-metabolizing enzymes,
dle pharmacological agents, variants that cause severe in particular the genetic variation in the cytochrome
G6PD deficiency also lead to hemolytic anemia when P450 enzymes. Regulatory mutations with important
affected males ingest fava beans (favism), because implications for drug metabolism have been identified
the enzyme is also important in the degradation in the gene that encodes cytochrome P450 3A5.37
of a toxic component of the beans.24,25 Additional In summary, certain SNP changes can significantly
well-described examples of loss-of-function mutations impact the functional activity of drug-metabolizing
in drug-metabolizing enzymes include cytochrome enzymes (Fig. 8.7). When a single base pair change
P450 2D6 (CYP2D6),26,27 thiopurine methyltrans- results in the coding change of a particular amino
ferase (TPMT),28,29 and dihydropyrimidine dehydro- acid to an entirely different amino acid, this change
genase (DPD); official name DYPD).30,31 Alterna- alters the primary amino acid sequence and can
tively, some mutations can result in a gain of function, potentially alter the secondary and tertiary or three-
whereby the protein can take on some new function or dimensional structure of an enzyme. A change in the
is simply more highly expressed. While fewer gain-of- three-dimensional protein structure of an enzyme can
function mutations have been identified, probably as a increase or decrease the binding affinity of a substrate
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Pharmacokinetics and pharmacodynamics | 301

Arg Tyr 248

145
Zn2+

Glu 270

Change
enzyme activity

AGT TAGAT T Change protein

conformation

AG T TCGAT T Change one

amino acid

One DNA
base change

Figure 8.7 How one SNP can impact on an individual’s response to drug therapy.

for that particular enzyme, which in turn can result marked increase in our understanding of the rela-
in an increase or decrease in the enzymatic activ- tionship between drug exposure and response. This is
ity of that particular enzyme. If this change occurs related to wider availability of the appropriate math-
in an enzyme responsible for drug metabolism, then ematical modeling methodologies. The application of
one may see a resulting impact on that individual’s these techniques in the timeline of drug development
response to a particular drug therapy. is presented in Fig. 8.8.
The clearest example of employing a pharmacoki-
netic/pharmacodynamic approach to drug develop-
ment can be seen in the area of anti-infective agents.
Pharmacokinetics/
Part of the reason for this is that these drugs are unique
Pharmacodynamics in drug in that we are not attempting to dock a molecule into
development a receptor in the human body. Rather, the target of
drug action and the site to which we are attempting to
Drug development is a long, expensive process of bind the drug is a receptor in the pathogen of interest.
discovery and preclinical development followed by This has several important consequences.
clinical trials resulting in the submission of a package The first is toxicity. Anti-infective targets are
of data to a regulatory agency that will ultimately chosen specifically so that they have little sequence
lead to licensure of that product for sale. homology to similar mammalian targets. A straight-
The goal of drug development is to find a dose forward example is the topoisomerase enzymes seen
of a drug for a specific indication that attains the in bacteria but also in man. The fluoroquinolone
desired therapeutic outcome while engendering a antimicrobials have a 100- to 1000-fold difference
low probability of the patient experiencing a toxic in the concentrations necessary for microbiological
event. Pharmacokinetics and pharmacodynamics can effect relative to activity for topoisomerase targets in
straightforwardly lead to attaining this goal. Indeed, man.37 In contrast, there is often a narrow thera-
in the past one to two decades there has been a peutic index, for example, between normal human
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302 | An Introduction to Pharmacy

bactericidal concentration). This ability to measure

Drug discovery and preclinical development
the difficulty a drug will encounter inhibiting or killing
In vitro work different pathogens allows the drug exposure neces-
Animal model sary to achieve different endpoints to be normalized
pharmacodynamics
across pathogens. In contrast, if one were to try to
Target delineation develop an antihypertensive agent, the true between-
patient variability in the affinity with which a drug will
Candidate molecule enters clinical trials bind to the receptor cannot currently be measured.
Phase i trials Certainly, in the near future, the widespread use of
Population PK modeling phamacogenomic profiling, looking, for example, for
Monte carlo simulation specific single nucleotide polymorphisms (SNPs) or
Pathogen collection deletions will allow identification of patients likely to
Target attainment respond less well to therapy. Currently, however, this
analysis
Phase II trials
true between-patient variance in receptor affinity is
completely unobserved variability.
Stochastic optimal
design
Population PK modeling
Map-bayesian estimation References
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of deficient CYP2D6 oxidative drug metabolism phe- 37. Albertini S et al. Genotoxicity of 17 gyrase-and four
notypes in black Americans. J Clin Invest 1993; 91: mammalian topoisomerase II-poisons in prokaryotic
2150–2154. and eukaryotic test systems. Mutagenesis 1995; 10:
27. Saxena R et al. Identification of a new variant CYP2D6 343–351.
allele with a single base deletion in exon 3 and its
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9
Pharmaceutical dosage forms:
manufacturing and compounding

Powders 305 Oral solid dosage forms 324

Solutions, emulsions, suspensions, and extracts 307 Coating of pharmaceutical dosage forms 327

Sterilization processes and sterility assurance 314 Oral modified-release drug delivery systems 329
Parenteral preparations 315 Aerosols 330

Pharmaceutical compounding: USP <797> Biotechnology and drugs 332

sterile preparations 316
Pharmaceutical packaging 337
Ophthalmic preparations 317
Pharmaceutical excipients 339
Medicated topicals 324
References 340

Powders flowablility, will influence the forming, packing, and

processing of a variety of dosage forms, such as gran-
Introduction ules, tablets, capsules, and suspensions. Additionally,
the solubility and bioavailability of a drug formu-
Powder applications are expanding in a variety of lation can be affected by some basic characteristics
highly developed fields, such as foods, cosmetics, of powders as well. Besides acting as pharmaceutical
chemicals, and many other fundamental fields, par- excipients, such as diluents, disintegrating agents, and
ticularly in pharmaceuticals. The majority of active lubricants, powders can also present as a pharmaceu-
pharmaceutical ingredients (APIs) are administered tical dosage form. In short, powders are fundamental
as solid dosage forms, prepared by processing and to pharmaceutics, which have a significant impact
formation of powders. A powder is defined as a on the development, manufacture, quality control,
dry, solid substance, consisting of a large number of and packing of a variety of dosage forms, including
finely divided particles (varying in size from 10 nm tablets, capsules, granules, suspensions, microcap-
to 1000 μm), and typically obtained by crushing, sules, microspheres, and dry powder inhalers (DPIs).
grinding, or comminuting.1 Powders have a large spe-
cific surface area and surface free energy, therefore,
Powders as a dosage form
exhibiting some physical and chemical properties.
Some of the properties related to pharmaceutics, such When the term ‘‘powder’’ is referred to as a dosage
as particle size, shape, surface area, density, porosity, form, it represents a formulation that is a mixture
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306 | An Introduction to Pharmacy

of powdered drug and excipients. Powders are one dissolved in an aqueous pharmaceutically acceptable
of the most conventional dosage forms. Nowadays, diluent, such as water, sterile liquid can be added
with the rapid development of formulations contain- to sterile powders contained in ampules to form the
ing highly potent compounds, the use of powders as solution just prior to use.
a dosage form has declined. Most of the powders
have been replaced by tablets and capsules. However, Divided powders
under certain circumstances, powders still have some Divided powders are bulk powders in which the
advantages over solid dosage forms on the market. individual dose has been packed separately. The tra-
Advantages of powders include: chemically stable; ditional packing of divided powders is in wrapped
relatively convenient, when able to provide a large paper. However, many problems are involved in this,
dose of drugs, rather than capsules or tablets; and when the materials are volatile, hygroscopic, or del-
the dissolution rate of oral powders containing water iquescent. Therefore modern packing methods have
soluble drugs is generally faster than that of tablets or been developed to replace the use of paper wrapping,
capsules, in which disintegration of the tablet or the such as foil and plastic laminates. Effervescent pow-
capsule shell is required prior to dissolution. Disad- ders can be packed into individual doses, because the
vantages of powders as a dosage form include: they plastic laminates can protect powders from moisture
are not convenient for patients to carry, compared adsorption. The powdered product should always be
to capsules or tablets; masking unpleasant tastes is protected from exposure to moisture.
difficult; potent drugs requiring low doses may not
be appropriate; and irritating drugs, which can cause Dusting powders
damage to the stomach, are not suitable. There are a Dusting powders are designed for external use, act-
variety of powdered dosage forms commercially avail- ing as a therapeutic, lubricant, or protective. Dusting
able, such as bulk powders, divided powders, dusting powders act locally and are intended to have no
powders, insufflations, and DPIs. systemic absorption. Dusting powders are usually
dispensed in a relatively fine state (micronized) to
Bulk powders increase efficacy and decrease irritation. Dusting pow-
Bulk powders refer to a mixture of all the materi- ders can be packed in glass or metal containers with
als, packed into a properly designed bulk container, a perforated lid to allow the powders to be dusted
such as a glass or plastic bottle. The major prob- to the effective area. Excellent flowability is necessary
lem of bulk powders is the inaccuracy of dose. The for this dosage form. Pressure aerosols are another
dose of bulk powders can be affected by many fac- delivery form that can generate dusting powders.
tors, including the measuring device (spoon), storage They are more expensive than the sifter-container,
humidity, degree of settling, and patient factors. For but several advantages are realized, such as conve-
example, the dose of bulk powder may vary for nient operation, and protection from moisture, air,
patients using differently sized spoons, or even those and contamination.
using the same spoon according to their technique.
In addition, drugs present in the bulk powders are Insufflations and Dry Powder Inhalers (DPIs)
better suited if they have a wider therapeutic window, Insufflations are fine powders of drugs, which are
a large dose, and pleasant taste. Effervescent powders dosed into the nose, ear, or throat by the use of an
are a special type of bulk powder. In addition to insufflator. The use of conventional insufflators has
drugs and other excipients, effervescent powders con- declined, due to poor patient compliance and dose
tain an effervescent couple (i.e., sodium bicarbonate non-uniformity. Some newly developed devices have
and citric acid), which reacts and effervesces when in been introduced to replace the traditional insufflators.
contact with water. The effervescent dosage form is In these devices, drugs are usually dispensed with a
helpful to cover the unpleasant taste of salty or bitter carrier excipient, such as lactose, and placed into a
drugs. In this section, bulk powders are described for hard gelatin capsule. When the device is operated, the
internal use, including oral powders, as well as pow- capsule is broken and the fine powder is inhaled into
ders for injection. For drugs that are not stable when the patient’s body.2
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Pharmaceutical dosage forms: manufacturing and compounding | 307

Pulmonary delivery of dry powder formulations the appropriate suspending properties, if it is an emul-
is a popular approach to deliver the drug to the lung sion or suspension. The theory of solutions involves
locally, for the treatment of such diseases as asthma solubility, ionization, pH control through the use of
and chronic obstructive pulmonary disease (COPD). buffers, and solubilization. Due to the complexity of
Dry powder inhalers are similar to the new insufflators some manufactured products, compounding may be
previously discussed above.3 carried out with the aid of linear programming models
to obtain the optimal product. Sterility requirement
information on the preparation and characteristics of
Solutions, emulsions, suspensions, liquid preparations that are intended for parenteral
and extracts and ophthalmic use is given in the Sterilization section.
Much has been written about the biopharmaceuti-
These dosage forms are prepared by employing cal properties of solid dosage forms. Many researchers
pharmaceutically and therapeutically acceptable begin their absorption studies of drugs administered
vehicles. The active ingredient(s) may be dissolved in in solution to assess the bioavailability relative to
aqueous media, an organic solvent, or a combination tablets and capsules. Absorption occurs when drugs
of the two, by suspending the drug (if it is insoluble) are in a dissolved state; thus, it is frequently observed
in an appropriate medium or by incorporating the that the bioavailability of oral dosage forms decreases
active pharmaceutical ingredient into one of the in the following order: aqueous solution > aqueous
phases of an oil and water emulsion. suspension > tablet or capsule. Formulation may
These dosage forms are useful for a number of influence the bioavailability and pharmacokinetics
reasons. They can be formulated for different routes of drugs in solution, including drug concentration,
of administration: orally, introduction into body cav- volume of liquid administered, pH, ionic strength,
ities, or external application. The dose can easily be buffer capacity, surface tension, specific gravity,
adjusted by dilution, making the oral liquid form viscosity, and excipients. Emulsions and suspen-
ready to be administered to children or people unable sions are more complex systems; consequently, the
to swallow tablets or capsules. Extracts eliminate the bioavailability and pharmacokinetics of these systems
need to isolate the drug in pure form, allow several may be affected by additional formulation factors,
ingredients to be administered from a single source such as surfactants, type of viscosity agent, particle
(e.g., pancreatic extract), and permit the preliminary size and particle-size distribution, polymorphism,
study of drugs from natural sources. Occasionally, and solubility of drug in the oil phase.
solutions of drugs, such as potassium chloride, are Liquid preparations may be dispensed in one
used to minimize adverse effects in the gastrointesti- of three ways: (1) in its original container, (2)
nal tract. repackaging a bulk product at the time a prescription
The preparation of these dosage forms involves is presented by the patient, or (3) compounding the
several considerations on the part of the pharmacist: solution, suspension, or emulsion in the dispensary.
the purpose of the drug, internal or external use, Compounding may involve nothing more than mixing
solubility and concentration of the drug, selection of marketed products in the manner indicated on the
the liquid vehicle(s), physical and chemical stability prescription or, in specific instances, may require the
of the drug and any excipients, preservation of the incorporation of active ingredients and excipients in
preparation, and use of appropriate excipients, such a logical and pharmaceutically acceptable manner
as buffers, solubility enhancers, suspending agents, into aqueous or organic solvents that will form the
emulsifying agents, viscosity controlling agents, col- bulk of the product.
ors, and flavors. Oral preparations require consider- The pharmacist, in the first instance, depends on
ation be given to improving patient compliance by the pharmaceutical manufacturer to produce a prod-
making an acceptable product; consequently, color, uct that is safe, efficacious, elegant, and stable until its
odor, and taste must be considered. The viscosity expiration date, when stored at conditions described
of a product must also be considered, so it has the on its label. Manufacturers guarantee efficacy of their
proper palatability for an oral preparation and has products, but, in some instances, consumer preference
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308 | An Introduction to Pharmacy

is variable. For example, cough syrups marketed by regulations (or comparable regulations in other coun-
two different manufacturers may contain the same tries), drinking water must be purified before it can
active ingredient(s), and the relative merits of the be used in pharmaceuticals. Water quality can have a
two products may appear interchangeable. In such significant impact on the stability of pharmaceutical
instances, the commercial advantage may be based on dosage forms.4 In manufacturing environments, the
factors such as flavor, color, aroma, mouth feel, and design of purified water systems must meet standards
packaging. outlined in the United States Pharmacopeia (USP) and
be validated.5 – 8
Five of the eight solvent waters described in the
Solvents for liquid pharmaceutical USP are used in the preparation of parenterals, irriga-
preparations tions, or inhalations. Purified Water must be used for
The pharmacist’s knowledge of the physical and all other pharmaceutical operations, dosage forms,
chemical characteristics of a given drug dictates the and, as needed, in all USP tests and assays. It must
selection of the appropriate solvent for a particu- meet rigid specifications for chemical purity. Purified
lar formulation. In addition to solubility, solvent Water is obtained by deionization, distillation, ion-
selection is also based on clarity, toxicity, viscos- exchange, reverse osmosis, filtration, or other suitable
ity, compatibility with excipients, chemical inertness, procedures. For parenteral administration, Water for
palatability, odor, color, and economy. In most cases, Injection, Bacteriostatic Water for Injection, or Sterile
especially solutions for oral, ophthalmic, or parenteral Water for Injection must be used. Sterile Water may
administration, water is the preferred solvent, because be sterile at the time of production but may lose this
it meets the majority of the above criteria better than characteristic, if stored improperly.
other available solvents. Often, an auxiliary solvent is The major impurities in water are calcium,
also employed to augment the solvent action of water iron, magnesium, manganese, silica, and sodium.
or to contribute to a product’s chemical or physical These cations are combined with the bicarbonate,
stability. Alcohol, glycerin, and propylene glycol have sulfate, or chloride anions. Hard waters are those
been frequently used for these purposes. that contain calcium and magnesium cations.
Solvents such as acetone and isopropyl alcohol Bicarbonates are the major impurity in alkaline
are too toxic for use in oral pharmaceutical prepa- waters. Deionization processes do not necessarily
rations, but they are useful as solvents in organic produce Purified Water that will comply with EPA
chemistry and in the preparatory stages of drug devel- requirements for drinking water. Resin columns
opment. For purposes such as this, certain solvents retain phosphates and organic debris. Either alone or
are officially recognized in the compendia. A number in combination, these substances can act as growth
of fixed oils, such as corn oil, cottonseed oil, peanut media for microorganisms. Observations have shown
oil, and sesame oil, serve useful solvent functions, par- that deionized water containing 90 organisms/mL
ticularly in the preparation of oleaginous injections, contained 106 organisms/mL after 24-hour storage.
and are recognized in the compendia for this purpose. Ultraviolet radiant energy (240 to 280 nm), heat, or
filtration can be used to limit the growth of, kill, or
Water remove microorganisms in water. The latter method
The major ingredient in most of the dosage forms employs membrane filters and can be used to remove
described herein is water. It is used both as a vehicle bacteria from heat-labile materials.
and as a solvent for the desired flavoring or medicinal The phenomenon of osmosis involves the
ingredients. Its tastelessness, freedom from irritating passage of water from a dilute solution across a
qualities, and lack of pharmacological activity make semi-permeable membrane to a more concentrated
it ideal for such purposes. There is, however, a ten- solution. Flow of water can be stopped by applying
dency to assume its purity is constant and it can pressure to the concentrated solution equal to
be stored, handled, and used with a minimum of the osmotic pressure. The flow of water can be
care. Although it is true that municipal supplies must reversed by applying a pressure greater than the
comply with Environmental Protection Agency (EPA) osmotic pressure. The process of reverse osmosis uses
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Pharmaceutical dosage forms: manufacturing and compounding | 309

the latter principle; by applying pressure greater than when ingested by children. For this reason, manufac-
the osmotic pressure to the concentrated solution turers of over-the-counter (OTC) oral drug products
(e.g., tap water), pure water may be obtained. have been asked to restrict, if possible, the use of alco-
Organic molecules are rejected on the basis of a sieve hol and include appropriate warnings in the labeling.
mechanism related to their size and shape. Small For OTC oral products intended for children under 6
organic molecules, with a molecular weight smaller years of age, the recommended alcohol content limit is
than approximately 200, will pass through the 0.5%; for products intended for children 6 to 12 years
membrane material. Because there are few organic of age, the recommended limit is 5%; and for prod-
molecules with a molecular weight of less than 200 ucts recommended for children older than 12 years of
in the municipal water supply, reverse osmosis is age and for adults, the recommended limit is 10%.
sufficient for the removal of organic material. The Rubbing Alcohol, USP, must be manufactured in
pore sizes of the selectively permeable reverse-osmosis accordance with the requirements of the US Trea-
membranes are between 0.5 and 10 nm. Viruses sury Department, Bureau of Alcohol, Tobacco, and
and bacteria larger than 10 nm are rejected, if no Firearms, Formula 23-H (8 parts by volume of ace-
imperfections exist in the membrane. The membranes tone, 1.5 parts by volume of methyl isobutyl ketone,
may and do develop openings that permit the passage and 100 parts by volume of ethyl alcohol). It contains
of microorganisms. Due to the semi-static conditions, not less than 68.5% and not more than 71.5% by vol-
bacteria can grow both upstream and downstream of ume of dehydrated alcohol, the remainder consisting
the membrane. of water and the denaturants with or without color
additives and perfume oils. Rubbing Alcohol con-
tains in each 100 mL not less than 355 mg of sucrose
Alcohols
octaacetate or not less than 1.40 mg of denatonium
Next to water, alcohol is the most commonly used sol- benzoate. The preparation may be colored with one
vent in pharmacy for many organic compounds. When or more color additives listed by the FDA for use in
mixed with water, a hydroalcoholic mixture is formed drugs, and a suitable stabilizer may be added. The
capable of dissolving both alcohol-soluble and water- use of this denaturant mixture makes the separa-
soluble substances, a feature especially useful for tion of ethyl alcohol from the denaturants a virtually
extraction and purification of active constituents from impossible task with ordinary distillation apparatus.
crude drugs and synthetic procedures. Alcohol, USP, is This discourages the illegal removal and use of the
94.9% to 96.0% by volume, at 15.56◦ C of C2 H5 OH, alcoholic content of Rubbing Alcohol as a beverage.
and Dehydrated Alcohol, USP, contains not less than The product is volatile and extremely flammable and
99.5% C2 H5 OH by volume. Dehydrated alcohol is should be stored in tight containers remote from igni-
utilized when an essentially water-free alcohol is nec- tion sources. It is used externally as a soothing rub
essary. Alcohol is widely used for its miscibility with for bedridden patients, a germicide for instruments,
water and its ability to dissolve many water-insoluble and a skin cleanser prior to injection.
ingredients, including drug substances, flavors, and Isopropyl Rubbing Alcohol is about 70% by vol-
antimicrobial preservatives. Alcohol is used in liq- ume isopropyl alcohol, the remainder consisting of
uid products as an antimicrobial preservative or in water with or without color additives, stabilizers, and
conjunction with parabens, benzoates, sorbates, and perfume oils. It is used exclusively as a vehicle in
other agents. Diluted Alcohol, NF, is prepared by topical products and applications. This preparation
mixing equal volumes of Alcohol, USP, and Purified and a commercially available 91% isopropyl alcohol
Water, USP. Due to contraction upon mixing, the solution are commonly employed to disinfect needles
final volume of such mixtures is not the sum of the and syringes for hypodermic injections of insulin and
individual volumes of the two components, but is for disinfecting the skin.
about 3% less. Glycerin is a clear, syrupy liquid with a sweet
The United States Food and Drug Administra- taste and is miscible with water and alcohol. Glycerin
tion (FDA) has expressed concern regarding undesired is used in a wide variety of pharmaceutical formula-
pharmacologic and potentially toxic effects of alcohol tions, including oral, otic, ophthalmic, topical, and
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310 | An Introduction to Pharmacy

parenteral preparations. In topical pharmaceutical idants may retard or delay oxidation by rapidly
formulations and cosmetics, glycerin is used primarily reacting with free radicals as they are formed (quench-
for its humectant and emollient properties. In par- ing). Common antioxidants include propyl, octyl, and
enteral formulations, glycerin is used mainly as a dodecyl esters of gallic acid, butylated hydroxyanisole
solvent. In oral solutions, glycerin is used as a sol- (BHA), butylated hydroxytoluene (BHT), and the
vent, sweetening agent, antimicrobial preservative, tocopherols or vitamin E. Connors and coworkers
and viscosity-increasing agent. provide a detailed approach for the prevention of
Propylene glycol has become widely used as a oxidative degradation of pharmaceuticals.9 Table 9.1
solvent, extractant, and preservative in a variety lists common antioxidants and chelating agents used
of liquid pharmaceutical formulations, including in pharmaceutical preparations.
parenterals. Propylene glycol is a viscous liquid and is The USP states that, if a product must be repack-
miscible with water and alcohol. It is a useful solvent aged, the container specified by the compendium must
with a wide range of applications and is often used be used. For example, a suitable opaque plastic con-
in place of glycerin. As an antiseptic, it is similar to tainer should be used, if a light-resistant container
ethanol, and against molds it is similar to glycerin and is specified. If a product is diluted, or where two
only slightly less effective than ethanol. Propylene products are mixed, the pharmacist should use his
glycol is also used as a carrier for emulsifiers and as or her knowledge to guard against incompatibility
a vehicle for flavors, as opposed to ethanol, due to its
lack of volatility.
Table 9.1 Common antioxidants and chelating
Stability considerations agents used in liquid pharmaceutical dosage
forms
The stability of the active ingredient in the final
product is a primary concern to the formulator, the Antioxidants Alpha tocopherol
pharmacist, and the patient. In general, drug sub- Ascorbic acid
stances are less stable in aqueous media than solid Acorbyl palmitate
dosage forms, and it is important to properly stabilize
Butylated hydroxyanisole
and preserve solutions, suspensions, and emulsions
Butylated hydroxytoluene
that contain water. Acid–base reactions, acid or
Monothioglycerol
base catalysis, oxidation, and reduction can occur in
these products. Reactions and interactions (adsorp- Potassium metabisulfite

tion) can arise from ingredient–ingredient interac- Propionic acid

tions or container–product interactions. For pH sen- Propyl gallate

sitive compounds, any of these interactions may alter Sodium ascorbate
the pH and cause precipitation. Sodium bisulfite
Vitamins, essential oils, and almost all fats and Sodium metabisulfite
oils can be oxidized. Formulators use the word ‘‘auto- Sodium sulfite
oxidation,’’ when the ingredient(s) reacts with oxy-
gen but without drastic external interference. Such Chelating Agents Citric acid monohydrate

reactions can be initiated by heat, light, including Disodium edetate

ultraviolet radiant energy, peroxides, or other labile Dipotassium edetate

compounds or heavy metals, such as copper or iron. Edetic acid

This initiation step results in the formation of a free Fumaric acid
radical that then reacts with oxygen. The free radical Malic acid
is regenerated and reacts with more oxygen (propa- Phosphoric acid
gation). The reactions are terminated when the free Sodium edetate
radicals react with one another. Tartaric acid
The effect of trace metals can be minimized using Trisodium edetate
chelating agents such as citric acid or EDTA. Antiox-
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Pharmaceutical dosage forms: manufacturing and compounding | 311

and instability. Oral antibiotic preparations consti- Tests and Assays, parts <51> and <61> of the USP,
tuted into liquid form should never be mixed with and other methods reported in the literature.12 – 15
other products. If the chemical stability of extempo- When a preservative is required, its selection is
raneously prepared liquid preparations is unknown, based on several considerations, in particular, the site
their use should be minimized and every care taken to of use, whether internal, external, or ophthalmic.16
ensure product characteristics will not change while Several researchers have described various interac-
used by the patient. tions that must be considered when preservatives are
Due to the number of excipients and additives selected.17,18 The major criteria that should be con-
in these preparations, it is recommended that all the sidered in selecting a preservative are as follows: its
ingredients be listed on the container to reduce the physicochemical properties, such as solubility and dis-
risks that confront hypersensitive patients when these sociation constant, and it should be effective against
products are administered. Finally, the pharmacist a wide spectrum of microorganisms, stable for its
should inform the patient regarding the appropriate shelf-life, nontoxic, nonsensitizing, compatible with
use of the product, the proper storage conditions, and the ingredients in the dosage form, inexpensive, and
the time after which it should be discarded. relatively free of taste and odor.
The chosen preservative should be sufficiently sta-
ble and soluble to achieve adequate concentration
Preservatives to provide protection. This choice is more critical in
In addition to stabilization of pharmaceutical prepa- two- and three-phase emulsion systems in which the
rations against chemical and physical degradation, preservative may be more soluble in the oil phase than
liquid and semisolid preparations must be protected in the aqueous phase.15,19 The pH of the preparation
against microbial contamination. Nearly all products must be considered to ensure the preservative does
described in this section contain water and, thus, with not dissociate, rendering it ineffective, or degrade by
certain exceptions, such as aqueous acids, will support acid- or base-catalyzed hydrolysis. The undissociated
microbial growth. Aqueous solutions, syrups, emul- moiety or molecular form of a preservative possesses
sions, and suspensions often provide excellent growth preservative capacity because the ionized form is
media for micro-organisms, such as molds, yeast, and unable to penetrate microorganisms. The preservative
bacteria (typically Pseudomonas, E.coli, Salmonella must be compatible with the formulation ingredi-
and Staphylococcus). ents and the product container and closure. Finally,
Kurup and Wan describe many preparations that the preservative must not impact the safety or com-
are not preserved adequately and are not able to fort of the patient when administered. For instance,
resist microbial contamination.10 Products such as preservatives used in ophthalmic preparations must
ophthalmic and injectable preparations are sterilized be non-irritating. Chlorobutanol, benzalkonium chlo-
by autoclaving (20 minutes at 15 pounds of pressure ride, and phenylmercuric nitrate are commonly used
at 120◦ C, followed by dry heat at 180◦ C for 1 hour) in these applications.
or filtration. However, many require the presence Although few microorganisms are viable below a
of an antimicrobial preservative to maintain aseptic pH of 3 or above a pH of 9, most aqueous phar-
conditions throughout their stated shelf-life.11 Cer- maceutical preparations are manufactured within the
tain hydroalcoholic and alcoholic preparations do not favorable pH range. Acidic preservatives, such as
require addition of a chemical preservative if the alco- benzoic acid, boric acid, and sorbic acid, are less dis-
hol content is sufficient to prevent microbial growth: sociated and more effective in acidic formulations.
an alcohol content of 15% by weight in acid solutions Similarly, alkaline preservatives are less effective in
and 18% by weight in alkaline solutions is sufficient acidic or neutral conditions and more effective in alka-
to prevent microbial growth. Most alcohol contain- line formulations. The scientific literature is rife with
ing preparations, such as elixirs, spirits, and tinctures, examples of incompatibilities between preservatives
are self-preserving and do not require preservation. and other pharmaceutical adjuncts.20 – 22 Commonly
Indeed, the formulator should challenge any new used macromolecules, including cellulose derivatives,
preparation by procedures described in the General polyethylene glycol, and tragacanth gum, have been
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312 | An Introduction to Pharmacy

reported to cause preservative failure, due to binding Suitable concentrations for preservative action are in
and adsorption.23,24 the range 0.05% to 2%. Its preservative action is
The mode of action by which preservatives due to the nonionized form; consequently, it is only
interfere with microbial growth, multiplication, effective in acid media. The optimum antibacterial
and metabolism occurs through one of several activity is obtained at pH 4.5, and practically no
mechanisms. Preservatives often alter cell membrane activity is observed above pH 6. Sorbic acid is subject
permeability, causing leakage of cell constituents to oxidation, particularly in the presence of light
(partial lysis), complete lysis and cytoplasmic leak- and in aqueous solutions. Activity against bacteria
age, and/or coagulation of cytoplasmic constituents can be variable, due to its limited stability. Thus,
(protein precipitation). Other preservatives inhibit sorbic acid is frequently used in combination with
cellular metabolism by interference with enzyme other antimicrobial preservatives or glycols in which
systems or cell wall synthesis, oxidation of cellular synergistic effects occur.
constituents, or hydrolysis.
Table 9.2 lists preservatives commonly used in Esters
pharmaceutical products with typical concentration Parabens are esters of p-hydroxybenzoic acid and
levels. Preservatives may be grouped into a number include the methyl, ethyl, propyl, and butyl deriva-
of classes, depending upon their molecular structure. tives. The water solubility of the parabens decreases
These basic groups are discussed below. as the molecular weight increases from 0.25% for the
methyl ester to 0.02% for the butyl ester. These com-
Alcohols pounds are used widely in pharmaceutical products,
Ethanol is useful as a preservative; when it is used stable over a pH range of 4 to 8, and have a broad
as a solvent, however, it does need a relatively high spectrum of antimicrobial activity, although they are
concentration (somewhat greater than 15%) to be most effective against yeasts and molds. Antimicro-
effective. Too high a concentration may result in bial activity increases as the chain length of the alkyl
incompatibilities in suspension and emulsion systems. moiety is increased, but aqueous solubility decreases;
Propylene glycol also is used as a solvent in oral solu- therefore, a mixture of parabens is frequently used
tions and topical preparations, and it can function to provide effective preservation. Preservative efficacy
as a preservative in the range 15 to 30%. It is not is also improved by the addition of propylene glycol
volatile like ethanol and is used frequently not only (2% to 5%) or by using parabens in combination with
in solutions, but also in suspensions and emulsions. other antimicrobial agents, such as imidurea. Activity
Chlorobutanol and phenylethyl alcohol are other is reduced in the presence of nonionic surface active
alcohols used in lower concentrations (approximately agents, due to binding. In alkaline solutions, ioniza-
1%) as preservatives. tion takes place, and this reduces their activity; in
addition, hydrolytic decomposition of the ester group
Acids occurs with a loss of activity.
Benzoic acid has a low solubility in water (about
0.34% at 25◦ C) but the apparent aqueous solubility Quaternary ammonium compounds
of benzoic acid may be enhanced by the addition Benzalkonium chloride is a mixture consisting prin-
of citric acid or sodium acetate to the solution. The cipally of the homologs C12 H25 and C14 H29 . This
concentration range used for inhibitory action varies preservative is used at a relatively low concentra-
from 0.1% to 0.5%. Activity depends on the pH of tion (0.002% to 0.02%) depending on the nature
the medium, because only the undissociated acid has of the pharmaceutical product. This class of com-
antimicrobial properties. Optimum activity occurs at pounds has an optimal activity over the pH range 4
pH values below 4.5; at values above pH 5, benzoic to 10 and is quite stable at room temperature. Due
acid is almost inactive.25 It has been reported that to the cationic nature of this type of preservative, it
antimicrobial activity of benzoic acid is enhanced by is incompatible with many anionic compounds and
the addition of the basic protein protamine.26 Sorbic can bind to nonionic surfactants. It is used in prepa-
acid also has a low solubility in water, 0.3% at 30◦ C. rations for external use or those solutions that come
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Pharmaceutical dosage forms: manufacturing and compounding | 313

Table 9.2 Common preservatives used in liquid pharmaceutical dosage forms and their typical
concentration levels

Antimicrobial preservatives Typical usage level (% w/w) Antifungal preservatives Typical usage level (% w/w)

Benzalkonium Chloride 0.002–0.02% Butyl Paraben 0.1–0.4%

Benzethonium Chloride 0.01–0.02% Methyl Paraben 0.1–0.25%

Benzyl Alcohol 3.0% Ethyl Paraben 0.1–0.25%

Bronopol 0.01–0.1% Propyl Paraben 0.1–0.25%

Cetrimide 0.005% Benzoic Acid 0.1–0.5%

Cetylpyridinium chloride 0.0005–0.0007% Potassium sorbate 0.1–0.2%

Chlorhexidine 0.002–0.5% Sodium Benzoate 0.1–0.2%

Chlorobutanol 0.5% Sodium Propionate 5–10%

Chlorocresol 0.2% Sorbic Acid 0.05–0.2%

Chloroxylenol 0.1–0.8%

Cresol 0.15–0.3%

Ethyl Alcohol 15–20%

Glycerin 20–30%

Hexetidine 0.1%

Imidurea 0.03–0.5%

Phenol 0.1–0.5%

Phenoxyethanol 0.5–1.0%

Phenylethyl Alcohol 0.25–0.5%

Phenylmercuric Nitrate 0.002–0.01%

Propylene Glycol 15–30%

Thimerosal 0.1%

in contact with mucous membranes. In ophthalmic strains of Pseudomonas. A concentration of 0.002%

preparations, benzalkonium chloride is widely used to 0.02% is used in nasal and otic formulations,
at a concentration of 0.01% to 0.02% w/w. Often, sometimes in combination with 0.002% to 0.005%
it is used in combination with other preservatives thimerosal. Benzalkonium chloride 0.01% w/v is also
or excipients, particularly 0.1% w/v disodium ede- employed as a preservative in small-volume parenteral
tate, to enhance its antimicrobial activity against products.
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314 | An Introduction to Pharmacy

Clearly, when the pharmacist dispenses or com- component of which in the context of sterile pharma-
pounds liquid preparations, responsibility is assumed, ceuticals and medical devices is ‘‘sterility’’. Sterility,
along with the manufacturer, for the maintenance of which has been defined as the absence of life (or inabil-
product stability. General chapter <1191> of the ity to reproduce), is an absolute concept. Items are
USP describes stability considerations for dispensing, ‘‘sterile,’’ or they are not; there is no middle ground.
which should be studied in detail.12 Stock should be However, at the present time, there are no nonde-
rotated and replaced, if expiration dates on the label structive means to demonstrate sterility. Instead we
so indicate. Products should be stored in the man- define processes to attain that goal, subject the mate-
ner indicated on the manufacturer’s label or in the rials to these processes, and then estimate the results.
compendium. Further, products should be checked For the lethal sterilization processes, whether termi-
for evidence of instability. With respect to solutions, nal or in-process, the ‘‘sterility’’ expectation is fulfilled
elixirs, and syrups, major signs of instability are color by demonstrating a minimum Probability of a Non-
change, precipitation, and evidence of microbial or Sterile Unit (PNSU) of not more than one positive
chemical gas formation. Emulsions may cream, but, if unit in 1 000 0000 units or 1 × 10−6 .28,29 It must be
they break (i.e., there is a separation of an oil phase), understood that the microorganism of concern in any
the product is considered unstable. Sedimentation and process is the bioburden present prior to treatment.
caking are primary indications of instability in suspen- In actual practice this target is often exceeded by a
sions. The presence of large particles may mean exces- substantial margin as the industry is inherently con-
sive crystal growth has occurred (Ostwald ripening). servative about such a critical quality attribute. The
focus of the treatment is on the removal/destruction of
any bioburden microorganisms that might be present
Sterilization processes and sterility on/in the materials prior to the process. Where liq-
assurance uids are sterilized by filtration, the filters utilized are
shown capable of removing a minimum of seven logs
Microorganisms represent a potential threat to human of a challenge microorganism specifically cultured for
health in various settings. The presence of some its small size and potential penetration of the filter.
microorganisms in foods, pharmaceuticals and even In aseptic processing, which relies on prior steriliza-
the environment can cause illness and even death. tion of the materials, equipment, and other items,
Louis Pasteur established the link between microbes the goal is to prevent the recontamination of those
and disease, and his seminal work influenced Joseph items in the assembly process. Aseptic process simu-
Lister to use phenol to reduce contamination risk lations are used to demonstrate contamination rates
during invasive surgery in the late 1800s.27 This of not more than one unit in 5000 units. The vari-
knowledge led to the introduction of multiple mea- ous estimations of performance from these processes
sures to mitigate the risks associated with microbial are established during the validation efforts with the
contamination and led to the development of ster- assumption that routine operations deliver compara-
ilization methods, sanitization practices, and other ble (or superior) results. In most instances everyday
microbial control measures intended to assure prod- manufacturing performance is well in excess of the
uct and procedural safety. targeted and demonstrated minimum levels estab-
In the pharmaceutical and medical device indus- lished by the validation efforts. Nevertheless, the level
tries, sterile products are produced using two primary of sterility present after any of these processes is never
methods: terminal sterilization or aseptic processing. known with any degree of precision.
Where products are manufactured with aseptic pro- Sterilization and aseptic processing are essential
cessing followed by terminal sterilization, there is practices for healthcare product manufacture and
little difference in the manner in which either process many healthcare services. The execution of these
is controlled compared to when they are performed processes in an appropriate manner is essential for
individually. patient safety. Products that are sterile but non-stable,
In addition to the therapeutic goal of all medi- due to excessive conditions during sterilization, are
cal products there is a safety requirement, a major unusable. Products that are stable but unsafe as a
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Pharmaceutical dosage forms: manufacturing and compounding | 315

result of inadequately robust aseptic processing are • Injectable solutions must be free from visible par-
equally inappropriate. Achieving suitably safe and ticulate matter. This includes reconstituted sterile
stable products for administration as parenterals, powders.
ophthalmics, or by inhalation requires careful con- • Products should be isotonic, although strictness of
sideration of many factors, including the method of isotonicity depends on the route of administration.
sterilization, its effects on the materials, and how Products administered into the cerebrospinal fluid
those materials are handled post-sterilization. must be isotonic. Ophthalmic products, although
not parenteral, must also be isotonic. Products to
be administered by bolus injection by routes other
Parenteral preparations than intravenous (IV) should be isotonic, or at least
very close to isotonicity. IV infusions must be iso-
Parenteral (Gk, para enteron, beside the intestine)
tonic.
dosage forms differ from all other drug dosage forms,
• All products must be stable, not only chemically
because they are injected directly into body tissue
and physically like all other dosage forms, but also
through the primary protective system of the human
‘‘stable’’ microbiologically (i.e., sterility, freedom
body, the skin, and mucous membranes. They must
from pyrogenic and visible particulate contamina-
be exceptionally pure and free from physical, chemi-
tion must be maintained throughout the shelf-life
cal, and biological contaminants. These requirements
of the product).
place a heavy responsibility on the pharmaceutical
industry to practice current good manufacturing prac-
• Products must be compatible, if applicable, with IV
diluents, delivery systems, and other drug products
tices (cGMPs) in the manufacture of parenteral dosage
co-administered.
forms and on pharmacists and other healthcare pro-
fessionals to practice good aseptic practices (GAPs) in
dispensing parenteral dosage forms for administration General manufacturing process
to patients.
The preparation of a parenteral product may encom-
Certain pharmaceutical agents, particularly pep-
pass four general areas:
tides, proteins, and many chemotherapeutic agents,
can only be given parenterally, because they are
1. Procurement and accumulation of all components
inactivated in the gastrointestinal tract when given
in a warehouse area, until released to manufactur-
by mouth. Parenterally-administered drugs are rel-
ing;
atively unstable and generally highly potent drugs
2. Processing the dosage form in appropriately
that require strict control of administration to the
designed and operated facilities;
patient. Due to the advent of biotechnology, par-
3. Packaging and labeling in a quarantine area, to
enteral products have grown in number and usage
ensure integrity and completion of the product;
around the world. Parenteral drugs are formulated as
and
solutions, suspensions, emulsions, liposomes, micro-
4. Controlling the quality of the product throughout
spheres, nanosystems, and powders to be reconsti-
the process.
tuted as solutions.

Procurement encompasses selecting and testing

Overview of unique characteristics of according to specifications of the raw-material ingre-
parenteral dosage forms dients and the containers and closures for the primary
Parenteral products are unique from any other type and secondary packages. Microbiological purity, in
of pharmaceutical dosage form for the following the form of bioburden and endotoxin levels, has
reasons: become standard requirements for raw materials.
Processing includes cleaning containers and equip-
• All produces must be sterile. ment to validated specifications, compounding the
• All products must be free from pyrogenic (endo- solution (or other dosage form), filtering the solution,
toxin) contamination. sanitizing or sterilizing the containers and equipment,
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316 | An Introduction to Pharmacy

filling measured quantities of product into the sterile not properly evaluated for compatibility with the final
containers, stoppering (either completely or partially product. Assessment and selection of containers and
for products to be freeze-dried), freeze-drying, termi- closures are essential for final product formulation,
nal sterilization (if possible), and final sealing of the to ensure the product retains its purity, potency, and
final primary container. quality during the intimate contact with the container
Packaging normally consists of the labeling and throughout its shelf-life. Administration devices (e.g.,
cartoning of filled and sealed primary containers. syringes, tubing, transfer sets) that come in contact
Control of quality begins with the incoming sup- with the product should be assessed and selected with
plies, being sure that specifications are met. Careful the same care as are containers and closures, even
control of labels is vitally important, as errors in though the contact period is usually brief.
labeling can be dangerous for the consumer. Each
step of the process involves checks and tests to ensure
the required specifications at the respective step are Pharmaceutical compounding: USP
being met. Labeling and final packaging operations <797> sterile preparations
are becoming more automated.
The quality control unit is responsible for review- Medications that are compounded and injected into
ing the batch history and performing the release humans or other animals must be sterile and free
testing required to clear the product for shipment from contaminants and pyrogen. Mortality and mor-
to users. A common FDA citation for potential viola- bidity from contaminants being injected into the
tion of cGMP is the lack of oversight by the quality blood-stream require that personnel involved in intra-
control unit in batch testing and review and approval venous compounding follow more stringent guidelines
of results. when compounding sterile preparations. In 2004, the
USP/NF published standards of practice for com-
pounding sterile preparations. The chapter, referred
Components
to as USP <797>, was developed in part as a result
Components of parenteral products include the active of patient injuries and deaths that had occurred sec-
ingredient, formulation additives, vehicle(s), and pri- ondary to problems with medication delivery and
mary container and closure. Establishing specifica- sterile compounding.30 Publication of USP <797>
tions to ensure the quality of each of these components is meant to increase practitioners’ understanding of
of an injection is essential. Secondary packaging is how sterile preparations must be prepared in order
relevant more to marketing considerations, although to achieve safe, accurate, quality sterile compounds
some drug products might rely on secondary packag- for patient use.31 The chapter was updated in 2008
ing for stability considerations, such as added protec- to clarify risk levels, primary engineering controls
tion from light exposure for light-sensitive drugs and (PECs), personnel training and evaluation, verifi-
antimicrobial preservatives. cation of compounding accuracy, finished prepa-
The most stringent chemical-purity requirements ration checks and tests, storage and beyond use
will normally be encountered with aqueous solutions, dating, maintenance of sterility and purity of dis-
particularly if the product is sterilized at an elevated pensed and distributed sterile preparations, and sug-
temperature where reaction rates will be accelerated gested standard operating procedures.31 The 2008
greatly. Dry preparations pose relatively few reaction USP <797> also introduced new topics and made
problems but may require definitive physical specifi- some significant changes in the areas of immedi-
cations for ingredients that must have certain solution ate use sterile preparations, single use and multiple
or dispersion characteristics when a vehicle is added. dose vials, hazardous compounding including radio-
Containers and closures are in prolonged, intimate pharmaceuticals and allergen extracts, environmental
contact with the product and may release substances quality control, personnel training and competency
into, or remove ingredients from, the product. Rubber evaluation.31 Since its publication in 2008, the Inter-
closures are especially problematic (sorption, leach- national Journal of Pharmaceutical Compounding
ables, air and moisture transmission properties), if and the American Society of Health Systems Pharmacy
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Pharmaceutical dosage forms: manufacturing and compounding | 317

(ASHP) have published numerous articles to help number one priority. Developing quality assurance
practitioners implement chapter USP <797> into all programs and following standard operating proce-
aspects of sterile compounding.30 – 52 The objective dures are necessary to maintain continuous quality
of the USP <797> chapter is to ‘‘describe con- care to patients.
ditions and practices to prevent harm, including
death, to patients that could result from (1) microbial
contamination (nonsterility), (2) excessive bacterial Ophthalmic preparations
endotoxins, (3) variability in the intended strength
of correct ingredients that exceeds either monograph Introduction53
limits for official articles [sic] or 10% for nonoffi- Ophthalmic preparations are specialized dosage forms
cial articles, (4) unintended chemical and physical designed to be instilled onto the external surface of
contaminants, and (5) ingredients of inappropriate the eye (topical), administered inside the eye (intraoc-
quality in compounded sterile preparations (CSPs).’’ ular) or adjacent to it (periocular, e.g., juxtascleral
31
While many pharmacies have become compliant, or subtenon), or used in conjunction with an oph-
others cite costs and lack of scientific justification to thalmic device. The last includes preparations used
support these changes.32,33 Most hospitals and facil- in conjunction with surgical implantation (such as an
ities have gradually implemented the standards from intraocular lens) and dry eye formulations compatible
the original recommendations in 2004, and are now with a punctal appliance (e.g., a punctal plug), and
taking steps towards becoming compliant with the extends to a variety of solutions used in the mainte-
2008 revisions.32,33 nance of contact lenses. The preparations may have
In order to facilitate implementation of the stan- any of several purposes (e.g., therapeutic, prophy-
dards, Baxter Healthcare Corporation and ASHP lactic, or palliative for topically administered agents)
developed a discussion guide that suggests among but include mechanical, chemical, and biochemical
other things, that a gap analysis be completed. A gap actions of agents used in the care of ocular appliances
analysis in this context is used to identify areas in need and tissue prophylaxis during or following surgery.
of improvement in sterile compounding facilities.30 Because of the dangers associated with the adminis-
USP <797> requirements should be compared to tration or repetitive administration of intraocular and
the current practices of compounding personnel and periocular preparations, their suitability is restricted
environmental standards of the compounding facility to therapeutic applications or surgical adjuncts.
to determine where ‘‘gaps’’ exist. Successful comple- The versatility of dosage forms of ophthalmic
tion of a gap analysis and subsequent revisions to preparations allows the clinician to choose the form
address the identified gaps may result in a direct pos- most suitable for the function desired. Therapeuti-
itive impact on the delivery of quality patient care cally active formulations can be designed to provide
and may be used to demonstrate compliance with the extended action for convenience or for reduction in
standards to regulatory authorities.34 risk of repetitive administration, improved bioavail-
In an effort to control the purity and steril- ability of the agent, or improved delivery to a targeted
ity of intravenous medications, the USP/NF devel- tissue. The residence of an ocular preparation can
oped rules and recommendations termed USP Chapter range from the few seconds needed for tears to clear an
<797>. These rules and recommendations apply to irritating substance; to hours for a gel, a gel-forming
all injected medications whether made by pharmacy, solution, or an ointment; to months or years for an
nursing, medicine, dental, or and any other healthcare intraocular or periocular dosage form. A preparation
provider. The costs associated with implementation may be strictly therapeutic or may serve in prophy-
have created some controversy. However, a majority laxis. The latter includes surgical adjuncts to maintain
of institutions have come into compliance with the the health of fragile cells, and postsurgical or post-
2004 standards, and are now in the process of imple- trauma preparations designed to prevent or reduce the
menting the 2008 standards. The risks associated likelihood of infection. Another form of prophylaxis,
with injectable medications are high when standards one for a device, is the antisoiling function provided
are not followed. Quality patient care must be the by some contact lens solutions.
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318 | An Introduction to Pharmacy

Ophthalmic preparations are similar to parenteral and into the 1950s, ophthalmic preparations were
dosage forms in their requirement for sterility as mostly compounded by the pharmacist for immediate
well as considerations for osmotic pressure (tonic- use. Not until 1953 was there a legal requirement
ity), preservation, tissue compatibility, the avoidance by the FDA that all manufactured ophthalmic solu-
of pyrogens in intraocular dosage forms, particulate tions be sterile. The range of medicinal agents to treat
matter, and suitable packaging. eye disorders was limited, as was the state of eye
Topical therapeutic dosage forms have custom- surgery and vision correction, which was limited to
arily been restricted to solutions, suspensions, and eyeglasses. In the past 50 years, a modern pharmaceu-
ointments. But with advances in materials science, the tical industry specializing in ophthalmic preparations
range of ophthalmic dosage forms has expanded sig- has developed to support the advances in diagnosis
nificantly to include gels, either preformed or sponta- and treatment of eye diseases, in eye surgery, and in
neous gels responsive to the ocular environment, and contact lens design and use. Because of the variety of
ocular inserts, both forms reducing dosage frequency. ophthalmic products readily available commercially,
These are most often multidose products, containing the pharmacist now is rarely required to compound
suitable preservative(s) to meet compendial preserva- a patient’s ophthalmic prescription. More important,
tive effectiveness test (e.g., US Pharmacopeia (USP),54 however, is that the pharmacist appreciate even subtle
European Pharmacopoeia,55 or Japanese Pharma- differences in formulations that may impact efficacy,
copoeia56 ) requirements. Now, however, single-dose comfort, compatibility, or suitability of a preparation
units (also referred to as unit-dose products) that are for particular patients.
preservative-free preparations have become available, Currently and in the future, in addition to the
generally packaged in 0.25 mL to up to 0.8 mL form- advances in dosage-form technology, drug molecules
fill-seal plastic containers. These unit-dose containers will be designed and optimized specifically for oph-
are designed to be discarded after a single use or after thalmic application. New therapies may become avail-
a single day’s use if the container has a reclosable able for preventing blindness caused by degenerative
feature and the product is so labeled. disease – including age-related macular degeneration
Injections and implants have been developed for (AMD), macular edema, and diabetic retinopathy.
intraocular drug delivery. Irrigating solutions and vis- Biotechnological products may also become available
coelastic gels are available specifically for adjunctive to treat causes of multifactorial eye disorders like
use in ophthalmic surgery. Specialized formulations glaucoma. Such specialized therapeutic agents also
are now available for use in the care of contact will require carefully designed and compatible dosage
lenses. The designs of these preparations, meeting all forms.
of the requirements for safety, efficacy, component
compatibility, tissue acceptability, storage, shipping,
Types of ophthalmic dosage forms
and shelf- life, are beyond the scope of this review.
Nonetheless, a description of the requirements and Ophthalmic products include prescription and OTC
the designs for some of these formulations should be drugs, products for the care of contact lenses, and
illustrative and didactic. products used in conjunction with ocular surgery.
From a historical perspective, preparations This section will focus on the pharmaceutical aspects
intended for treatment of eye disorders can be traced of the various ophthalmic dosage forms encompassed
to the writings of the Egyptians, Greeks, and Romans. by these types of products. The therapeutic uses
In the Middle Ages, collyria were referred to as mate- of individual products can be found in several ref-
rials that were dissolved in water, milk, or egg white erence books along with the individual product’s
and used as eyedrops. One such collyrium contained labeling.57,58
the mydriatic substance belladonna to dilate the
pupils of milady’s eyes for cosmetic purposes. Ophthalmic solutions
From the time of belladonna collyria, ophthalmic These are by far the most common dosage forms for
technology progressed at a pharmaceutical snail’s delivering drugs to the eye. By definition, ingredients
pace until after World War II. Before World War II are completely soluble such that dose uniformity is
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Pharmaceutical dosage forms: manufacturing and compounding | 319

not an issue, and there is little physical interference particles to be retained in the cul-de-sac, the contact
with vision. The principal disadvantage of solutions time and duration of action of a suspension could
is their relatively brief contact time with the drug theoretically exceed that of a solution. The drug is
and the absorbing tissues of the external eye. Contact absorbed from solution, and the solution concentra-
time can be increased by the inclusion of viscosity- tion is replenished from retained particles. Each of
imparting agents; however, their use is limited to these actions is a function of particle size, with solu-
relatively low viscosities so as to allow dispensing of bility rate being favored by smaller size and retention
the eyedrop from the container or eyedropper and favored by a larger size; thus, optimum activity should
to minimize excessive blurring of vision. A residue result from an optimum particle size.
can be produced on the eyelashes and around the eye For aqueous suspensions the parameters of intrin-
when any excess of a viscous solution spills out of sic solubility and dissolution rate must be considered.
the eye and dries. The residue usually can be removed The intrinsic solubility determines the amount of
easily by careful wiping with a moist towel to the drug actually in solution and available for immediate
closed eye. absorption upon instillation of the dose. As the intrin-
sic solubility of the drug increases, the concentration
Gel-forming solutions of the drug in the saturated solution surrounding the
Ophthalmic solutions (usually water-based), which suspended drug particle also increases. For this rea-
contain a polymer system that is a low-viscosity liq- son, any comparison of different drugs in suspension
uid in the container but gels on contact with the tear systems should include their relative intrinsic solu-
fluid, have increased contact time and can provide bilities. The observed differences in their biological
increased drug absorption and prolonged duration of activities may be ascribed wholly or in part to the
therapeutic effect. The liquid-to-gel phase transition differences in this physical parameter. As the drug
can be triggered by a change in temperature, pH, penetrates the cornea and the initial saturated solu-
ionic strength, or presence of tear proteins, depending tion becomes depleted, the particles must dissolve to
on the particular polymer system employed. Timolol provide a further supply of the drug. The requirement
maleate gel-forming solutions formulated with spe- here is that the particles must undergo significant dis-
cific patented gellan or xanthan gums have clinically solution within the residence time of the dose in the
demonstrated prolonged duration of intraocular pres- eye if any benefit is to be gained from their presence
sure (IOP) lowering, such that their dosing frequency in the dosing system.
can be reduced from twice to once a day.59,60 For a drug whose dissolution rate is rapid, the
dissolution requirement may present few problems,
Powders for solutions but for a slowly soluble substance the dissolution rate
Drugs that have very limited stability in aqueous becomes critical. If the dissolution rate is not suffi-
solution can sometimes be prepared as sterile powders ciently rapid to supply significant additional dissolved
for reconstitution by the pharmacist before dispensing drug, there is the possibility that the slowly soluble
to the patient. The sterile powder should be aseptically substance in suspension provides no more drug to the
reconstituted with the accompanying sterile diluent aqueous humor than does a more dilute suspension
that has been optimized for dissolution, preservation, or a saturated solution of the substance in a similar
and stability. The pharmacist must convey to the vehicle. Obviously, the particle size of the suspended
patient any special storage instructions, including the drug affects the surface area available for dissolu-
expiration date. tion. Particle size also plays an important part in the
irritation potential of the dosing system. This con-
Ophthalmic suspensions sideration is important, because irritation produces
Suspensions are dispersions of finely divided, rela- excessive tearing and rapid drainage of the instilled
tively insoluble drug substances in an aqueous vehicle dose, as discussed earlier. It has been recommended
containing suitable suspending and dispersing agents. that particles be smaller than 10 μm to minimize irri-
The vehicle is, among other things, a saturated solu- tation to the eye. It should be kept in mind, however,
tion of the drug substance. Because of a tendency of that in any suspension system the effects of prolonged
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320 | An Introduction to Pharmacy

storage and changes in storage temperature might considered more potent anti-inflammatories for topi-
cause the smallest particles to dissolve and the largest cal ocular use. A resin-bound form of the beta-blocker
particles to become larger. betaxolol has been formulated as a suspension and
The pharmacist should be aware of two potential is prepared in situ using a carbomer polymer.62 The
difficulties inherent in suspension dosage forms. In novel suspension formulation improves both comfort
the first instance, dosage uniformity nearly always and ocular bioavailability of betaxolol, the 0.25% sus-
requires brisk shaking to distribute the suspended pension therapeutically equivalent to a 0.5% solution.
drug. Adequate shaking is a function not only of
Ophthalmic ointments
the suitability of the suspension formulation but
also – and most importantly – patient compliance. Ophthalmic ointments are primarily anhydrous and
Studies have demonstrated that a significant number contain mineral oil and white petrolatum as the base
of patients may not shake the container at all; others ingredients, the proportions of which can be varied
may contribute a few trivial shakes. The pharmacist to adjust consistency and the melting temperature.
should use a ‘‘Shake Well’’ label and counsel the Dosage variability probably is greater than with
patient whenever an ophthalmic suspension is solutions (though probably no greater than that with
dispensed. An improved ophthalmic suspension has suspensions). Ointments will interfere with vision,
been developed for insoluble drugs such as steroids, and their use is usually limited to bedtime instillation.
which tend to cake upon settling.61 The improved They remain popular as a pediatric dosage form and
suspension controls the flocculation of the drug par- for postoperative use. The anhydrous nature of the
base enables its use as a carrier for moisture-sensitive
ticles such that they remain substantially resuspended
drugs. The petrolatum base can be made more
for months and provides for easy resuspension of
miscible with aqueous components by the addition
any settled particles. Nonetheless, the pharmacist
of liquid lanolins.
also should be aware of the possibility of crystal
Ointments do offer the advantage of longer con-
growth over time. This potential stability problem
tact time and greater total drug bioavailability, albeit
is especially problematic for drug substances whose
with slower onset and time to peak absorption.
solubility is significantly dependent on temperature.
The relationship describing the availability of finely
The majority of suspension products have a ‘‘Do
divided solids dispersed in an ointment base was
Not Freeze’’ warning on the label, because they are
given by Higuchi,63 where the amount of solid (drug)
likely to agglomerate on freezing and will not be
released in unit time is a function of concentration,
resuspended by simple shaking.
solubility in the ointment base, and diffusivity of the
A second and infrequently occurring characteristic
drug in the base.
of suspensions is the phenomenon of polymorphism,
or the ability of a substance to exist in several dif- Ophthalmic emulsions
ferent crystalline forms. A change in crystal structure An emulsion dosage form offers the advantage of
may occur during storage, resulting in an increase the ability to deliver a poorly water-soluble drug
(or decrease) in crystal size and alteration in the in a solubilized form as an eyedrop. The drug is
suspension characteristics, causing solubility changes dissolved in a nonaqueous vehicle, such as castor oil,
reflected in increased or decreased bioavailability. and emulsified with water, using a nonionic surfactant
Manufacturers of commercial suspensions take these and, if needed, an emulsion stabilizer. An emulsion
possibilities into account in the development and with water as the external phase can be less irritating
testing of the final formulation and the labeled and better tolerated by the patient than use of a
storage conditions. purely nonaqueous vehicle. Such an emulsion is used
In some cases a water-soluble drug has been con- to deliver cyclosporine topically for the treatment of
verted to an insoluble form and formulated as a chronic dry eye conditions.64
suspension to improve the drug’s stability, compatibil-
ity, bioavailability, or patient tolerance. The insoluble Ophthalmic gels
forms of steroids such as prednisolone and dexam- Gel-forming polymers, such as carbomer, have been
ethasone have better ocular bioavailability and are used to develop aqueous, semisolid dosage forms,
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Pharmaceutical dosage forms: manufacturing and compounding | 321

which are packaged and administered the same An erodible insert is available (Lacrisert) for treat-
as ointments. The viscous gels have significantly ment of dry eye. It is molded in the shape of a rod from
increased topical residence time and can increase a hydroxypropyl cellulose polymer, which is the active
drug bioavailability and decrease dosage frequency, ingredient. When inserted into the lower cul-de-sac,
compared to solutions. Although they contain a large the polymer imbibes tear fluid and forms a gel-like
proportion of water, they can still cause blurring of mass that gradually erodes while thickening the tear
vision. A carbomer gel of pilocarpine administered at film over a period of several hours. The unit-dose
bedtime has been shown to prolong the IOP-lowering insert is anhydrous, and no preservative is required,
effect in patients for up to 24 hours.65 which is beneficial for some sensitive patients.

Ocular inserts
Ophthalmic preparation characteristics
Ocular inserts have been developed in which the drug
is delivered on the basis of diffusional mechanisms. Clarity
Such a solid dosage form delivers an ophthalmic drug Ophthalmic solutions, by definition, contain no undis-
at a near-constant known rate, minimizing side effects solved ingredients and are essentially free from foreign
by avoiding excessive absorption peaks. The delivery particles. Filtration can enhance clarity in some cases.
of pilocarpine by such an insert was commercialized It is essential that the filtration equipment be clean and
in 1975 (Ocusert Pilo) by Alza Corporation. The well rinsed to avoid introduction of particulate matter
Ocusert is designed to be placed in the lower cul-de- into the solution by equipment designed to remove
sac to provide a weekly dose of pilocarpine, at which it. Operations performed in clean surroundings, the
time the system is removed and replaced by a new use of laminar-flow hoods, and proper nonshedding
one. The near zero-order rate delivery is based on garments will contribute collectively to the prepara-
the selection of a noneroding copolymer membrane tion of clear solutions essentially free from foreign
enclosing the drug reservoir.66 particles. In many instances the same filtration step
Ocular inserts are plagued with some of the same can produce both clarity and sterility. If viscosity-
manipulative disadvantages as conventional eyedrops. imparting polymers are used, a polish-filtering step
The insert must be placed in the eye in a manner simi- may be necessary before the final filtration.
lar to the insertion of a contact lens. Additionally, the Both container and closure must be thoroughly
insert must be removed from the eye when exhausted clean, sterile, and non-shedding, so that neither one
of its drug content. Such manipulations can be difficult introduces particulate matter to the solution during
for the elderly patient. Nonetheless, such therapeutic prolonged contact for the duration of the shelf-life.
inserts represent a notable commercialized scientific Normally this is established by thorough stability
achievement in pharmaceutical sciences. The Ocusert testing, which also will indicate whether insoluble
Pilo product is no longer marketed, because the drug particles (by-products of drug degradation) have been
has largely been replaced in glaucoma therapy by generated. Solution formulations may also contain
topical beta-blockers. viscosity-imparting polymers that can diminish clar-
Ocular inserts that gradually erode in the tear ity. In these situations it may be important to both
fluid have been studied but not commercially devel- define the visual clarity of the product and monitor
oped as ocular drug delivery systems.67 In theory, its stability. The European Pharmacopoeia describes
an erodible insert would be advantageous, because it visual clarity and recommends standards that can be
would not require removal at the end of its thera- used for clarity specifications.55
peutic cycle, would provide precise unit dosing, and,
if anhydrous, would not require a preservative. It Stability
may also increase ocular bioavailability and reduce The stability of a drug in an ophthalmic product
the therapeutic dosage and possible systemic effects. depends on a number of factors, including the chem-
The chief disadvantages may be related to patient use ical nature of the drug substance, whether it is in
issues, control of erosion and drug release rates, and solution or suspension, product pH, method of prepa-
sterilization. ration (particularly temperature exposure), solution
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322 | An Introduction to Pharmacy

additives, and type of packaging. A pharmaceutical expiration dating for each product. In addition to
manufacturer strives for a shelf-life measured in years monitoring the standard chemical and physical sta-
at controlled room-temperature conditions, whereas bility of the pharmaceutical, they test the stability of
the compounding pharmacist often is uncertain about the preservative by chemical means or by actual chal-
the shelf-life of his or her preparation and thus pro- lenge of its efficacy with appropriate test organisms.
vides relatively small quantities at one time, assigns Sterility is not a stability parameter per se, but each
a shelf-life in terms of days or weeks, and may container-closure system can be tested by microbial
specify refrigerated storage as a further precaution. challenge to assure integrity of the package against
The attainment of optimum stability often requires environmental contamination before opening.
some compromises in the formulation, packaging, Some of the newer classes of ophthalmic drugs,
and preparation of the final product. like prostaglandins, are very hydrophobic and have
The product’s pH is often the stability-controlling very low concentrations. For example, in the prod-
factor for many drugs. Drugs such as pilocarpine and uct Xalatan, latanoprost is present at 0.005%, and
physostigmine are both active and comfortable in the in the product Travatan, travoprost is present at
eye at a pH of 6.8; however, at this pH, chemical 0.004%. Active agents at such low concentrations
stability (or instability) can be measured in days or present a challenge for formulators, because the loss
months. Either drug will lose a substantial amount of of even small amounts of drug (e.g., from adsorption
chemical stability in less than a year. On the other losses to packaging) can become significant. Phar-
hand, at a pH of 5.0, both drugs are stable for a period macia’s Xalatan requires refrigerated storage, and
of several years. (With regard to eye comfort at acidic as indicated earlier, temperature cycling also can
pH, see the later discussion under Buffer and pH.) reduce the concentration of active drug. It is impor-
In addition to optimal pH, if oxygen sensitivity tant that the pharmacist knows the properties of the
is a factor, adequate stability may require inclu- drug substance, in order to maintain product quality
sion of an antioxidant or special packaging. Plastic throughout the shelf-life of the product.
packaging, such as the low-density polyethylene con-
tainers (e.g., the DropTainer from Alcon) that are Buffer and pH
convenient for patient use, may prove detrimental to Ideally, ophthalmic preparations should be formu-
stability by permitting oxygen permeation, resulting lated at a pH equivalent to the tear fluid value of 7.4.
in oxidative decomposition of the drug substance. Practically, formulators seldom achieve this. Most
Development of an epinephrine solution with 2 to 3 active ingredients used in ophthalmology are salts of
years’ stability in a plastic package requires the use weak bases and are most stable at an acid pH. This
of a pH of about 3.0 for protection from oxidation, property generally holds for suspensions of insoluble
whereas an epinephrine borate solution formulated corticosteroids.
at a pH of about 7.0, which is more comfortable to Optimum pH adjustment generally requires a
the patient, requires an antioxidant system and the compromise on the part of the formulator, who
use of glass packaging. The prodrug of epinephrine, should select not only a pH that is optimal for stabil-
dipivefrin, significantly increases ocular bioavailabil- ity but a buffer system that has adequate capacity to
ity and is effective at one-tenth the concentration of maintain pH within the stability range for the dura-
epinephrine. The structure of the chemical derivative tion of the product shelf-life. Buffer capacity is the
protects the active epinephrine portion from oxida- key in this situation.
tion, so that it can be packaged in plastic. However, It generally is accepted that a low (acid) pH per
the a labile ester linkage introduced in the prodrug se necessarily will not cause stinging or discomfort on
requires that it be formulated at a pH of about 3.0 instillation. If the overall pH of the tears, after instilla-
to minimize hydrolysis; even with this precaution, the tion, reverts rapidly to pH 7.4, discomfort is minimal.
shelf-life of dipivefrin stored at room temperature can On the other hand, if the buffer capacity is sufficient to
be extended to no longer than 18 months. resist adjustment by tear fluid and the overall eye pH
Pharmaceutical manufacturers conduct compre- remains acid for an appreciable period of time, then
hensive stability programs to assure the assigned stinging and discomfort may result. Consequently,
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Pharmaceutical dosage forms: manufacturing and compounding | 323

buffer capacity should be adequate for stability but viscosity may impede initial resuspension, particularly
minimized, so far as possible, to allow only momen- in a suspension that has a tendency to cake during
tary disruption of the overall pH of the tear fluid. storage. The hydrophilic polymers most often used
Special care in formulating intraocular products is for these purposes are methylcellulose, hydroxypropyl
required regarding their pH and buffer capacity. The methylcellulose, hydroxyethyl cellulose, and polyvinyl
corneal endothelium can tolerate much less devia- alcohol – at concentrations that produce viscosities in
tion from physiological conditions, compared to the the range of about 5 to 100 centipoise. These poly-
external corneal epithelium.68 mers also themselves appear as the active ingredients
in artificial-tear solutions for dry eye therapy because
Tonicity of their lubrication and moisturizing properties. Vis-
Tonicity refers to the osmotic pressure exerted by cosity agents can have several disadvantages, in that
salts in aqueous solution. An ophthalmic solution is they sometimes produce blurring of vision and can
isotonic with another solution when the magnitudes leave a residue on the eyelids. These effects are most
of the colligative properties of the solutions are equal. often seen at the higher end of the viscosity range.
An ophthalmic solution is considered isotonic when The added viscosity can make filtration more diffi-
its tonicity is equal to that of a 0.9% sodium chloride cult, particularly for the small pore-size filters used to
solution (290 mOsm). However, the osmotic pressure sterilize solutions.
of the aqueous intraocular fluid is slightly higher than Newer ophthalmic dosage forms, such as gel-
that of normal tears, measuring about 305 mOsm. forming solutions and semisolid aqueous gels with
In actuality the external eye is much more tolerant their increased viscosity and gel elasticity, significantly
of tonicity variations than was at one time sug- improve drug bioavailability and duration of effect.
gested and usually can tolerate solutions equivalent With these advances, the frequency of dosing can
to a range of 0.5% to 1.8% percent sodium chlo- be reduced and patient compliance improved. These
ride. Given a choice, one will find that isotonicity is newer dosage forms incorporate novel polymer sys-
desirable and is particularly important in intraocular tems with special rheological properties to enhance
solutions.69 However, in certain cases a nonisotonic their effect. Their complex rheology and intricate
topical product is desirable. Tear fluid in some cases dependence on environment, however, increase the
of dry eye (keratoconjunctivitis sicca) is reported to complexity of the sterile manufacturing process.
be hypertonic, and a hypotonic artificial-tear product
is used to counteract this condition. Hypertonic oph- Additives
thalmic products are used to relieve corneal edema, Most ophthalmic dosage forms contain additives
and solutions and ointments containing 2% or 5% or pharmaceutical excipients as inactive ingredients.
sodium chloride are available for this use. Because of the need for tissue compatibility in oph-
The tonicity of ophthalmic (and parenteral) solu- thalmics, particularly in intraocular products, how-
tions has been the subject of intensive investigation ever, the use of additives is perhaps less common.
over the years. These studies have resulted in the The most common inactive ingredient is the prod-
accumulation and publication of a large number of uct’s vehicle. For topical dosage forms, Purified Water
sodium chloride equivalents that are useful in calcu- USP is used. Because of the requirement for non-
lating tonicity values. pyrogenicity, Water for Injection USP is used for
intraocular products. While a mineral oil and petro-
Viscosity latum combination is the vehicle used for ophthalmic
Ophthalmic solution and suspension eyedrops may ointments, nonaqueous liquids are rarely used in top-
contain viscosity-imparting polymers to thicken the ical eyedrops because of their potential for ocular
tear film and increase corneal contact time (i.e., reduce irritation and poor patient tolerance. Some mineral
the rate of tear fluid drainage). For suspensions, the and vegetable oils have served as vehicles for very
increased viscosity also retards the settlng of parti- moisture-sensitive or poorly water-soluble drugs. Use
cles between uses and at the same time maintains of the purest grade of oil, such as that used for
their suspension for uniform dosing. However, added parenteral products, is a requirement.
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324 | An Introduction to Pharmacy

Multiple-dose topical ophthalmic products com- wearers. Continuing advances in the general field of
monly contain microbiological preservatives. Other ophthalmic pharmaceutics and pharmacokinetics can
commonly used additives in topical eye products are be expected to assist in maintaining and improving
ingredients to adjust pH and tonicity, and to buffer ocular health.
pH, in addition to the viscosity agents previously dis-
cussed. Ingredients to adjust pH and tonicity and to Medicated topicals
buffer pH are essentially the same as those used in
parenteral products. Less commonly used additives The application of medicinal substances to the skin
are antioxidants, such as sodium bisulfite, ascorbic and its appendages (e.g., nails) or various body orifices
acid, and acetylcysteine. is a concept as old as humanity. The papyrus records
Topical eye products sometimes incorporate sur- of ancient Egypt describe a variety of such medications
factants to disperse insoluble ingredients or to aid in for external use. Galen described the use in Roman
solubilization. Formulators use them in the small- times of a forerunner to today’s vanishing creams.
est concentration possible to achieve the desired Medications are applied in a variety of forms
function, because they can be irritating to sensitive reflecting the ingenuity and scientific imagination of
ocular tissues. Nonionic surfactants are preferable, pharmacists through the centuries. New modes of
because they are generally less irritating than ionic drug delivery have been developed to remedy the
surfactants. Polysorbate 80 is the surfactant used shortcomings of earlier vehicles or, more recently,
to prepare an ophthalmic emulsion. Polyoxyl 40 to optimize drug delivery. Conversely, some external
stearate and polyethylene glycol function to solu- medications have fallen into disuse because of changes
bilize a drug in an anhydrous ointment so that it in the practice of medicine.
can be filter-sterilized. Formulators often add sur- Medications are applied to the skin or its
factants to stabilize more hydrophobic drugs, for appendages or inserted into body orifices in liquid,
example, preventing loss to adsorption on the con- semisolid, or solid form.
tainer walls. For example, the nonionic surfactant
like polyoxyl 40 hydrogenated castor oil (HCO-40)
stabilizes travoprost, a prostaglandin derivative.70
Oral solid dosage forms
Similarly, Cremophor EL stabilizes diclofenac in the
Medicinal substances are most frequently adminis-
Voltaren formulation marketed by Novartis.
tered orally, by means of solid dosage forms, such as
The FDA has published a list of all inactive ingre-
tablets and capsules. Large scale production methods
dients used in approved drug products on its website
used for their manufacture, as is described in this
at http://www.fda.gov/cder. The list includes dosage
section, require the incorporation of other materials,
forms and concentration ranges.
in addition to the active ingredients. These additives
are usually included in the formulation to facilitate
Summary handling, enhance the physical appearance, improve
stability, and aid in the delivery of the medicament
There has been considerable progress in ophthalmic
to the bloodstream after administration. These mate-
pharmaceutics and in lens care products during
rials, as well as the employed production methods,
the last decade. Very substantial advances have
have been shown to potentially influence the absorp-
occurred in designing vehicles and packaging for
tion and/or bioavailability of the drugs.71 In addition,
highly potent active ingredients presented at very low
the physicochemical characteristics of the drug sub-
concentrations; in increasing ophthalmic bioavail-
stances may influence the physiological bioavailability
ability and controlling factors influencing ophthalmic from solid dosage forms.72
drug absorption; in the design of implants and
means of delivering them for providing therapeutic
Tablets
agents to the retina and other deep ophthalmic
tissues; and in devising robust yet delicately bal- According to the USP, tablets are solid dosage forms,
anced multipurpose solutions for contact lens containing medicinal substances with or without
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Pharmaceutical dosage forms: manufacturing and compounding | 325

suitable diluents. They may be classed, according to Compressed Tablet (CT)

the method of manufacture, as compressed tablets Compressed tablets are formed by compression and,
or molded tablets. The vast majority of all tablets in their simplest form, contain no special coating.
manufactured today are made by compression, and They are made from powdered, crystalline, or gran-
compressed tablets are the most widely used dosage ular materials, alone or in combination with binders,
form. Compressed tablets are prepared by the appli- disintegrants, controlled-release polymers, lubricants,
cation of high pressures, utilizing steel punches and diluents, and, in many cases, colorants. The vast
dies, to powders or granulations. Recently, punching majority of tablets commercialized today are com-
of laminated sheets, electronic deposition methods, pressed tablets, either in an uncoated or coated state.
and three-dimensional printing methods have been
used to make tablets. Tablets have been in widespread Sugar-Coated Tablets (SCT)
use since the latter part of the nineteenth century, and Sugar-coated tablets are compressed tablets sur-
their popularity continues. The term ‘‘compressed rounded by a sugar coating. Such coatings may
tablet’’ is believed to have been first used by John be colored and are beneficial in covering up drug
Wyeth and Brother, Inc. of Philadelphia. During this substances possessing objectionable tastes or odors
same period, molded tablets were introduced for and in protecting materials sensitive to oxidation.
use as hypodermic tablets, for the extemporaneous These coatings were once quite common, but lost
preparation of solutions for injection. Tablets remain commercial appeal due to the high cost of process
popular as a dosage form, due to the advantages validation. Recently, they have made a comeback,
afforded both to the manufacturer (e.g., simplicity due to patient popularity and technical advances.
and economy of preparation, stability, and conve-
nience in packaging, shipping, and dispensing) and Film-Coated Tablets (FCT)
to the patient (e.g., accuracy of dosage, compactness, Film-coated tablets are compressed tablets covered
portability, blandness of taste, and ease of admin- with a thin layer or film of a water-soluble material.
istration). Although the basic mechanical approach A number of polymeric substances with film-forming
for most tablet manufacture has remained the same, properties may be used. Film coating imparts the same
tablet technology has undergone great improvement general characteristics as sugar coating with the added
and experimentation. Efforts are continually made to advantage of the greatly reduced time required for
understand more clearly the physical characteristics the coating operation. Advances in material science
of powder compaction and the factors affecting the and polymer chemistry have made these coatings the
availability of the drug substance from the dosage first-choice of formulators.
form after oral administration. Tableting equipment
continues to improve as regards both production Enteric-Coated Tablets (ECT)
speed and the uniformity of tablets. Recent advances Enteric-coated tablets are compressed tablets coated
in tablet technology have been reviewed.73,74 with substances that resist solution in gastric fluid
Although tablets are frequently discoid in shape, but disintegrate in the intestine. Enteric coatings can
they also may be round, oval, oblong, cylindrical, be used for tablets containing drug substances inac-
or triangular. Other geometric shapes, such as dia- tivated or destroyed in the stomach, for those that
monds, pentagons, and hexagons have also been used. irritate the mucosa, or as a means of delayed release
They may differ greatly in size and weight, depend- of the medication.
ing on the amount of drug substance present and the
intended method of administration. Most commer- Multiple Compressed Tablets (MCT)
cial tablets can be divided into two general classes: Multi-compressed tablets are compressed tablets
whether they are made by compression or mold- made by more than one compression cycle. This
ing. Compressed tablets are prepared by large-scale process is best used when separation of active
production methods, whereas molded tablets involve ingredients is needed for stability purposes or if the
small-scale operations. The various tablet types and mixing process is inadequate to guarantee uniform
abbreviations used in referring to them are listed here. distribution of two or more active ingredients.
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326 | An Introduction to Pharmacy

Layered tablets Solution and Potassium Permanganate Tablets for

Layered tablets are prepared by compressing addi- Solution.
tional tablet granulation on a previously compressed Effervescent tablets
granulation. The operation may be repeated to pro-
In addition to the drug substance, effervescent tablets
duce multilayered tablets of two or more layers.
contain sodium bicarbonate and an organic acid, such
as tartaric or citric. In the presence of water, these
Press-coated tablets
additives react, liberating carbon dioxide that acts
Press-coated tablets, also referred to as dry-coated as a disintegrator and produces effervescence. Except
tablets, are prepared by feeding previously com- for small quantities of lubricants present, effervescent
pressed tablets into a special tableting machine and tablets are soluble.
compressing another granulation layer around the
preformed tablets. They have all the advantages of Compressed suppositories or inserts
compressed tablets (i.e., slotting, monogramming, Occasionally, vaginal suppositories, such as Metron-
speed of disintegration), while retaining the attributes idazole tablets, are prepared by compression. Tablets
of sugar-coated tablets in masking the taste of the for this use usually contain lactose as the diluent. In
drug substance in the core tablets. An example of this case, as well as for any tablet intended for admin-
a press-coated tablet press is the Manesty Drycota. istration by means other than swallowing, the label
Press-coated tablets can also be used to separate must indicate the manner in which it is to be used.
incompatible drug substances; in addition, they can
provide a means of giving an enteric coating to the
Buccal and sublingual tablets
core tablets. Both types of multi-compressed tablets Buccal and sublingual tablets are small, flat, oval
have been widely used in the design of prolonged- tablets. Tablets intended for buccal administration by
action dosage forms. inserting into the buccal pouch (the space between
the lip and gum in the mouth) may dissolve or erode
Controlled-Release Tablets (CRT) slowly; therefore, they are formulated and compressed
with sufficient pressure to give a hard tablet. Proges-
Compressed tablets can be formulated to release
terone tablets may be administered in this way. Some
the drug slowly over a prolonged period of time.
newer approaches have employed materials that act
Hence, these dosage forms have been referred to as
as bioadhesives to increase absorption of the drug.
‘‘prolonged-release’’ or ‘‘sustained-release’’ dosage
Other approaches use tablets that melt at body tem-
forms as well. These tablets, as well as capsule
peratures. The matrix of the tablet is solidified, while
versions, can be categorized into three types: (1)
the drug is in solution. After melting, the drug is auto-
those that respond to some physiological condition
matically in solution and available for absorption,
to release the drug, such as enteric coatings; (2) those
thus eliminating dissolution as a rate-limiting step in
that release the drug in a relatively steady, controlled
the absorption of poorly soluble compounds. Sublin-
manner; and (3) those that combine combinations
gual tablets, such as those containing nitroglycerin,
of mechanisms to release pulses of drug, such as
isoproterenol hydrochloride, or erythrityl tetranitrate,
repeat-action tablets. Other names for these types
are placed under the tongue. Sublingual tablets dis-
of tablets are; Extended Release, Sustained Release,
solve rapidly, and the drug substances are absorbed
Prolonged Release, Delayed Release, and, in the case
readily by this form of administration.
of pulsatile tablets, Repeat Action, Pulsatile Release,
or Pulse Release. Molded Tablets or Tablet Triturates (TT)
Tablet triturates are usually made from moist mate-
Tablets for Solution (CTS) rial, using a triturate mold that gives them the shape
Compressed tablets used for preparing solutions or of cut sections of a cylinder. Such tablets must be
imparting given characteristics to solutions must be completely and rapidly soluble. The problem arising
labeled to indicate they are not to be swallowed. from compression of these tablets is the failure to find
Examples of these tablets are Halazone Tablets for a lubricant that is completely water-soluble.
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Pharmaceutical dosage forms: manufacturing and compounding | 327

Dispensing Tablets (DT) extemporaneously or in large quantities commer-

Dispensing tablets provide a convenient quantity of cially. In prescription practice, the use of hard gelatin
potent drug that can be incorporated readily into capsules permits a choice in prescribing a single drug
powders and liquids, thus circumventing the necessity or a combination of drugs at the exact dosage level
to weigh small quantities. These tablets are supplied considered best for the individual patient. This flexi-
primarily as a convenience for extemporaneous bility is an advantage over tablets. Some patients find
compounding and should never be dispensed as a it easier to swallow capsules than tablets, therefore
dosage form. preferring to take this form when possible. This pref-
erence has prompted pharmaceutical manufacturers
Hypodermic Tablets (BT) to market products in capsule form, even though the
Hypodermic tablets are soft, readily soluble tablets products have already been produced in tablet form.
and were originally used for the preparation of solu- Although the industry prepares approximately 75%
tions to be injected. Since stable parenteral solutions of its solid dosage forms as compressed tablets, 23%
are now available for most drug substances, there as hard gelatin capsules, and 2% as soft elastic cap-
is no justification for the use of hypodermic tablets sules, market surveys indicated a consumer preference
for injection. Their use in this manner should be of 44.2% for soft elastic capsules, 39.6% for tablets,
discouraged, since the resulting solutions are not and 19.4% for hard gelatin capsules.75
sterile. Large quantities of these tablets continue to
be made, but for oral administration. No hypoder- Coating of pharmaceutical dosage
mic tablets have ever been recognized by the official
compendia.
forms
Introduction
Capsules
Any introduction to tablet coating must be prefaced
Capsules are solid dosage forms in which the drug by an important question – Why coat tablets? – since
substance is enclosed in either a hard or soft, solu- coatings are often applied to dosage forms that are
ble container or shell of a suitable form of gelatin. already functionally complete. That said, a broad
The soft gelatin capsule was invented by F.A.B. range of pharmaceutical oral solid dosage forms are
Mothes, a French pharmacist, in 1833. During the coated, for a plethora of reasons that include
following year, A. DuBlanc obtained a patent for his
soft gelatin capsules. In 1848, J. Murdock patented 1. Protecting the drug from its surrounding environ-
the two-piece hard gelatin capsule. Although devel- ment (particularly air, moisture, and light) in
opment work has been done on the preparation order to improve stability.
of capsules from methylcellulose, starch, and cal- 2. Masking unpleasant taste and odor.
cium alginate, gelatin, due to its unique properties, 3. Making it easier for the patient to swallow the
remains the primary composition material for the product.
manufacture of capsules. The gelatin used in the 4. Improving product identity, from the manufac-
manufacture of capsules is obtained from collage- turing plant, through intermediaries, and to both
nous material by hydrolysis. There are two types of healthcare workers and patients.
gelatin, Type A, derived mainly from pork skins by 5. Facilitating handling, particularly in high-speed
acid processing, and Type B, obtained from bones packaging/filling lines, and automated counters in
and animal skins by alkaline processing. Blends are pharmacies, where the coating minimizes cross-
used to obtain gelatin solutions with the viscosity and contamination due to dust elimination.
bloom strength characteristics desirable for capsule 6. Improving product appearance, particularly
manufacture. where there are noticeable visible differences in
The encapsulation of medicinal agents remains a tablet core ingredients from batch to batch.
popular method for administering drugs. Capsules are 7. Reducing the risk of interaction between incom-
tasteless, easily administered, and easily filled either patible components. This would be achieved by
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328 | An Introduction to Pharmacy

using coated forms of one or more of the offending Pharmaceutical pan-coating processes were ini-
ingredients (particularly active compounds). tially based on those used in the candy industry,
8. Improving product robustness because coated where techniques were highly evolved, even in the
products generally are more resistant to mishan- Middle Ages. Candy coating processes typically used
dling (abrasion, attrition, etc.). coating pans made of copper because drying was
9. Modifying drug release, as in repeat-action, accomplished by applying an external heat source
delayed release (enteric coated) and sustained- directly to the outside of the coating pan. Current
release products. pharmaceutical coating processes use coating pans, of
a broad range of designs, made from stainless steel,
Evolution of the coating process where drying of the product being coated is achieved
Coating of medicinal products is a concept steeped by means of a supply of heated air, and moisture, and
in history. Rhazes (850–932 AD) used the mucilage dust-laden air is removed from the vicinity of the pan
of psyllium seeds to coat pills that had an offending by means of an air-extraction system.
taste. Subsequently, Avicenna76 was reported to have Conventional pharmaceutical pan-coating pro-
used gold and silver for pill coating. Since those cesses, employed essentially for sugar coating,
early times, a wide range of materials have been remained unchanged for the first half of the twentieth
used in tablet coating. White77 mentioned the use of century. However, since then there have been signif-
finely divided talc in what was at one time popularly icant advances made in coating-process technology,
known as pearl coating, while Kremers and Urdang78 mainly as a result of a steady evolution in pan design
described the introduction of the gelatin coating of and associated ancillary equipment, primarily control
pills by Garot in 1838. systems.
An interesting reference79 reports the use of Until the early 1950s, pharmaceutical coating was
waxes to coat poison tablets. These waxes, being dominated by the sugar coating of tablets. However,
insoluble in all parts of the gastrointestinal tract, at that time, a new form of technology (called film
were intended to prevent accidental poisoning (the coating) was developed. Recognizing the potential
contents could be ‘‘activated’’ by breaking the tablet limitations of the sugar-coating process, the pioneers
open prior to administration). of film coating created significant improvements by
While earlier coated products were produced by employing coating formulations based on polymers
individuals working in pharmacies, particularly when dissolved in highly volatile organic solvents, with the
extemporaneous compounding was the common result that coating processes that took days to carry
practice, that responsibility now has been assumed out could now be completed in only a few hours.
by the pharmaceutical industry. Early attempts to While the use of organic solvents circumvented
apply coatings to pills yielded variable results and the problems associated with the poor drying capabil-
usually required the handling of individual pills. Such ities of conventional equipment available at the time,
pills would have been mounted on a needle or held this approach had its disadvantages; these organic
with a pair of forceps and literally dipped into the solvents were highly flammable, potentially toxic,
coating fluid, a procedure that would have to be and presented significant handling and environmental
repeated more than once to ensure that the pill was problems.
coated completely. Subsequently, the pills were held Fortunately advances in equipment design, includ-
at the end of a suction tube, dipped, and then the ing the introduction of fluid-bed coating processes and
process repeated for the other side of the pill. Not those using side-vented coating pans, have resulted in
surprisingly, these techniques often failed to produce the gradual emergence of coating processes where
a uniformly coated product.80 drying efficiencies have been maximized. The result
Initially, the first sugar-coated pills seen in the has been the emergence of aqueous coating processes
United States were imported from France in about as the preferred means, with a few exceptions, of
1842;80 while Warner, a Philadelphia pharmacist, coating pharmaceutical products.82
became among the first indigenous manufacturers While advances in equipment design have resulted
in 1856.81 in film coating becoming the dominant process for
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Pharmaceutical dosage forms: manufacturing and compounding | 329

coating pharmaceutical oral solid dosage forms, a result of the market success and thus opportuni-
these improvements in equipment design have also ties for enhanced drug delivery systems, considerable
benefited the sugar-coating process, creating fully efforts have been expended on developing appropriate
automated processes that can produce a batch in less polymeric carriers and sophisticated processing and
than one day. manufacturing machineries. A tremendous amount of
research has been directed toward the development
of robust modified-release (MR) oral dosage forms.
Oral modified-release drug delivery These efforts have followed the science-based and
systems risk-managed process of drug product development,
supported by quality-by-design (QbD) principles. This
Introduction section describes various MR technologies used for
In recent years, the scope of drug delivery technologies drug delivery to the oral cavity (oral route of admin-
has expanded significantly, irrespective of the route istration) as well as formulation approaches and
of administration, as a result of an advanced under- manufacturing considerations.
standing of disease, science, and safety associated with
pharmaceuticals. The overall purpose of drug delivery Rationale and definitions of oral
systems, however, has remained constant: to provide a modified-release technologies
therapeutically effective amount of drug to the appro-
priate site in the body for a desired duration of action. The oral route for delivering medications has been
The site at which a drug is delivered (drug targeting) the preferred route for most drugs due to patient
and the rate at which the drug is released (profile) have acceptance, ease of administration, accurate dos-
to be carefully considered during dosage form design ing, cost-effective manufacturing methods, and gen-
and product development. Site-specific drug delivery erally the improved shelf-life of the product. For
has been one of the key focus areas for pharmaceuti- conventional oral dosage forms, the drug (API) is
cal formulation scientists for many decades. The main rapidly released after administration and subsequently
purpose of site-specific drug delivery systems is to absorbed into the body from the gastrointestinal tract.
improve the efficacy and safety of drugs. Pharmaceu- The concentration of drug in the blood peaks shortly
tical scientists have also focused on the development after administration as the drug absorption process
of formulations that deliver drugs at a desired-release dominates, then decreases over time as metabolism
rate, the duration of which may span from very fast and/or excretion processes dominate. Conventional
(a few seconds) to very slow and controlled (days, immediate-release (IR) dosage forms, however, do
weeks, and months). Combining site-specific aspects not maintain the plasma levels of the drug within the
of drug delivery with controlled-release rates is highly therapeutic range for an extended period of time and
desirable for patient treatment. thus a short duration of action may be observed. For
With better understanding of gastrointestinal tract many drugs and therapeutic indications, multiple dos-
anatomy, physiological barriers to drug absorption, ing of IR formulations provides satisfactory clinical
and the need for different release profiles for differ- performance with an appropriate balance of efficacy
ent disease conditions, more efficient and advanced and safety. For example, multidose therapy may be
drug delivery systems have been developed. In recent tolerated for short-term treatment, but is not desir-
years, the purposes of such modified-release drug able for treating chronic conditions. To reduce dosing
delivery technologies have evolved to optimize drug frequency and eliminate the fluctuations in blood
performance and enhance patient tolerance (reduce concentration associated with conventional delivery,
in side-effects). These technologies have not only had extended-release (ER) systems have been and continue
a significant impact on the success of developing to be developed, where the drug is slowly released
and commercializing new chemical entities, but the over an extended timeframe. Delayed-release (DR)
reformulation of marketed drug products for better technologies exhibit a lag time in drug release (no
patient acceptance has allowed pharmaceutical com- drug released immediately) to target the drug to a
panies to extend the patent life of their products. As specific site in the body. Both ER and DR systems are
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330 | An Introduction to Pharmacy

broadly referred to as modified-release (MR) dosage other essential uses. Because of these restrictions, new
forms. The common goal for the development of any valve systems and dispensing systems, which allowed
MR formulation is to enhance the drug’s therapeutic greater use of liquefied hydrocarbons and compressed
benefits, minimize side-effects, and improve the over- gases, were developed for non MDIs. Individual drugs
all management of the disease. These technologies which have been successfully converted to hydroflu-
may be combined with conventional IR delivery or oroalkane propellants have had the CFC products
combined with other MR technologies phased out.

Summary Aerosol delivery systems

Advancements in the science and technology of oral Inhalation therapy has been used for many years, and
modified-release drug delivery systems have resulted there has been a resurgence of interest in delivery of
in the commercial availability of a number of prod- drugs by this route of administration. The number
ucts. More importantly, these improved delivery sys- of new drug entities delivered by the inhalation route
tems are impacting the health of patients worldwide. has increased over the past five to ten years. This
The development and commercialization of modified- type of therapy also has been applied to delivery of
release products is no longer considered just a life- drugs through the nasal mucosa, as well as through
cycle management strategy for the manufacturer. the oral cavity for buccal absorption. Originally, this
Formulation scientists will continue to investigate and type of therapy was used primarily to administer
develop novel drug delivery platforms to improve the drugs directly to the respiratory system (treatment
overall effectiveness of drug therapies. of asthma); inhalation therapy is now being used
for drugs to be delivered to the bloodstream and
finally to the desired site of action. Proteins (insulin),
Aerosols steroids, cardiac agents, immunizing agents, etc., are
being developed for delivery in this manner. Drugs
Definitions administered via the respiratory system (inhalation
The term aerosol is used to denote various systems therapy) can be delivered either orally or nasally.
ranging from those of a colloidal nature to systems Further, these products can be developed as a
consisting of pressurized packages. Aerosols have
been defined as colloidal systems consisting of very • nebulizer/atomizer
finely subdivided liquid or solid particles, dispersed in • dry powder inhaler
and surrounded by a gas. Originally, the term aerosol • nasal inhaler
referred to liquid or solid particles having a specific • metered-dose aerosol inhaler.
size range, but this concept has fallen into disuse.
The present-day definition refers to those prod- Drugs delivered via a nebulizer/atomizer are generally
ucts that depend upon the power of a liquefied or formulated as sterile aqueous solutions (or suspen-
compressed gas to dispense the active ingredient(s) in sions) and are inhaled by the patient through an
a finely dispersed spray, foam, or semisolid. Pump atomizer, nebulizer, or other similar devices.
systems that also dispense the active ingredient(s) Dry powders have been used for inhalation ther-
in the form of a finely dispersed mist (although of apy for over 75 years. The active ingredients were
greater particle size) often are classified as aerosols. packaged in capsules, representing a single dose of
These pump systems generally are used to dispense drug. The capsule was punctured, and a small amount
medication intranasally. of powder fell into a chamber while the patient
In 1978, the use of certain chlorofluorocarbons inhaled. The procedure was repeated until all of the
(CFCs) was curtailed by the FDA, EPA, and CPSC. powder was inhaled. While these dry powders were
These restrictions applied to the use of Propellants somewhat popular during the early 1940s to 1950s,
11, 12, and 114 (CFCs) for use in all aerosol prod- they fell into disuse with the introduction of the
ucts. Exemptions were granted to MDIs and a few aerosol metered-dose inhaler (MDI), which became
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Pharmaceutical dosage forms: manufacturing and compounding | 331

available around 1955. This first generation MDI size distribution to achieve maximum deposition of
was formulated with chlorofluorocarbons (CFC), was drug into the lungs. The aerosol dosage form (MDI)
compact and portable, and contained epinephrine has become the dosage form of choice for delivery of
hydrochloride or albuterol as the active ingredient. drugs to the lungs.
These MDIs quickly became the dosage form of choice Topical aerosol products are becoming more pop-
for inhalation therapy, especially for the treatment of ular because they are easy to administer and have a
asthmatics. The dry powder inhalers, powders con- better feel than ointments and creams. Topical phar-
taining about 25–30 to 60 doses of active ingredient, maceutical aerosols can be formulated as a spray,
were developed and became commercially available foam, and semisolid. They can be used to deliver ther-
from 2000 to 2003. Several dry powder inhalers cur- apeutic agents topically (to the skin surface), rectally,
rently available include salmeterol, fluticasone, and and vaginally. They consist of a liquid, emulsion, or
budesonide. Mometasone dry powder inhaler is avail- semisolid concentrate and liquefied gas or compressed
able in Europe. These dry powder inhalers do not con- gas propellant. Many therapeutically active ingredi-
tain a propellant. These consist of active, very potent ents have been administered or applied to the body
drugs that are dispensed from a specially designed by means of the aerosol dosage form. This dosage
package. An accurate amount of drug as a dry pow- form has been used orally to dispense a variety of
der is released from a small unit dose package while agents, such as budesonide, salmeterol xinafoate, fluti-
the patient inhales deeply. The dry powder will then casone propionate, fenoterol, epinephrine hydrochlo-
travel to the lungs along with the inspired air. Carrier ride, albuterol, albuterol sulfate, metaproterenol sul-
molecules, such as lactose, are often used to reduce fate, cromolyn sodium, flunisolide hemihydrate, ipra-
agglomeration of the small drug particles as well as tropium bromide, beclomethasone dipropionate, and
facilitate fluidization during the inhalation process. triamcinolone acetonide.
The nasal metering drug delivery system produces
an aqueous spray, consisting of active ingredient and Advantages
excipients. The drugs used can act locally within the One of the main reasons for the rapid and widespread
nasal mucosa or systemically by passing through the acceptance of the MDI dosage form for the adminis-
nasal mucosa and enter the general circulation system. tration of therapeutically active agents is that it affords
This occurs via numerous capillary vessels present in many distinct advantages to the user. These advan-
the mucosa. These nasal sprays can also be formulated tages have been described by various investigators
similarly to MDIs, using propellants and a nasal actu- and, for MDIs, include the following:
ator. The development of the MDI in the mid-1950s
made possible a convenient dosage form for the deliv- • Rapid onset of action
ery of medication to the respiratory system. Atomizers • Circumvention of the first-pass effect and
and nebulizers were cumbersome to use and in many avoidance of degradation in the gastrointestinal
instances did not offer convenience of use, so that tract
administration of drugs by atomizers/nebulizers was • Lower dosage that will minimize adverse reactions,
generally left to hospital or at-home use. While many especially in the case of steroid therapy, in which
improvements were made to these nebulizers and most of the steroid reaches the respiratory tract
atomizers, they lacked convenience of use, especially and less is swallowed
as to their portability and use outside of a hospital • Dose titration to individual needs and ideal for prn
and/or home setting. (when required) medication
MDIs consist of a pressurized container filled • Alternative route when therapeutic agent may
with solutions or suspensions of active drug in a interact chemically or physically with other medic-
mixture of solvents, dispersing agents, and liquefied inals needed concurrently
gas propellants, and a metered-dose valve. The • Viable alternative when the drug entity exhibits
pressurized container is placed within an oral adapter erratic pharmacokinetics upon oral or parenteral
(mouthpiece), and when the unit is dispensed, an administration
exact amount of drug is expelled in the proper particle • Container and valve closure are tamperproof.
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332 | An Introduction to Pharmacy

The pressure package is convenient and easy to use. of molecular biology. Interestingly, the term biotech-
Medication is dispensed in a ready-to-use form at the nology was first coined in 1919 by the Hungarian
push of a button. There is generally no need for fur- engineer Károly (Karl) Ereky to describe how prod-
ther handling of the medication. Since the medication ucts could be produced from raw materials with the
is sealed in a tamperproof pressure container, there aid of living organisms as agriculture began to join
is no danger of contamination of the product with forces with industry following World War I.83 Hence,
foreign materials, and at the same time, the contents biotechnology is not a new concept. Humans have
can be protected from the deleterious effects of both been manipulating living organisms over the millen-
air and moisture. Easily decomposed drugs, such as nia to solve problems and improve the quality of life.
epinephrine, lend themselves to this type of package, But today, especially in the context of science and
for oxygen is excluded from the headspace. health, the term biotechnology is used interchange-
Sterility is always an important consideration with ably with ‘‘genetic engineering.’’ The concept of DNA
certain pharmaceutical and medicinal preparations. manipulation is central to most modern references to
While initial sterility is generally no problem to the biotechnology.
manufacturer, there is concern for the maintenance of The practical realization of this technology has
the sterility of the package during use, for example, followed from our ability to now detect, decode, iso-
with ophthalmic preparations. When necessary, the late, produce, and characterize the various proteins
aerosol package can be prepared under aseptic con- that coordinate the numerous functions essential to
ditions, and sterility can be maintained throughout human life and health. Processes that precede or are
the life of the product. For those products requiring causative in pathophysiology can not only be identi-
regulation of dosage, a metering valve can be used. fied but also now manipulated in an attempt to restore
An accurately measured dose of therapeutically active normal function. This relatively new methodology
drug can be administered quickly and, in the case of involves the synergism of discoveries in recombinant
drugs for inhalation, buccal, or nasal application, in DNA methodology, genetic engineering, immunol-
the proper particle-size range. ogy, genomics, proteomics, and bioinformatics, with
There are many advantages to the administra- advances in automation and data analysis to create a
tion of medicinal agents by inhalation, buccally and cogent, high-technology industry. Overall, biotech-
nasally. Response to drugs administered by inhala- nology has led to the creation of new products
tion, buccally and nasally, is prompt, often very for home and industry, improvement of agricul-
specific and with minimal side-effects, faster in onset tural yields, diagnosis of genetic disorders, and the
of activity than drugs given orally and, with most enhancement of our medical arsenal against disease.
drugs, approaching intravenous therapy in rapidity The publications in February 2001 of the virtually
of action. Drugs that normally are decomposed in complete sequence of the human genome84,85 are
the gastrointestinal tract can be administered safely certainly accelerating the application of these tech-
by inhalation, buccally and nasally. The use of the nologies. While the close of the past millennium
self-pressurized aerosol package makes this type of has clearly witnessed the benefits resulting from the
therapy simple, convenient, and acceptable, compared proliferation of biotechnology-derived products, new
with the use of atomizers and nebulizers, which are questions have arisen regarding issues of ethics and
bulky and require cleaning. pharmacoeconomics. Nonetheless, it is clear that the
benefits of biotechnology already have far outweighed
the drawbacks.
Biotechnology and drugs
Background
The past 40 years have witnessed the emergence,
development, and maturation of biotechnology in Now that biotechnology-derived pharmaceuticals
medicine and pharmaceuticals. Previously rare, or have become commonplace in healthcare, pharmacy
even unattainable, pharmaceuticals can now be pro- practitioners should have a detailed knowledge of the
duced in useful quantities by harnessing the power manufacture and use of these newer agents.86,87 As a
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Pharmaceutical dosage forms: manufacturing and compounding | 333

backdrop to understanding modern biotechnology, it the Internet by Cold Spring Harbor Laboratory and
will be instructive to review some of the basic biolog- the journals, Science and Nature). DNA, the genetic
ical milestones that precede it. Table 9.3 provides a blueprint of an organism, is made up of building
compilation of milestones in biotechnology, especially blocks known as nucleotides (molecules containing
for their connections with pharmaceutical sciences. It a sugar, nitrogen-containing purine or pyrimidine
is clear that technology is proceeding at a rate that is bases, and a phosphate group) that are connected in a
already threatening to bypass our ability to manage very long ladder-like structure. When this rubber-like
the ethical dilemmas presented by these advances. twisted-ladder structure is coiled tightly, it is referred
Fortunately, visionaries such as Nobel laureate James to as a two-stranded, or double, helix.
Watson have used their positions to encourage the There are four different nucleotides (containing
proper and ethical use of genetic information and the bases adenine, cytosine, guanine, and thymidine)
technology. As the initial director of the publically with a total of about 3 billion nucleotide units in the
funded Human Genome Project, Watson announced human genome, tightly packed into chromosomes.
a plan to set aside 3% of the project budget These include the genetic code for a large number of
devoted to Ethical, Legal, and Social Implications genes, originally estimated at 100,000 in the human
(ELSI) research, a decision he subsequently deemed, but downgraded to roughly 25,000 as a result of the
‘‘probably the smartest thing I did.’’88 Human Genome Project, a surprisingly low number
Nature has for some 3.5 billion years been con- compared with other species. Each of these genes
ducting what we may call natural genetic exper- controls the synthesis of a protein made up of a
iments. These include mutation (random heredity long strand of anywhere from 50 to 3000 amino
alteration), crossing-over (breakage and exchange acids. Nirenberg and Matthei, in 1961, and others
of corresponding segments of homologous chromo- later, elucidated how the nucleotide sequence of a
somes), and recombination at meiosis (fertilization). gene regulates the particular sequence in which the
These processes all have contributed to the current 20 different amino acids will be united to produce
diversity of life on this planet. In addition, it is well a particular protein. A single codon is made up of
known that humans have been manipulating genetic units of three adjacent nucleotides; each codon spec-
characteristics of different species for over 10,000 ifies one amino acid. The arrangement of codons
years through inbreeding and cross-breeding experi- in the DNA, following transcription into messenger
ments. To cite a few examples, one can point to the RNA (mRNA), determines the sequence of amino
modern robust strains of wheat or corn, which are acids that will form a particular protein. The detailed
a far cry from their puny ancestors. Similarly, the understanding of how these genes and their proteins
varied breeds of dogs, cats, poultry, and cattle may govern basic cellular processes is the underpinning of
be mentioned. These manipulative efforts continue, molecular biology and biotechnology.
and in less than a lifetime, the development of larger Because each of the major organs of the body
and sweeter oranges, seedless watermelons, and flam- (brain, liver, blood, etc.) has a specified set of tasks to
boyant ornamental plants has occurred. Also familiar perform, certain specific sets of genes in each organ
are such hybridizations as the tangelo (crossing the (collection of specialized cells) must be activated and
tangerine and the grapefruit) and the mule (crossing deactivated, that is, turned on and off as needed. Fol-
a donkey and a horse). lowing the directions laid down by the genetic code
All cell structures and functions begin with pro- of DNA and mediated by mRNA, each cell type con-
teins, and the code for building the proteins is found tinuously produces a unique and characteristic array
in deoxyribonucleic acid (DNA). This is why the of proteins. Each cell type maintains a complement
discovery of the double-helix structure of DNA by of transcriptional activating and repressing proteins
Watson and Crick in 1953 fundamentally began the whose actions balance to create the specific gene
unraveling of the mystery of cell processes. (The expression profile of a particular tissue. Moreover,
50th anniversary of publication of their model was epigenetic processes such as gene methylation and
celebrated in 2003, with some exceptional retro- histone acetylation status also contribute to tissue-
spective documentation published in print and on specific gene expression. Expressed proteins are then
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334 | An Introduction to Pharmacy

Table 9.3 Milestones in Biotechnology. The recent explosion of growth in the development and
application of biotechnology may be traced to a number of successive, discrete, milestone discoveries
and events.

Discoveries and events Time, scientists, and companies

1. X-ray diffraction data and proposed double-helix model for the 3- RE Franklin and MH Wilkins; JD Watson and FH
dimensional structure of DNA Crick, 1953

2. Site-specific recognition and cleavage of DNA by restriction endonucle- W Arber, 1962; M Meselson and R Yuan, 1968; HO
ases Smith, 1970; D Nathans, 1971

3. Determination of the genetic code M Nirenberg, S Ochoa, and P Leder, 1966; HG

Khorana, 1966

4. Identification of DNA ligase M Gellert, 1967

5. Identification of RNA-directed DNA polymerase (reverse transcriptase) HM Temin and S Mizutani, 1970; D Baltimore, 1970

6. DNA cloning techniques HW Boyer, S Cohen, and P Berg, 1971–1972

7. Formal discussions on emerging DNA technologies Gordon Conference on Nucleic Acids, June 1973

8. Self-imposed standards for rDNA research Asilomar Conference, Feb 1975

9. Hybridoma created C Milstein and G Kohler, 1975

10. Recombinant Advisory Committee (RAC) issues guidelines Recombinant Advisory Committee, 1976

11. DNA sequence technologies F Sanger, 1977; W Gilbert, 1977

12. US Supreme Court ruled that microorganisms are patentable General Electric superbug, 1980

13. US approval of first diagnostic kit using mAb technology, anti-C3d Ortho Diagnostics, 1981
BioClone

14. US approval of first ethical pharmaceutical produced by using rDNA Genentech and Eli Lilly and Co, 1982
technologies, Humulin (human insulin)

15. Expression of a foreign gene in plants: bacterial antibiotic resistance Monsanto Co, Washington University, and Max
gene expressed in tobacco plants Planck Institute, 1982

16. FDA approval of first monoclonal murine antibody drug, Orthoclone Ortho Biotech, 1986
OKT3, for reversal of acute kidney transplant rejection

17. The polymerase chain reaction (PCR) methodology enables targeted KB Mullis; Cetus Corp., 1983; use of thermostable
amplification of DNA sequences DNA polymerase, 1988

18. FDA approval of first recombinant vaccine for hepatitis B virus Chiron Corp., 1986

19. US Patent and Trademarks Office issues first patent for genetically P Leder and Harvard University, 1988
engineered mammal, transgenic mouse

20. Formal launch of Human Genome Project USA, 1990

(continued overleaf)
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Pharmaceutical dosage forms: manufacturing and compounding | 335

Table 9.3 (continued)

Discoveries and events Time, scientists, and companies

21. First human patient received gene therapy for adenosine deaminase WF Anderson, 1990
deficiency

22. Dolly the sheep becomes the first cloned mammal I Wilmut, 1997

23. RNA interference’s gene silencing activity in nematode worm C. elegans A Fire and C Mello, 1998

24. FDA approval of the first rationally designed and target specific cancer Novartis, 2001
chemotherapy drug, Gleevec, to treat certain types of leukemia

25. Simultaneous publication of human genome sequence by Human Human Genome Project and Celera Genomics,
Genome Project and Celera Genomics 2001

26. Approval of the first gene therapy drug worldwide, Adenovirus-based Gendicine, in China, 2003
delivery of p53 tumor suppressor

27. EMEA approval of the first biosimilar drug, Omnitrope (recombinant Sandoz, 2006
human growth hormone)

28. US district court in New York rejected the breast cancer gene patents US district court in New York, 2010

secreted into the extracellular milieu, while many are hormones for organism regulation, fuel for energy
used within the cell itself. The number of possible production, and important molecules such as DNA.
biosynthetic permutations is very high if one consid- Proteins also make up the cell cytoskeleton provid-
ers that a typical protein can be made up of some 500 ing an organized, three-dimensional structure. They
amino acids and, further, that every one of these sites permit directed transport and movement of molecules
may be occupied by any one of 20 different amino throughout the cell. They are embedded in the outer
acids. It is likely that over the long periods of evolu- cell membrane and pump nutrients and ions across the
tion of each organism, given the vast array of possible membranes. They serve as receptor sites for hormones
combinations of these amino acids, a multitude of that finitely adjust the functions of the cell according
unique proteins with all sorts of optimized functions to changing bodily needs. Another group of proteins
have developed. regulates gene activities by binding to DNA and acti-
The concept that genetic information flows from vating or repressing gene transcription. Still other
DNA to RNA to proteins has become a fundamental proteins, and their smaller fragments (peptides), are
milestone of modern biology. Thus, with the discov- secreted by cells as neurotransmitters or hormones
ery of reverse transcriptase (from an RNA virus) by like insulin. Some serve as carrier molecules, like
Temin and Baltimore, in 1970, which could convert hemoglobin, the body’s oxygen carrier.
its own genomic RNA into double-stranded RNA, As is well recognized, these hormones and various
a second milestone was reached. Molecular biology related peptide molecules hold enormous power, and
relies heavily on this enzyme to convert mRNA into because they can act on numerous specific cell sur-
DNA for gene cloning, library construction, and gene face receptors, they can influence virtually all bodily
sequencing and detecting. Examples of cellular cata- functions from the nervous system to the immune
lysts, or enzymes, include those that are involved in the system. It is obvious that their selectivity, potency,
digestion of food and others that produce the chemical and often-desired evanescent effects on selective tar-
building blocks of cell life, such as sugars and lipids, get cells make them enormously attractive candidates
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336 | An Introduction to Pharmacy

as a new generation of drugs in the magic bullet As a further refinement in the understanding of
concept of Paul Ehrlich. Further, when administered the immune system, several key weapons are involved
parenterally, hormones have the potential to reach in the process. These include the antibodies, which
target receptors on the surface of cells, without the are circulating freely or membrane-bound receptor
need to penetrate membranes. Not unlike the nor- molecules that bind specific foreign invaders and
mal bodily processes, they can bind to cell surface thereby tag them for destruction by the complement
receptors and activate the cell’s particular function. system or phagocytes. There are the perforin proteins,
An example of one such approach is seen with the which are secreted by certain T cells and kill their
anticancer drug interferon-alpha, which can stimulate cellular targets by punching holes in them. Finally,
some immune cells to attempt to overcome cancerous there are the lymphokines and interleukins, which are
cell growth. secretions by which white blood cells communicate
The body’s specific defense response to invading with each other. Thus, the immune system has two
organisms is due to the immune system. Normally, fighting branches with specificity, and often both are
phagocytes called to a site of inflammation induced employed against infections and antigens in general.
by pathogens mount a generalized attack response. The T cells dominate one part of the system, and when
Indiscriminately, they engulf cellular debris as well as they are activated, it is referred to as a cell-mediated
anything recognized as foreign. Occasionally, how- response. The B cells dominate the other branch, and
ever, this is not enough, and illness ensues. At this events associated with their activation are referred to
point, several more focused counterattacks proceed as antibody-mediated response.
by the three types of white blood cells known as Before the broad application of whole genome
macrophages, T lymphocytes, and B lymphocytes. sequencing, expressed sequence tags (ESTs) of com-
The key features of the immune system are specificity plementary DNA provided shortcuts to uncover a
(the ability to focus on specific pathogens) and mem- large number of new genes. Similarly, lighthouses
ory (the ability to recognize and respond rapidly to have been developed along the chromosomes to guide
previously encountered infections). About 1% of the the way for sequencing dim restriction maps. DNA
blood cells are white blood cells. The ones that are research, using the polymerase chain reaction (PCR),
central to the immune responses are the following: has become a powerful tool in forensic and research
applications. Based on the principle of PCR, real-time
B Cells – Lymphocytes that produce antibodies polymerase chain reaction (RT-PCR) or quantitative
(antibody-mediated immune response). real time polymerase chain reaction (Q-PCR) has been
Macrophages – Phagocytic cells that alert helper T developed and applied as another powerful technol-
cells to the presence of pathogens. ogy to detect or quantify one or multiple gene targets
Helper T Cells – Master switches of the immune sys- precisely and simultaneously. Non-specific fluorescent
tem that stimulate the rapid division of both killer dyes or sequence-specific DNA probes can be used as
T cells and B cells. indicators. In the clinic, RT-PCR provides rapid and
Suppressor T Cells – Lymphocytes with regulatory accurate diagnoses.89
functions; i.e., they slow down or prevent immune New publications have described how modern
responses. metabolic engineering has brought intermediary
Killer T Cells and Natural Killer (NK) Cells – metabolism back to life through techniques involving
Lymphocytes that directly destroy body cells enhancing copies of a gene at a rate-controlling point,
that already have been infected by pathogens (or adding a gene to remove a poisonous product, or
cancer cells). adding several genes to introduce a new pathway into
Memory Cells – A group of the T cell and B cell pop- an organism that stops short of the desired product.
ulation that was produced during the primary This metabolic engineering has had numerous
encounter with a pathogen but was not used in practical results in addition to helping develop
the battle. These circulate through the body ready new theories. DNA technology has been applied to
to respond rapidly to later attacks by the same metabolic pathways so that branch point control
organisms. problems can be solved. Even the insertion of similar
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Pharmaceutical dosage forms: manufacturing and compounding | 337

enzymes from different species into the studied in uneven application across the population. Senators
organism has introduced new flexibility and better Jeffords and Daschle have outlined their respective
metabolic characteristics into the older organism. views on the passage of federal laws that protect the
The recent developments of the vaccinia virus collection and use of genetic information, particu-
mean that it now can serve as a molecular vehicle larly relating to employment and health insurance.93
for carrying foreign genes into other organisms. As a The Human Genome Project’s ELSI program (Ethi-
means for research, this recombinant vaccinia vector cal, Legal, and Social Implications of Human Genetics
has served as a vehicle for producing live vaccines Research) is now charged with addressing issues that
that would otherwise be difficult to produce. Mono- appear as daunting as the sequencing of the genome
clonal antibodies have also been used successfully in itself. The benefits of biotechnology in disease preven-
diagnosis and therapy. The first monoclonal antibody tion and treatment are numerous, and the decoding
drug for humans, OKT3, was approved by the FDA in of the human genome will continue to produce new
1986 for treatment of acute renal allograph rejection. opportunities to improve our quality of life. But
Antibody power has been enhanced by attachment as with all technological advances, safeguards are
of a biological toxin such as ricin, a cytotoxin such required to prevent discriminatory and unethical use
as calicheamycin, or a radioisotope such as an alpha of this new information.
emitter. The latter can be used to damage tissue adja-
cent to that with which the antibody interacts. These
are all good examples of combined basic research Pharmaceutical packaging
followed by rapid practical application.
A container closure system must be designed to pro-
tect the drug during actual conditions of storage,
Moral and ethical questions
shipment, and use, and be able to deliver the correct
On the matter of moral and ethical questions of amount of product at the time of use. It must not inter-
biotechnology applications in medicine, numerous act with the product over its shelf-life to the extent
articles appear periodically90 – 92 to debate the issue. that it renders the drug ineffective or unacceptable for
Francis Collins, Director of the National Human use. As defined in the USP, ‘‘a container, including
Genome Research Institute (NHGRI) has written, ‘‘It the closure, does not interact physically or chemically
is estimated that all of us carry dozens of glitches in with the pharmaceutical preparation in any manner to
our DNA – so establishing principles of fair use of alter the strength, quality, or purity beyond the official
this information is important for all of us.’’ requirements under ordinary or customary condition
There are many questions, such as the following: of handling, shipment, storage, sale or use.’’94
The general requirements for containers for foods,
• Does genetic testing constitute invasion of privacy? including dietary supplements, drugs, cosmetics, and
• Will there be an increase in abortions that discrim- medical devices, are provided in the Food Drug and
inate against the genetically unfit? Cosmetic Act as amended.95 The regulations are pro-
• Should those destined to be stricken with a fatal vided in Code of Federal Regulations Title 21. The
genetic disease be informed of their fate, especially FDA Center for Food Safety and Nutrition (CFSAN)
if there is no remedy available? is responsible for the regulations that apply to foods
• Will these decisions become mandated legally and and dietary supplements. The Center for Drug Evalu-
ultimately demean humans or create a new under- ation (CDER) and the USP/NF are responsible for the
class of the genetically less-fortunate? regulations that apply to drug packaging. The Center
• Should gene therapy be used only for treating dis- for Biologics Evaluation and Research (CBER) and
ease or also for improving an individual’s genetic USP are responsible for the regulations that apply
legacy? to biologics. The Center for Veterinary Medicine
(CVM) relies on CDER and USP/NF for its packaging
Currently, most protections on the use of genetic requirements. The Center for Devices and Radio-
information are regulated at the state level, resulting logical Health (CDRH) uses 21 CFR Subchapter
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338 | An Introduction to Pharmacy

H – Medical Devices, ISO, and ASTM International function at one temperature but not another. There-
standards. If a liquid medication dispenser is pur- fore, all evaluations must include storage and use
chased by a pharmacist, independently of the drug, it temperatures and packaging conditions. The follow-
is regulated by CDRH. If it is sold with the drug, it ing is a list of dosage forms from highest to lowest risk
is regulated by CDER. If an injection syringe is sold for use by patients: injectables, implants, inhalation
by itself, it is regulated by CDRH, and if it contains a drugs, ophthalmics and otics, oral liquids, oral solids,
drug (prefilled syringe) it is regulated by CDER. and transdermals and topical liquids. The concerns
The standards for drug packaging in USP/NF about containers have been fostered by actual events
include General Notices, General Chapters <87>, of either interaction or the failure to perform. Some
<88> Biological Reactivity Testing, <381> Elas- examples of those instances are as follows:
tomeric Closures for Injection, <660> Containers-
Glass, <661> Containers-Plastic, <670> Auxiliary • Migration of nitrosamines from rubber;
Packaging Components, <671> Containers- • Degradation of components from sterilization;
Performance Testing, and <698> Deliverable • Reactions to latex allergens in natural rubber;
Volume. In addition to these requirements, one • Concentration of drug in pouches and polyethy-
must be cognizant of the EPA requirements for lene vials, due to excessive water loss;
monomer content in Polyvinyl Chloride (PVC), waste • Migration of inks, adhesives, and chemicals in
disposal policies, CONEG (Coalition of Northeastern paper into inhalation solutions;
Governors), and Toxics in Packaging Clearing House • Migration of vanillin for labels and cartons into
(TPCH) requirements. For certain drugs, such as most inhalation solutions;
tablets and capsules, the regulations of the Poison • Migration of chemicals from heat seals, plastics,
Prevention Packaging Act (PPPA) apply. There are and foils into drugs;
also regulations in 21 CFR §201.25 Barcoding, which • Presences of vinyl monomer in polyvinyl chloride
require barcoding the National Drug Code (NDC) (toxic);
number on the drug labels, including blisters. On • Ions and glass in injection solutions;
May 2, 2011, the ASTM issued a new standard for • Migration of drug to plastic or coating glass;
Water Vapor Permeation titled D7709 – Standard • Migration of preservatives;
Test Methods for Measuring Water Vapor Trans- • Migration of plastic additives to drugs;
mission Rate (WVTR) of Pharmaceutical Bottles • Migration of environmental estrogens to drugs;
and Blisters.96 Although these standards are current • Cross-linking of gelatin capsule shells from fur-
at the time of publication, it is important to note fural in Rayon Coil;
that the standards in USP and ASTM are evolving, • Interaction of residual bleach and dyes in Cotton
and it is important to refer to the current versions Coil;
of these standards, which are reviewed and revised • Failure of a delivery system to deliver the correct
routinely. In addition to the law, regulations, ASTM dose;
and USP standards, FDA CDER provides guidance • Low potency or dissolution properties from excess
in the amount and type of testing required for drug moisture permeation; and
containers.97 • Degradation from light.
The amount of effort required to develop or select
the appropriate container system is based on a risk Container designs and materials have evolved to
assessment considering the route of administration, meet new demands and more sophisticated require-
class of drug product, therapeutic range, and the ments. Due to a tightening of limits on drug product
chemical and physical stability of the drug substance, impurities, degradants, and migrants, the selection of
drug product matrix, packaging components, and the containers has become more complicated. Pharmaceu-
conditions of storage and use. The route of adminis- tical companies must conduct compendial tests on the
tration determines the degree of testing necessary to containers98 and compatibility tests99 on the contain-
determine the acceptability of a container. In some ers with the actual product, using validated methods.
cases, a component, such as a delivery system, will The test methods used by the drug companies to test
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Pharmaceutical dosage forms: manufacturing and compounding | 339

for impurities and migrants are specific to the phar- appropriate container, when the drug manufacturer
maceutical formulation and the packaging material. does not provide repackaging instructions and the
Container components must also perform, as container supplier does not provide chemical or
needed, to protect the products from physical change, performance information. In these cases, the most
loss of contents, and exposure to moisture, oxygen, conservative approach may be the best approach.
and light. To develop the appropriate container Selecting materials that CDER already approved
closure system, the scientist must know the critical for use for similar products reduces the risk of com-
attributes of the specific drug product and chemical ponent failure. Certain chemicals have become asso-
and physical properties of the container options. The ciated with concern regarding their safety and appro-
importance of selecting the appropriate materials of priateness of use in packaging drug products. These
composition cannot be underestimated. This critical include, but are not limited to, nitrosamines, buty-
step is often not considered until problematic issues lated hydroxytoluene (BHT), certain carbon blacks,
arise. It is essential to consider, first, the container’s and some antistatic agents. It is best to eliminate these
requirements, and then select materials that fulfill concerns by selecting components manufactured with-
those needs. To determine the appropriate container out these chemicals. If possible, the packager should
closure system, one should consider the following: know which 21 CFR references, Food Contact Num-
bers, and USP or EU requirements the component
• Preformulation information on the drug substance or material meets. It is advisable to choose materials
(sensitivity to heat, oxygen, humidity, light, glass, available commercially. Medical grade materials are
metals, pH, reactivity with plastics, metals, or preferred, but are often more expensive. The classifi-
types of glass); cation of medical grade does not mean the materials
• The nature of the dosage form (solid oral, are of a particular composition; it means the supplier
liquids – aqueous, alcohol, oil, suspensions, inhala- complies with a change control program. Although
tion powders, creams, ointments, biodegradable selecting medical grade materials is preferable, the
polymers, implants, transdermals, etc.); materials should, at least, come from a reliable source
• Drug product information (open pan studies on and be cGMP manufactured. One should know the
impact of humidity, light, heat, pH, and compati- details of the suppliers change control program. When
bility studies with the components); suppliers are not willing to report changes to the
• Container material qualification (CAS number, 21 packager or pharmacist or control their changes, the
CFR qualification, USP qualification, etc.); quality of every lot is in question and may require full
• Container/product compatibility; extensive testing, particularly if it is used to package
• Impact of the packaging operation on the drug a high-risk product.
product;
• Ruggedness of the container system under actual
conditions of packaging, shipping, storage and use; Pharmaceutical excipients
• Performance; and
• Cosmetic features. The practice of pharmacy is an ever-evolving profes-
sion. A non-scientific survey of community pharma-
The drug manufacturer has access to all of the cies has revealed that extemporaneous compounding
data listed, and the information is reviewed by of prescriptions increasingly occurs. Whether this is
the FDA in support of their submission. Container a result of the physician not writing for compounded
manufacturers file Type III Drug Master Files (DMFs) medicines or the pharmacy not being interested in
with the FDA, so the information can be reviewed preparing such medicines is a topic for discussion
in conjunction with the drug application and FDA elsewhere. It is, however, undoubtedly driven by
can determine if the container is compatible and the pharmaceutical industry, addressing many dis-
the information is sufficient for approval of the ease treatment and prevention efforts by commercially
drug product. The challenge for the repackager, manufacturing products for mass distribution by the
pharmacist, or pharmacy compounder is selecting the healthcare system in the United States.
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340 | An Introduction to Pharmacy

The FDA has levied large fines on manufactur- by extemporaneously compounding it in a practice
ers who have failed to comply with cGMPs. Several setting.
companies have been forced to operate under what is
known as a ‘‘Consent Decree,’’ due to significant defi-
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McGraw-Hill.
Bibliography – General
Lachman L et al. eds (1986). The Theory and Practice of Bibliography – Excipient Properties
Industrial Pharmacy, 3rd edn. Philadelphia: Lea &
Rowe RC et al. eds (2009). Handbook of Pharmaceutical
Febiger.
Excipients, 6th edn. Washington DC: American
Lieberman HA et al. eds (1998). Pharmaceutical Dosage
Pharmaceutical Association.
Forms. Volume 3: Disperse Systems, 2nd edn. New
Reynolds J, ed (1996). Martindale, The Extra
York: Marcel Dekker.
Pharmacopoeia, 31st edn. London: Pharmaceutical
Nielloud F, Marti-Mestres G, eds (2000). Pharmaceutical
Press.
emulsions and suspensions. New York: Marcel Dekker.

Bibliography – Solutions, Emulsions and

Suspensions
Becher P (1983). Encyclopedia of Emulsion Technology.
New York: Marcel Dekker.
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10
Fundamentals of pharmacy practice

Application of ethical principles to practice The prescription 385

dilemmas 345
Drug product safety reporting programs 411
Applied ethics and healthcare 346
Providing a framework for ensuring medication
Technology and automation 347 use safety 413
Pharmacy informatics 349 Adverse drug reactions 417
Technology and HIPAA 350 Drug interactions 418
Emerging technologies 351 Poison control 423
Clinical drug literature 351 Medication disposal 424
Roles, responsibilities, and drug information 352 Surgical supplies 431
The patient: behavioral determinants 354 Health accessories 431
Drug education 358 The entrepreneurial and intrapreneurial
Professional communications 364 pharmacist 433

References 435

Application of ethical principles to deal with the aforementioned broader ethical issues
shared by all health professionals and those unique to
practice dilemmas
or more commonly encountered in pharmacy practice.
The growing sophistication and complexity of con- New and difficult questions face pharmacists. How
temporary healthcare practice presents many ethical does one reduce or eradicate the under-treatment of
challenges including: protecting privacy and confi- pain? Should pharmacists participate in the practice
dentiality in an environment of easily accessible infor- of capital punishment by lethal injection?1 Whose
mation and perplexing regulations, maternal–fetal responsibility is it to manage an impaired colleague?
conflicts, cost containment and downsizing of profes- What are acceptable boundaries to avoid inappro-
sional staff, threats to the rights of human subjects in priate interactions with industry?2 Do pharmacists
research, genetic engineering and screening, and deliv- have the right to refuse to fill a legal prescription
ery of treatment and services in a highly fragmented on the grounds of conscience?3 How should scarce
system, to name only some of the more problematic drug resources be rationed? How will changes in state
issues. As pharmacy practice becomes more complex and federal laws and new court decisions impact the
and increasingly patient-oriented, pharmacists have to delivery and quality of pharmaceutical care?
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346 | An Introduction to Pharmacy

‘‘Because ethical dilemmas are commonplace in ethics is the study of good and evil, of right and
pharmacy practice, pharmacists must develop a work- wrong. But, ethics is much more than that. Ethics is
ing knowledge of formal and systematic ethical anal- concerned with the duties and obligations one has to
ysis, as well as learn to distinguish ethical issues from others and to him- or herself. Ethics is also concerned
social, psychological, political, and legal issues.’’4 with the rights of individuals and how those rights
Moreover, the difficulty of the ethical issues men- are recognized and respected. The systematic nature
tioned thus far suggests that a collaborative approach of ethics helps illuminate what one ought to do, who
to resolving them would be preferable to individuals one should be as a human being, and what and whom
struggling alone. Pharmacists must be able to work one should nurture and sustain in life.
with others on the healthcare team to find a justifi-
able resolution. To collaborate with others and work Values
effectively, there must be a systematic approach to
working through an ethical dilemma. Applied ethics Values are an important part of ethics. One uses val-
is defined as well as its application to pharmacy prac- ues to help explain how and why things are important
tice with emphasis on the use of normative models of to us. ‘‘Values are not to be confused with concrete
ethical decision-making to resolve practice dilemmas. goods. They are ideas, images, and notions. Values
A process for ethical decision-making is explained and attract us. One aspires after the good they articulate.
applied to clinical cases that refer to issues encoun- One expects to find our own good in relation to
tered on an individual, institutional, and societal level. what they offer.’’6 When one looks at the goodness
Resources to help in the resolution of ethical dilemmas or badness of an action, one must also look at the
are also noted. values attached to the action. Values are the inter-
nal motivators for our actions. Evidence of values is
observed in human behavior. True values elicit deeply
Applied ethics and healthcare held positive or negative attachments. Basic values
and a value system are developed in childhood and
The contemporary application of the ideas and con- result from such influencing factors as family, teach-
cepts of ethics to issues in healthcare began in the ers, friends, religious traditions, and culture. People
late 1960s with questions about the allocation of of different religious faiths or of no faith ascribe to
the new technologies such as hemodialysis and vital many values and principles one acts upon on a daily
organ transplantation, and the protection of human basis. Values also have their roots in professions.
research subjects. ‘‘General normative ethics attempts Some traditional values of the pharmacy profession
to answer the question, ‘which general moral norms are compassion, faithfulness, and fairness. With the
for the guidance and evaluation of conduct should we introduction of pharmaceutical care as a standard for
accept, and why?’’’5 When theories or norms derived pharmacy practice, the values of patience, respon-
from normative ethical inquiries are used to examine siveness, and kindness have been added to the list of
moral problems in professions, the term applied or traditional values.7
practical ethics is used. The term ‘‘applied’’ ethics in Usually, values remain unchanged after one
this case is applied to practical ethical questions in reaches adulthood unless they are challenged by
pharmacy practice. To arrive at a clearer understand- great spiritual or emotional distress. Values can also
ing of ethics in general, it helps to have a baseline change when it becomes apparent that an old value
knowledge of key terms. Three terms underlie all the system doesn’t work anymore. Whatever their origin
discussion in this section: (1) ethics, (2) values, and or evolution, the resulting personal and professional
(3) dilemmas. values can profoundly affect the ethical decisions that
pharmacists make.
Ethics
Dilemmas
Ethics is a careful, systematic inquiry into the nature
of morality, guidelines, or standards that give meaning An individual has a dilemma when, wanting to make
and direction to the human community. Simply put, a good choice he or she realizes that no matter what
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Fundamentals of pharmacy practice | 347

is done, a choice will result in loss or harm. Simply conflicts between personal values or one’s own code
put, a dilemma is choosing among equally unap- of ethics and the professional code. There can also
pealing alternatives. ‘‘A difficult problem becomes a be conflicts between the professional code and the
‘dilemma’ when one is quite sure that one will be code of the institution in which one works. In such
making a big mistake regardless of what path one cases, which code takes priority? On the other hand,
chooses. It is instructive to consider moral dilemmas a code might be silent on a particular ethical issue and
in this context. The anxiety one experiences as one provide no guidance to members of the profession as
faces each unpalatable alternative informs us about to how they should respond. The principles in a code
the nature of moral dilemmas. It seems that any deci- of ethics are not self-justifying; that is, just because
sion one makes will violate one or another value the code of ethics prescribes certain conduct doesn’t
which one holds dear.’’8 In particular, moral dilem- make it ethically correct. The thoughtful pharmacist
mas in pharmacy can arise in several ways. They should ask, ‘‘Why should I follow this tenet of the
can arise when the right thing to do, such as telling Code of Ethics of the APhA?’’ Finally, codes appeal
the truth, conflicts with obligations like loyalty to to our desire to have things simplified. We like clear
a peer or protecting the patient from harm. They answers to complicated questions and muddy situa-
can also arise when what is best for the patient runs tions. As mentioned previously, codes are written in
counter to patient self-determination or one’s own general terms. Because of this, there are gaps between
well-being, that is, one’s health, obligations to family actual ethical issues in pharmacy practice and what is
or one’s employer, and so on. To resolve a dilemma included in the Code.
effectively, one must have a method for reviewing the
facts, generating alternatives, and choosing the ‘‘best’’
alternative given the circumstances of the dilemma.
Technology and automation
The American Heritage Dictionary defines a system as,
Ethical codes
‘‘A group of interacting, interrelated, or interdepen-
Ethical principles and rules that apply to medical dent elements forming a complex whole; a condition
practice and research have long served as the basis of harmonious, orderly interaction.’’10 Systems are
for a system or code of ethical conduct. Ethical codes so important to the profession that they are major
provide healthcare professionals with ethical princi- contributors to the efficiency and effectiveness of a
ples and standards by which to guide their practice. pharmacy operation, as well as the underlying factor
However, ethical principles and codes cannot provide involved in medication errors. Providing contempo-
healthcare professionals with answers to every ethical rary pharmacy services involves such a sufficiently
question that may arise in the course of their prac- complex process that it most certainly necessitates a
tice. Ethical questions in healthcare involve decision- systems approach. Pharmacy is, of course, a subsystem
making that is usually situation-specific. The purpose of a larger, comprehensive healthcare system. In this
of such principles and codes is not to provide practi- section the authors will focus on a systems approach
tioners with right and wrong answers but to offer them in utilizing technology to support the practice of
a framework to use when faced with ethical questions. pharmacy and describe the complex interactions that
The Code of Ethics of the American Pharmacists Asso- occur in a pharmacy practice between people, data,
ciation (APhA) is the only code of ethics that specif- and technologies. These interactions focus primarily
ically guides the practice of pharmacy (Fig. 10.1). on the welfare of patients and are performed by phar-
The current version of the code was adopted in 1994 macists and their associates, who share a common
and includes eight ethical principles to guide ethical vision because they are involved in the pursuit of
decision-making by pharmacists. ‘‘It espouses both an rendering appropriate pharmaceutical care.11
ethic of respect for patient autonomy and pharmacist It is impossible to imagine any scenario for the
responsibility for outcomes of care in the context of future of pharmacy that does not involve the use
a covenantal pharmacist–patient Relationship.’’9 of many forms of technology and automation. This
Although codes of ethics are helpful, they are assumption holds true regardless of the practice
not without their flaws. For example, there may be setting selected. Consider that technology has two
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348 | An Introduction to Pharmacy

Code of Ethics

American Pharmacists Association

Preamble
Pharmacists are health professionals who assist individuals in making IV. A pharmacist acts with honesty and integrity in professional
the best use of medications. This Code, prepared and supported by relationships.
pharmacists, is intended to state publicly the principles that form the
fundamental basis of the roles and responsibilities of pharmacists. A pharmacist has a duty to tell the truth and to act with conviction of
These principles, based on moral obligations and virtues, are conscience. A pharmacist avoids discriminatory practices, behavior or
established to guide pharmacists in relationships with patients, health work conditions that impair professional judgment, and actions that
professionals, and society. compromise dedication to the best interests of patients.

I. A pharmacist respects the covenantal relationship between V. A pharmacist maintains professional competence.
the patient and pharmacist. A pharmacist has a duty to maintain knowledge and abilities as new
Considering the patient-pharmacist relationship as a covenant means medications, devices, and technologies become available and as health
that a pharmacist has moral obligations in response to the gift of trust Information advances.
received from society. In return for this gift, a pharmacist promises to
VI. A pharmacist respects the values and abilities of colleagues
help individuals achieve optimum benefit from their medications, to be
committed to their welfare, and to maintain their trust.
and other health professionals.
When appropriate, a pharmacist asks for the consultation of colleagues
II. A pharmacist promotes the good of every patient in a caring, or other health professionals or refers the patient. A pharmacist acknowl-
compassionate, and confidential manner. edges that colleagues and other health professionals may differ In the
A pharmacist places concern for the well-being of the patient at the beliefs and values they apply to the care of the patient.
center of professional practice. In doing so, a pharmacist considers
VII. A pharmacist serves individual, community, and societal needs.
needs stated by the patient as well as those defined by health science.
A pharmacist is dedicated to protecting the dignity of the patient. With a
caring attitude and a compassionate spirit, a pharmacist focuses on The primary obligation of a pharmacist is to individual patients. However,
serving the patient in a private and confidential manner. the obligations of a pharmacist may at times extend beyond the
individual to the community and society. In these situations, the pharma-
III. A pharmacist respects the autonomy and dignity of each cist recognizes the responsibilities that accompany these obligations
patient. and acts accordingly.

A pharmacist promotes the right of self-determination and recognizes VIII. A pharmacist seeks justice in the distribution of health
individual self-worth by encouraging patients to participate in decisions resources.
about their health. A pharmacist communicates with patients in terms
that are understandable. In all cases, a pharmacist respects personal When health resources are allocated, a pharmacist is fair and equitable,
and cultural differences among patients. balancing the needs of patients and society.

Figure 10.1 Code of ethics. (Originally published in ‘‘Code of Ethics for Pharmacists.’’ Am J Health-Syst Pharm 1995;52:2131.
© 1995, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission.)

primary purposes. Both of the purposes of technology per day would need to be read from the literature
involve the work of humans. One purpose for technol- to maintain one’s professional competency at the
ogy is to replace completely the work done by humans. highest level. Information technology can present the
Technology usually excels at replacing work that is highest quality, empirically derived, evidence-based
repetitive and work that is often found to be tedious information that reduces a pharmacist’s uncertainty
by humans. Ideally, technology should be considered while making decisions. Information technology
for selection and implementation when it can free a
helps to overcome the limits of human memory and
human being to be redeployed into a work process
helps reduce the use of conjecture (opinion) based
that requires the abstract, judgmental, and higher-
decision-making.13
level cognitive processes at which humans excel.12
Another example of a performance enhancing
The second role of technology involves the
enhancement of human work. With over 6000 technology can be found in the use of bar codes.
articles being published every week in the biomedical In community pharmacies, hospitals, and nursing
literature, it is impossible for any human to ‘‘keep homes, bar codes can be scanned in the dispensing
up’’ with the dynamic field healthcare represents. process and at the point-of-administration to assure
Evidence-based medicine experts estimate that in even that the right drug is being given to the right patient,
the narrowest specialty, approximately 14 articles in the right form, by the right route, in the right
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Fundamentals of pharmacy practice | 349

strength, at the right time. Use of bar codes in health- Compare the adoption of ‘‘cash cards,’’ a.k.a.
care is showing great promise to significantly reduce ATM cards, and imagine that a similar card for health-
accidents and errors.14 care would serve as the means for caregivers to gain
Generally one can assert that, over time, technol- access to patients’ medical records. There are several
ogy continues to weigh less while it does more. The technologies that provide this kind of access. Every-
ubiquitous nature of the Internet, microcomputers, thing from biometric fingerprint or retina scanning to
portable information appliances in the form of smart- smart cards is being examined. No true standard has
phones, and more recently, iPad-like tablets allow emerged as of yet, and new entries such as Google
technology to touch everyone to an increasing extent Wallet are emerging. In fact, some people say (tongue
in our everyday work and existence. Do you know in cheek), that the nice thing about information tech-
anyone who receives more voicemail than e-mail? nology standards is that there are so many to pick
Can you reach certain colleagues in minutes by a text from. The authors do not believe the smart card is
message, while voicemail may take days to receive the future unless it can totally reduce the thickness
a reply? This level of connectivity has led to a new of one’s wallet by serving all identity functions for
definition of the Internet, which includes every com- all health, business, travel, entertainment, and other
puter, smartphone, tablet, and other portable devices related transactions of daily living.16 Getting all of the
being connected in wired and wireless environments, businesses represented to agree on a single standard
allowing text and voice communication from almost would certainly be a prodigious task or require strong
anywhere in the world. Where will it end? While it is government intervention.
difficult to imagine all of the permutations and possi-
bilities, it is safe to say that pharmacy students today
have had the ability to connect as much as they wish Pharmacy informatics
for most of their life.
Healthcare as a discipline tends to lag behind ‘‘Medical informatics is the rapidly developing
other areas and industries with regard to its adop- scientific field that deals with the storage, retrieval,
tion and diffusion of technological innovation. In and optimal use of biomedical information, data,
fact, healthcare had been described as one of the few and knowledge for problem-solving and decision-
remaining predigital industries. Fortunately, incen- making.’’17 Healthcare informatics is the umbrella
tives and penalties offered by the federal government term for all health-related disciplines, and phar-
for the adoption of electronic health records are begin- macy’s related discipline is commonly called either
ning to change the paper-based dominance found in pharmacy informatics or pharmacoinformatics.18 It
our care-delivery systems. The authors believe the is impossible to consider that any individual can
banking and financial industries are the best examples keep up with the flood of information that is being
to follow when determining how healthcare will con- created concerning the safe and appropriate use of
tinue to evolve. Granted, there are differences, but medications in humans. Information technology is,
trust is needed in both systems and technologies used. therefore, required to manage these data efficiently
If people are willing to trust their finances to elec- and effectively.
tronic banking technologies, it is reasonable to expect One might ask the question, ‘‘While I am pro-
that they will become more comfortable trusting the viding pharmaceutical care or performing medication
management of their healthcare information to elec- therapy management (MTM) services, what are my
tronic technologies. Most pharmacists tell us that they technology systems supposed to be doing?’’ At the
are less than 10% paperless in their practices. Today, core of nearly every pharmacy software program
there are many examples today of health systems that is a database application. In a pharmacy manage-
are now 100% paperless. The care they provide has ment database application program, there are mul-
been greatly enhanced by this digital information con- tiple databases being managed. Database tables can
vergence, yielding greater situational awareness in all include information relating to patients, prescribers,
patient care scenarios. The authors can imagine no drugs, payors, drug interactions, and many others.
scenario or practice setting where the digitization of Historically, pharmacists assisted by their technol-
transactions will not increase over time.15 ogy, have always been challenged to deliver the right
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350 | An Introduction to Pharmacy

information, to the right people, at the right time and One will still see books being published. One will
place, in the right format. Today, information appli- also see CD-ROM and Internet versions of the same
ances are now ready to provide assistance in achieving products. The majority of these reference tools are
these ‘‘rights,’’ but the integration of this information also available in formats that allow them to be
into the workflow of the pharmacist remains the displayed on portable devices, such as tablets and
largest challenge facing all. smartphones. This allows mobile practitioners to use
Years ago, the only format for the delivery of high quality evidence in decision-making wherever
decision support information was a tertiary refer- they require it. These tools are also updated on a
ence book that was, hopefully, from an authoritative daily basis, and in some cases wireless access makes
source. Some of these trusted references were only it possible for real-time updates to arrive where
updated every few years. As computer systems began they are needed and when they are needed. An ideal
to be commonplace, decision-supporting ‘‘nuggets’’ informatics support system allows the integration,
of information from the literature were incorpo- management, delivery, and display of data in support
rated into prospective drug utilization review (DUR) of a pharmaceutical care practice.
databases, and pharmacists would be ‘‘flagged’’ when
patients were about to be exposed to duplicate ther-
Technology and HIPAA
apy, significant drug interactions, or the entry of a
new prescription to which a patient was potentially
‘‘Medical records contain intimate information about
allergic. As these DUR products matured, mono-
a person’s physical and mental health, behaviors, and
graphs discussing the management of the problem
relationships. Intrusions into privacy can result in loss
were included on the systems. ‘‘Alert fatigue’’ is a
of trust, with an unwillingness to confide in health care
term to describe when too many flags (represent-
professionals. Unauthorized disclosures of intimate
ing false positive alerts that interrupt a pharmacist’s information can cause embarrassment, stigma, and
workflow) are presented to a pharmacist, impairing discrimination.’’19 Many pharmacists remain con-
their ability to separate the important warnings from cerned about changes due to the Health Insurance
these false alarms. Portability and Accountability Act confidentially, and
Initially, respected tertiary books were trans- the regulations impose severe penalties for security
formed to onscreen versions of the books upon breaches. The authors know of at least 14 different
which they were based and were typically distributed methods to secure electronically held information. In
every three months by CD-ROM. As the Internet many ways, it is more secure than paper records.
developed, drug information became increasingly Events such as Hurricane Katrina in 2005 remind
available from providers who offered their products us that there are many limitations to paper-based
online. While a pharmacist’s printed books might records and many advantages to electronically stored
be available for new editions annually or have information.
inserts mailed out on a quarterly basis, online drug The regulations of HIPAA also provide that
information could be updated on a daily basis. patients should have better access to their own
It was also found that many busy practitioners medical records. In most US states, patients own
needed information packaged in phrases rather than the information contained in their medical records.
sentences and paragraphs. Many products now reflect Unfortunately, they do not feel as if they own
a ‘‘just the facts’’ approach to information. The best it or have access to it as they desire. Some US
products are workflow-sensitive and anticipate the companies are creating a collaborative medical
special circumstances in which decisions are being record that allows patients, through the World Wide
made to include all of the information, such as patient Web, to become partners or coproducers in their
demographics and current health status extracted own healthcare by allowing access to their medical
from the electronic medical record. Decision support records. The patient can also elect to allow access to
cannot be ‘‘smart’’ without these data. their medical record by trusted relatives and other
The latest trends place these resources into the agents. In this way, an adult child can ‘‘look in’’ on
hands of practitioners in a variety of different media. his parents or grandparents health status.
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Fundamentals of pharmacy practice | 351

Other technologies such as computerized physi- networking on the Internet. Previously, the Internet
cian order entry (CPOE) are actually complementing had the functionality of what we describe as the three
HIPAA regulations and provide additional incentives ‘‘C’s’’ to include content, communication, and com-
for moving toward electronic medical record imple- merce. A fourth functionality is that of community.
mentation. The portability aspect of the regulations Online, trusted communities allow patients to learn
can also be made possible through technology sup- what to do and how to do it and partner with people
port. An Internet standard called extensible markup who share a similar condition, to remain motivated
language (XML) allows the health information that in their active participation in healthcare. A website
is stored on the World Wide Web to be able to like http://patientslikeme.com is an excellent example
‘‘move’’ between systems because the information on of an online healthcare community.
the web page is field-tagged so that it can be portable The name for this expanded use of the Internet
between systems. Technology standards will again is Web 2.0 or Health 2.0. We have reached a point
facilitate many processes and are necessary for rapid at which the majority of adult American citizens
improvement. have cell phones or smart phones with them day and
The HITECH Act of 2009 (a component of the night, within three feet of their person. Applications
American Recovery and Reinvestment Act) added a are bound to assist patients and healthcare providers
requirement for self-assessment of the security pro- alike with decision-making regarding all aspects of
vided for protected health information concerning patient care. The vision for how technology allows
patients. The legislation empowered the Office of a higher quality of life to all citizens while keeping
Civil Rights to investigate and assess penalties to any them in their homes and out of institutions is made
healthcare entity when any breach of protected health possible by the integration of health enterprises that
information occurs. Each entity must have undergone range from the intensive care unit all the way into the
a self-assessment on three levels to document that patient centered medical home.
steps needed to protect these data were undertaken by A center for excellence that promotes aging
the entity. Failure to address these security issues and in place is found at the University of Missouri at
the technology of the entity could result in large fines Columbia. In this community, networked homes
if the healthcare organization would be found to have allow for affordable, consumer electronics to pro-
willful neglect regarding the requirements of the act. vide peace of mind that the health status of each
networked home’s occupant is receiving monitoring
and real-time communication with the health system.
Emerging technologies Thus, a true continuity of care can be achieved, and
family members can be assured that their loved ones
‘‘The imperatives of improving documentation, reduc-
are receiving the best care possible.
ing errors, and empowering patients to engage in their
own healthcare management will continue to moti-
vate use of information technology in health care.’’20 Clinical drug literature
There are so many exciting and emerging technologies
to investigate that we usually find it more interesting Accessing, reviewing, analyzing, evaluating, and inter-
to look at the technological ‘‘low hanging fruit’’ than preting clinical drug literature are important responsi-
to elaborate on the future implications of advanced bilities of healthcare practitioners; this is particularly
innovations, such as genomics and nanotechnologies. true for pharmacists, who are experts about drugs
There are a number of futurists who predict that dis- and medication therapy management. Pharmacists
ruptive technologies must be anticipated because they have been using and providing drug information
will heavily impact organizations on both strategic for decades, focusing initially on drug product com-
and tactical levels. pounding and dispensing information. However, the
A growing trend to make participatory healthcare need for drug information has expanded along with
(in which patients and their nonprofessional care- the pharmacists’ roles. The 1975 report of the Study
givers are fully engaged in healthcare management) Commission on Pharmacy concluded that the phar-
has been facilitated with the rapid growth of social macy profession was not effective in developing,
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352 | An Introduction to Pharmacy

organizing, and distributing knowledge and infor- to look for health-related information during the
mation about drugs. In fact, they felt that pharmacy’s previous year,23 with a 2010 Harris Poll estimating
greatest deficiency was its inadequacy as an informa- that 175 million American adults have sought
tion transmitting system to patients, physicians, and health information online.24 Key responsibilities of
other healthcare practitioners.21 pharmacists and other health professionals regarding
Although more work is needed to fully realize the Internet use include differentiating good from
pharmacist’s potential in all practice settings, the pro- poor quality information, identifying strengths and
fession has certainly made great strides forward since limitations of available information, appropriately
the Study Commission’s report with regard to provid- applying the information patients obtain to their
ing enhanced drug and therapy-related information to personal health needs, reviewing with patients the
patients, physicians, and other healthcare profession- applicability of the information they locate, and
als. This is evidenced by the continual growth and recommending to patients high quality websites on
development of patient-oriented pharmacy services topics of interest or websites that review and select
across practice settings. Also, the establishment of the Internet resources based on specified criteria (e.g.,
entry-level Doctor of Pharmacy degree program and Medlineplus: http://www/nlm.nih.gov/medlineplus/).
the expansion of residency opportunities are helping
to better prepare future practitioners to function as Roles, responsibilities, and drug
information specialists on the healthcare team.
information
The types of drug information needed by phar-
macy practitioners and other healthcare professionals
Pharmacists have diverse responsibilities that neces-
are varied and include, but are not limited to, infor-
sitate information use, including responding to
mation about side/adverse effects, interactions, uses,
medication inquiries of a variety of types from
teratogenicity, stability, and compatibility; product
patients and health professionals, adverse drug
identification and availability; dosages and adminis- event monitoring and management, resolving drug
tration; toxicity, pharmacokinetics, pharmacodynam- therapy related problems, making drug use decisions,
ics, pharmacogenomics, health-related quality of life, providing educational activities, and engaging in
and pharmacoeconomics; and efficacy, including com- clinical research. To accomplish these responsibili-
parative efficacy among drugs in the same chemical or ties, pharmacists must be able to locate complete,
pharmacological class as well as among drugs from up-to-date information on which to base patient-care
different classes. Health professionals must be knowl- and other important decisions. Locating information
edgeable about not only the variety of information includes selecting a proper database, using an optimal
resources available and how, why, and when to use search strategy, and having the needed information
them, but importantly, must be able to critically ana- readily available. It is clear that the appropriate
lyze, evaluate, interpret and apply the information use of technology is critical for the contemporary
they locate. pharmacist as well as other healthcare professionals.
Advances in computer and hand-held tech- A field has emerged, termed biomedical informatics,
nologies, the growth of the Internet, and the defined as the study and pursuit of ‘‘the effective
widespread availability of user-friendly MEDLINE uses of biomedical data, information, and knowledge
and other database-searching capabilities have placed for scientific inquiry, problem solving, and decision
unprecedented and continually expanding amounts making, motivated by efforts to improve human
of information readily within an individual’s grasp. health.’’25 Biomedical informatics encompasses
In particular, patients and healthcare providers ‘‘medical informatics,’’ ‘‘health informatics,’’ and
are increasingly turning to the Internet as an ‘‘clinical informatics;’’ the latter terms have been
information resource, despite the unregulated and used synonymously with each other.26
variable quality of information provided there.22 Once acceptable sources of information are iden-
A National Health Interview Survey conducted tified and retrieved, health professionals must analyze
in 2009 found that approximately 51% of adults and evaluate the published literature and develop
aged 18 to 64 years old had used the Internet recommendations based on the best available data.
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Fundamentals of pharmacy practice | 353

Knowledge of searching techniques, research design, drug packaging or names, or the misuse of medical
and biostatistics is fundamental to the critical evalu- equipment with the goal of improving patient
ation of literature, particularly clinical studies. Once safety. This program can be accessed online at:
relevant evidence from published clinical research https://www.ismp.org/orderforms/reporterrortoISMP
is obtained, evidence-based medicine (EBM) princi- .asp. Pharmacists can access ISMP safety guidelines
ples should be applied to arrive at drug therapy on a number of different topics from their website,
related decisions. Two fundamental principles of EBM as well as listings of often confused drug names that
involve: (1) considering the hierarchy of evidence resulted in medication errors, oral dosage forms that
(e.g., observations, clinical studies and the strength of should not be crushed, and error-prone abbreviations
study designs) when making clinical decisions, and (2) to avoid.
considering benefits/risks, inconvenience, costs, and Another important role that pharmacists perform
patient values and preferences together with evidence is actively participating in pharmacy and therapeutics
in making clinical recommendations.27 Since EBM is committees that establish and maintain formulary
being increasingly taught to and applied by healthcare systems and make decisions and recommendations
practitioners, pharmacists should be knowledgeable concerning rational drug use within healthcare
about this process. The Evidence-Based Medicine institutions. This type of committee is generally
Working Group has published an easy to carry book multi-disciplinary and reviews medication safety
that reviews the essentials for applying EBM to clin- data, develops drug therapy guidelines, and conducts
ical practice, and this resource is recommended to medication use evaluations. Drug use evaluation
readers wishing to learn more about this area.27 (DUE) and medication use evaluation (MUE) have
Adverse drug events/experiences/reactions and often been used interchangeably, although MUE
medication errors not only result in patient morbidity has been used to emphasize the entire multidisci-
and mortality, but also increase healthcare costs by plinary approach to enhancing medication use in
millions of dollars annually. Pharmacists play an an institution, beyond the process of evaluating
active role in preventing, detecting, and reporting the appropriateness of medication therapy through
adverse events. Pharmacists are one of the major a systematic process using defined criteria and
groups of healthcare professionals who report adverse standards (DUE).28 Through the design and conduct
drug events to the Food and Drug Administration of DUEs and MUEs, pharmacists can play a key role
(FDA) via MedWatch. Information about this in ongoing improvement in drug use and patient care.
program can be found online at http://www.fda.gov/ Pharmacists are involved in many different drug
Safety/MedWatch/default.htm. Serious adverse events information-related educational activities conducted
can be reported by calling the FDA at 800-FDA-1088, for other healthcare professionals and patients. Since
by completing the FDA 3500 Voluntary Adverse the practice of medicine and pharmacy involves
Event Report Form online or by downloading the lifelong learning about the ongoing advances in
form and submitting it by fax to 800-FDA-0178. pharmacotherapeutics, pharmacists can contribute
Safety alerts that the FDA has issued over the past to the continuing education (and continuing pro-
several years can be accessed through the website fessional development) of healthcare professionals
listed above, and health professionals can sign-up to through preparing and disseminating newsletters
receive free e-mail MedWatch updates. Pharmacists and by providing seminars and lectures. Pharmacists
can also implement systems to prevent drug misad- also play a key role in providing verbal and written
ventures (such as errors in the prescribing, dispensing, information to patients about their medications,
and administration of medications) and to enhance medical conditions, and nondrug therapies useful for
patient adherence. The Institute for Safe Medication managing these conditions.
Practices (ISMP) operates the National Medication Participating in clinical and practice-based
Errors Reporting Program (ISMP MERP), through research trials is another application of the drug
which health professionals can report medication information skills of pharmacists, allowing them to
errors of a variety of types (e.g., dosing or calculation improve their understanding of how drugs work,
mistakes, route of administration errors), confusing comparative drug efficacy, and how to better deliver
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354 | An Introduction to Pharmacy

medication therapy and related information to appropriately, a pharmacist to dispense appropri-

enhance patient care. Familiarity with the research ately, and a patient to follow directions and take
process and medication use also makes pharmacists the medication properly. Similarly, it is tempting to
especially well suited to serve on institutional review believe that patients, upon following physician and
boards, which are established to protect the rights of pharmacist suggestions, readily experience symptom
study subjects. improvement and better health. The reality is that
Drug information centers were established in the many individuals needing healthcare do not receive
mid-1960s.29,30 They are usually staffed by pharma- it, receive it late, or do not follow through with
cists who review, collect, organize, and analyze drug directions. For example, a National Health Survey
information and disseminate it to healthcare profes- shows that at least 30% of those considering help
sionals and consumers.31,32 Drug information centers for emotional problems do not actually seek care.38
or services often exist as functioning departments In other cases, there may be a considerable delay in
within healthcare institutions, within the pharma- seeking care. While most breast cancer symptoms are
ceutical industry (e.g., medical information contact discovered by women, at least one third of breast
centers),33 in academic settings, or as independent cancer patients will be aware of their symptoms
centers serving healthcare professionals and the for three months or more before seeking an initial
public.34 – 36 The activities of drug information cen- provider evaluation.39 In addition, 30% to 60% of
ters or services have changed considerably since they all individuals who obtain medical care do not follow
were first established to primarily answer inquiries. through with prescribed treatment,40 and almost half
A regularly administered survey of US pharmacist- of those taking medications do not ask any questions
operated drug information centers offering services to when visiting the physician.41
healthcare professionals found that 54 such centers Why do some people seek medical advice while
existed in 1974; this number increased to a maximum others with similar symptoms do not? Why do some
of 127 in 1986 and the most recently published 2008 individuals who obtain medical care follow recom-
survey reported a total of 75 centers.37 The activities mendations and take an active role in their care,
reported by these centers included educating health- while others with similar diagnoses and treatments
professions students, conducting pharmacoeconomic do not follow through with recommendations and
evaluations, providing direct patient care at bedside, do not ask any questions about their treatment? To
providing informatics support, reporting adverse answer these questions, we need to understand the
drug reactions, and providing educational in-services, determinants of patient behavior.
among other functions. Despite the proliferation of
readily available information and resources, many Types of patient behavior in health
of the surveyed centers reported an increase in the The three main areas in the study of patient behav-
complexity of drug inquiries received.37 Thus, drug ior are: (1) preventing illness or detecting it in an
information centers or services can be an excellent asymptomatic stage, (2) obtaining a diagnosis and
resource for healthcare practitioners when assistance discovering suitable treatment, and (3) undertaking
is required in handling a difficult clinical problem or or maintaining treatment aimed at restoring health or
when significant time or resource constraints exist. halting disease progression. Kasl and Cobb42 defined
these health-related behaviors and labeled them health
behavior, illness behavior, and sick-role behavior,
The patient: behavioral respectively. The definitions are still useful today,
determinants although some terminology has changed to reflect
contemporary theory and research on health behavior.
Introduction Health behavior that is preventive in nature gen-
erally is referred to as preventive health behavior. By
Health professionals often assume that the process expanding on the original definition, preventive health
of healthcare simply involves a patient to seek care behavior is defined as actions taken to prevent ill-
for his or her symptoms, a physician to prescribe ness and maintain physical, emotional, intellectual,
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Fundamentals of pharmacy practice | 355

spiritual, and social well-being. Examples of preven- Patient communication

tive health behaviors include participation in health
A constructive pharmacist–patient relationship is
screening programs, following healthy diet recommen-
essential to sound healthcare practice and the optimal
dations, participation in relaxation and cardiovascular
well-being of the patient. This relationship involves
exercises, and creating and maintaining close personal
using both verbal and nonverbal communication.
relationships.
To provide quality patient care, pharmacists must
Illness behavior is any activity undertaken by indi-
have the desire and ability to communicate effectively
viduals who perceive themselves to be ill that defines
with patients, other healthcare professionals, and the
the state of their health and aids in discovering a
public.
suitable remedy.43 Illness behavior is the way persons
respond to bodily indications that they experience as
abnormal; thus it involves the manner in which per-
Communicating and patient
sons monitor their bodies, define and interpret their
empowerment
symptoms, and seek healthcare.44 Individuals attempt
to ascribe cause and meaning to their illness symptoms Communication is the sharing of information, ideas,
and may self-diagnose and treat. Alternatively, indi- thoughts, and feelings where the goal is achieving an
viduals may visit a doctor or another prescriber and understanding between the participants. It involves
a pharmacist in order to obtain a prescription drug. the spoken word and also what is conveyed through
Actions taken to restore health or halt disease inflection, vocal quality, facial expression, body, and
progression traditionally have been referred to as other behavioral responses. The interactions of a phar-
sick-role behaviors and now are referred to as treat- macist and a patient usually can be categorized as
ment behaviors. Originally, the conceptualization of either an information-gathering or information-giving
sick-role behavior45 offered a systematic approach for communication session.48 Information gathering usu-
analyzing the behavior of sick individuals in the US ally occurs during a medication-history interview,
and other modern Western societies. This function- which is a conversation with a multifaceted pur-
alist perspective regarded illness as dysfunctional to pose. Pharmacists initiate the interaction to investigate
society and considered sick-role behavior as seeing and acquire data about a patient’s medication-taking
the physician, passively following his or her prescrip- experiences, assess a patient’s understanding of pre-
tion, and regaining health. This traditional view of vious and current medication-taking experiences, and
the patient as a passive individual has been criticized gauge a patient’s motivation for adhering to the med-
extensively in recent years.46 ication regimen. In addition, pharmacists may suggest
Patients today are considered to be thinking, able to the patient’s prescriber a change in regimen if the
decision makers who can play an important role in information gathered warrants such an action.
the treatment process.47 Because patients are now Patient empowerment is a concept that refers to
recognized as active individuals, more attention is patients’ rights to make their own choices about their
being paid to ways of restoring health or slowing ill- healthcare.49 Research has revealed that a patient
ness progression through improved provider–patient who is involved in deciding on his or her treatment
communication and patients’ involvement in their regimen is more likely to adhere to the treatment.50,51
own treatment. For example, patients are actively Feste argues that ‘‘the empowerment model has
searching the Internet and other sources for health evolved out of the realization that patients cannot
information. Emphasis therefore is placed on a range be forced to follow a lifestyle dictated by health-care
of patient treatment behaviors, including sharing professionals.’’49 The patient empowerment model is
beliefs and expectations, asking questions, adhering based on the assumption that to be healthy, people
to regimens, using home monitoring devices, keeping must be able to bring about changes not only in their
appointments, identifying and reporting side effects personal behavior but also in their social situations
and drug-taking problems, and other valuable forms and the institutions that influence their lives.
of communication that are necessary in contemporary Effective healthcare communication should
healthcare. include patient empowerment in the patient–provider
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356 | An Introduction to Pharmacy

relationship. Funnell and associates explain the pro- • A value-added service to offer patients
cess and outcome of patient empowerment.52 They • Revenue generation through payment for cognitive
suggest that ‘‘people are empowered when they have services
sufficient knowledge to make rational decisions, • Fulfillment of legal responsibility to counsel
sufficient control and resources to implement their patients according to the OBRA 90 and other
decisions, and sufficient experience to evaluate the required guidelines.
effectiveness of their decisions. Empowerment is
more than an intervention or strategy to help people The Ad Hoc Panel on Medication Counseling Behav-
make behavior changes to adhere to a treatment ior Guidelines of the USP has identified six desired
plan. Fundamentally, patient empowerment is an outcomes of patient counseling.6 It is expected that,
outcome. Patients are empowered when they have as a result of a properly conducted counseling inter-
knowledge, skills, attitudes, and self-awareness action, the patient will
necessary to influence their own behavior and that
of others in order to improve the quality of their • Recognize why a prescribed medication is helpful
for maintaining or promoting well-being
lives.’’52 Table 10.1 provides an outline of patient
empowerment as adapted from Funnell’s model. This • Accept support from the healthcare professional
in establishing a working relationship and founda-
outline may be used by pharmacists to achieve more
tion for continual interaction and consultation
effective patient counseling encounters.
• Make more appropriate medication-related deci-
sions concerning compliance or adherence
Benefits of effective patient counseling
• Improve coping strategies to deal with medication
Using effective communication strategies and engag- side effects and drug interactions
ing patients in their healthcare treatment can provide • Become a more informed, efficient, active
significant benefits to both the patient and the phar- participant in disease treatment and self-care
macist. Patients will have a better understanding of management
the purpose for the prescribed therapy and the appro- • Show motivation toward taking medications to
priate use of the medication. This leads to several improve his or her health status.
potential benefits:

• Improved therapeutic outcomes and decreased Patient adherence

adverse effects
Healthcare continues to advance in the understanding
• Improved patient adherence to the treatment plan
and treatment of many disease states. This has lead
• Decreased medication errors and misuse
to the development of new treatment options for the
• Enhanced patient self-management by involving
control or cure of many clinical disorders. Despite the
the patient in designing the therapeutic plan
advances in care, treatment can fail to be successful. In
• Decreased healthcare costs resulting from appro-
order for treatment to be effective, a patient must still
priate use of medications and prevention of
ultimately make the decision to follow the prescribed
adverse events.
regimen as instructed.
The pharmacist also benefits in this process. Potential This concept of compliance in healthcare can be
benefits to the pharmacist in this process include viewed broadly as it relates to instructions concerning
diet, exercise, rest, return appointments, and the use
• Enhanced professional status in the view of of medications. It is in discussions concerning drug
patients and other healthcare providers therapy that the designation patient compliance is
• Establishment of an essential component of patient used most frequently. Many terms such as compliance,
care that cannot be replaced by technicians or adherence, and persistence are used interchangeably,
automation but there are differences between them.
• Enhanced job satisfaction through improving Adherence can be defined as ‘‘the extent to
patient outcomes which a patient’s behavior corresponds with the
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Fundamentals of pharmacy practice | 357

Table 10.1 Outline of a patient empowerment program

Healthcare professional assesses current status (physical, emotional, cognitive, etc.)

Reviews patient’s actual self-care practices

Reviews patient’s recommended self-care practices

Healthcare professional provides relevant medical information

Describes various treatment options

Reviews costs and benefits for each option

Healthcare professional acknowledges patient’s responsibility for self care

Helps patient clarify personal values specific to their illness

Helps patient assess level of personal responsibility for their care

Helps patient select treatment goals

Patient identifies barriers and strengths related to achieving self care

Assesses medical barriers and sources of support

Assesses life/social barriers and sources of support

Patient assumes problem-solving responsibility

Develops skills to optimize support (e.g., communication and assertiveness skills to enhance support from family and
friends; increases support networks)

Identifies potential barriers

Learns strategies/skills to overcome barriers (e.g., negotiation, self-care agreements and plans, conflict resolution)

Patient establishes plan with assistance from provider

Patient carries out plan

Patient and provider evaluate and review plan using problem-solving model.

(Adapted from Funnell MM, et al. Diabetes Educator 1991; 17(1): 37.)

recommendations of a healthcare provider.’’53 When self-benefit and a positive outcome associated with
viewed in this context, adherence and compliance are the prescribed treatment, such as enhanced daily
synonyms and can be substituted for one another. functioning and well-being.
Adherence with therapy implies an understanding of Persistence is a similar concept to adherence but
how the medication is to be used, as well as a positive can be defined as ‘‘the duration of time from initia-
behavior in which the patient is motivated sufficiently tion to discontinuation of therapy.’’54 Persistence to a
to use the prescribed treatment in the manner regimen is maintained as long as the patient does not
intended. It also implies that the patient perceives exceed the permissible gap (the time frame for which
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358 | An Introduction to Pharmacy

a patient may discontinue medication without expe- concern of most societies, and it usually is highlighted
riencing an adverse outcome).55 Patients can demon- when specific outbreaks of problems or inappropriate
strate persistence with a given regimen while not being use occur. As pharmacy is the profession to which the
adherent to that regimen if they continue to take some control of drugs is attributed, it should be involved
medication but not in the prescribed manner. intimately with those activities aimed at preventing or
Problems concerning patient compliance with reducing drug use problems. In fact, the pharmaceuti-
instructions have been recognized for years. Hip- cal profession should be providing the leadership and
pocrates once cautioned, ‘‘Keep watch on the fault directing the research in this area. It is unfortunate
of patients which often makes them lie about the that, on the whole, pharmacy has been lacking in
taking of things prescribed.’’ Twenty-three centuries its social responsibility for the chemical substances it
later, attaining patient adherence in the use of their develops, promotes, and dispenses.
medications continues to represent a formidable Most pharmacists are aware of the important
challenge for healthcare providers. problems that potentially can occur with the appro-
When the complexity of the illnesses and the priate use of prescription medications, such as adverse
actions of therapeutic agents are considered, the reactions and drug interactions. Many pharmacists
physician, pharmacist, and other health profession- also are knowledgeable about potential problems
als easily can become preoccupied with the diagnosis
inherent in self-medication with a non-prescription
of the disease state. It is often assumed that the patient
drug, though they probably are less familiar with
will follow the instructions provided as the medica-
the use of herbal remedies and homeopathic medica-
tions are being provided to improve and maintain the
tions in the same context. Few pharmacists, however,
patient’s health. Studies continue to show that a large
are aware of potential problems that can arise with
percentage of patients do not take their medication in
social–recreational drug use. Regardless of the situa-
the manner intended.
tion, the problem of poisoning or overdose by a drug
Some patients make a conscious decision to devi-
should be delegated to poison-control centers and
ate from the prescribed regimen (i.e., intentional non-
hospital emergency rooms. The individual pharma-
adherence). However, many patients intend to take
cist, particularly one working in a community setting,
their medication according to instructions and may
may not feel capable of consulting or educating a
even be unaware that their use differs from what the
prescriber intended. The term patient non-adherence particular drug consumer in these problem areas.
implies that the patient is at fault for the inappropriate Most societies are in great need of learning more
use of medication. While this may often be the case, rational and appropriate uses of all types of drugs and
the physician and pharmacist may not have provided of gaining control over the products (drugs) of their
the patient with adequate instructions in a manner own technology. Humans have learned how to create
that the patient understands. The most basic ques- (extract and/or synthesize) drug products, yet humans
tions regarding drug usage must be addressed: Has have not learned fully how to use these products in
the patient been provided with adequate instructions? an optimal manner. The primary importance of drug
Does the patient understand how the medication is education is its benefit to the drug user (patient or
to be taken? Nothing should be taken for granted consumer); such education can improve the appropri-
regarding the patient’s understanding of how to use ateness of drug taking behaviors to achieve optimal
their medication. health and well-being. At the center of any educational
effort is the provision of drug information, the strat-
egy with which pharmacists and pharmacy students
Drug education are most familiar. In today’s highly complex, techno-
logical world, the availability of current and precise
Drug use occurs in virtually every society and culture. information allows one to understand, to make better
Whether the use of a particular drug is for a medical choices, and to prevent or solve problems.
or a nonmedical reason, problems resulting from use The individual best suited to assist people in pre-
often arise. Preventing drug use problems is a major venting drug use problems and in achieving optimal,
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Fundamentals of pharmacy practice | 359

desired experiences from their drug taking is the phar- the audience about their beliefs and perceptions. The
macist. The pharmacist is an accessible source of audience is shown a list of chemical substances and
high-quality information and educational programs, asked to indicate which ones are drugs and which ones
and should be concerned with a person’s drug tak- are not. Not only can this exercise, and its results, pro-
ing behavior. Whether it be the use of a prescription vide the educator with a better idea of the opinions
medicine or a herbal remedy to achieve or maintain and level of drug knowledge of an individual or group,
a state of health, the use of a drug for its socially but it also can be used as a focal point for discussion
oriented effects in a recreational setting, or the inges- at that time or during subsequent sessions. The belief
tion of a chemical substance to enhance a religious or that certain substances may be drugs is important in
aesthetic experience, the perspective presented herein understanding why and how people use such sub-
considers the pharmacist to be the leader in efforts to stances, and it should be a primary consideration in
prevent or limit drug use problems. the development of any drug education program.
Although information about, and inherent prob- The nature and extent of certain types of drug
lems resulting from, specific types of drug taking taking vary by drug, availability (or accessibility),
might vary from drug to drug or among reasons and the reason for use. In the medical realm, drug
for use, the fundamental approach to educating peo- taking may be initiated by the patient, as in self-
ple and fostering changes in drug use is the same. medication, or it may be directed by another person,
The word drug refers to any substance, other than usually a physician, who writes a prescription. Studies
food, which by its chemical or physical nature, alters of self-medication are limited. The research done in
structure or function in a human being, resulting this area indicates that self-diagnosis, rather than
in physiological, behavioral, or social changes. This making contact with the healthcare delivery system,
includes all medicinal agents (whether defined legally occurs in the majority of illness episodes and that
as prescription or non-prescription), herbal and home self-medication occurs from 60% to 90% of the time
remedies, alcohol and caffeine (and other substances in these situations.56 Studies of nonprescription-drug
that are often considered food by consumers, but are consumption indicate that, in general, approximately
used for their pharmacological activity), substances one-third of a population can be defined as current
used primarily in a nonmedical context, and even users of such substances and that from 25% to 60%
poisons. of a population are users of such drugs during any
These techniques and strategies, and their basic specific period.56 The prevalence of nonprescription
principles, are also applicable to educating patients drug use is even higher in the older adult population
about medicines or providing drug education pro- (ranging from 50% to 90%), in addition to their
grams in any context. It is important to realize that, extensive use of prescription drugs.56
conversely, ideas, strategies, and programs from the The annual Slone Survey (1999–2007) studies
field of patient drug education can be relevant to the medication use of all types at the population level.57
development of programs on the nonmedical use of The most recent results of this survey determined that
drugs, and some examples of this broader view of during 2006, 82% of adults had used at least one
drug education are provided. medication in the week prior to the study interview;
52% used at least one prescription medication; and
29% used five or more. The highest prevalence of
Drug use and drug education
medication use was among older women; 57% used
Human beings engage in a great variety of drug taking at least five medications, and 19% used at least ten.
behaviors, but one of the most important and rudi- Herbal products were used by 22% of the population,
mentary considerations involves the definition of what and 32% of prescription users also used a herbal
constitutes a drug and which situations characterize concurrently. Vitamin and mineral supplements were
drug taking. Individuals hold different beliefs and per- used by 41% of the population.57
ceptions about which chemical substances they regard When a drug is prescribed for a patient, health pro-
as being drugs. A useful and interesting exercise in a fessionals expect that the drug will be taken precisely
drug education program involves asking or surveying as directed. Adherence with medication regimens is
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360 | An Introduction to Pharmacy

another type of drug taking considered of major use of prescription medications has increased over
importance in a successful treatment plan. There have 500% in the past decade. This category has become
been many studies in this area; their results have the most significant problem area in nonmedical drug
shown that anywhere from 5% to 90% of patients use. The misuse of drugs, including the development
may be non-adherent in some manner.58 Although of an addiction, also decreased slightly in the past
there is a wide variation in non-adherence, caused couple of years.59 Among 12 to 17 year olds, 7.3%
by various factors as well as the research design misuse or are dependent on any drug (including alco-
of particular studies, the rate of non-adherence, in hol); among 18 to 25 year olds, it is 19.8%; and for
general, probably ranges from 33% to 50% in any people 26 years of age and older, it is 7%. Alcohol
given population.58 This situation represents a dif- is the biggest problem, by far, followed by marijuana
ferent behavior; many patients are not taking drugs and then by the nonmedical use of a prescription
when they should be. psychotherapeutic agent (primarily pain relievers).59
Drug taking also occurs in a nonmedical con- Drugs are also the cause of almost one-half of all poi-
text. Although cigarette smoking has declined steadily soning episodes, a type of drug-taking behavior that
among adults, tobacco use has increased in young is usually unintentional, except in cases of suicide.
people during the past few years.59 The prevalence of Drugs clearly are used appropriately in certain
alcohol use has remained stable for many years, but situations for beneficial reasons, are not used in some
there is an increase in binge drinking among young instances when they should be, and are used inappro-
adults, especially college students.59 Nationwide sur- priately on many occasions. In all three circumstances,
veys of drug use, conducted by the National Institute though most often in the last two examples, problems
on Drug Abuse in 2010, found that 11% of youths can result from drug use. The prevention or recog-
(less than 18 years), 41% of young adults (18 to 25 nition and management of problems resulting from
years), and 27% of adults (26 years or older) were drug use are the main reasons for developing and
current users of tobacco, whereas 14% of youths, providing drug education programs.
65% of young adults, and about 60% of adults were Two additional aspects of drug use important in
current users of alcohol.59 The survey was sponsored assisting drug users are their type of drug use behavior
by the Substance Abuse and Mental Health Services and their reasons or motivations for use. The focus
Administration (SAMHSA). of many drug education programs is on the drug
The annual National Survey also found that mar- itself and not the behavior (drug use). This has led
ijuana use is on the rise, while methamphetamine use to programs that focus on illegal drugs, but not legal
is on the decline. The survey found the most popular drugs; on ‘‘hard’’ drugs, but not ‘‘soft’’ drugs; and on
drug is marijuana, with 17.4 million regular users. In the pharmacology of the drug, but not on how that
2007, 14.4 million Americans said they used mari- drug is used. Instead of focusing on these ill-defined or
juana. An estimated 6.9% of those surveyed in 2010 irrelevant terms, the focus of drug education should
said they use marijuana regularly, compared with be on behavior, how and why the drug is being used.
5.8% in 2007. Among 12 to 17 year olds, 7.4% said A typology of drug taking behaviors was developed
they had used marijuana in the previous month in by the National Commission of Marijuana and Drug
2010, about the same percentage as 2009. Among 18 Abuse in 1973,60 and it can be useful in orienting
to 25 year olds, 18.5% said they had used marijuana both the educator’s and audience’s focus on drug use
in 2010, up from 16.5% in 2008. behavior, rather than on the drug itself (Table 10.2).
The nonmedical use of most other types of psy- Reasons or motivations for using drugs are the key
choactive drugs has declined during the past decade, to understanding why individuals use drugs. These
but there have been increases in the use of some reasons also should be addressed in developing and
substances over the past couple of years.59 The non- offering drug education programs (Table 10.3).
medical use of Ecstasy and some psychedelic drugs Drug education in a medical context has occurred
(e.g., LSD) have increased in the past two years. for some time. Patient counseling always has been
The nonmedical use of prescription psychotherapeutic a part of the health professional’s role, though the
drugs also has increased in the past year. Nonmedical assumption of this role has varied from time to
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Fundamentals of pharmacy practice | 361

Table 10.2 Typology of drug taking behaviors

Intensity – how much (single dose)

Frequency – how often (dosing schedule)

Duration – how long (length of use)

Experimental

Short-term, non-patterned trial

Variable intensity but minimal frequency

Reason: curiosity about effects

May be a shared social activity or individual

Low risk to individual and society

Limited long-term problems

Social–Recreational

Patterned use

Variable intensity, frequency, and duration

Social setting of use

Reason: for effects or group acceptance

Voluntary act

May not escalate, but can lead to habit formation

Low to high individual risk (differs by drug and dose)

Low to moderate societal risk

Circumstantial–Situational

Patterned use

Variable intensity and frequency, limited duration

Reason: task-specific and usually self-limiting achievement of effect to cope with symptom, condition, situation, or need

Personal (individual) use (setting)

Low to moderate risk to individual (dose-dependent)

(continued overleaf)
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362 | An Introduction to Pharmacy

Table 10.2 (continued)

Low to moderate societal risk

Can lead to escalation in drug taking behaviors

(Self-medication hypothesis)

Intensified

Long-term patterned use (duration)

At least daily use with moderate to high intensity

Reason: achievement of relief from symptoms, situation, personal problems, possibly to prevent withdrawal

All settings of use

Drug Is a part of everyday life

Moderate to high risk for individual (dependence)

Moderate to high risk for society

Compulsive

Long-term patterned use (duration)

High intensity and frequency

Reason: dependence and loss-of-functioning, lifestyle drug and its use become central focus of life

High individual and societal risk

(Natl. Comm. on Marijuana and Drug Abuse, Drug Use in America: Problem in Perspective. Washington, DC: USGPO, 1973.)

time, especially in pharmacy. The principal strate- Early efforts in education about non-medical drug
gies have been to provide either drug information or use consisted of negative portrayals of drugs and
drug education to patients through verbal interaction. classroom moralizing about drug use and through the
Structured educational programs have been developed mass media, with little objective information being
throughout the twentieth century, but it was only after presented. Such an approach unfortunately still can
World War II that concerted efforts to develop and
be found in many contemporary drug education pro-
implement health education programs began to occur
grams. Several studies in the 1970s found that drug
in public health. In the 1960s and 1970s, several atti-
information programs, consisting simply of lecturing
tudinal and behavioral approaches were studied to
to young people, aroused their curiosity about drugs
expand the traditional information-based approach
and improve on the effectiveness of information only and increased the likelihood of experimentation with
programs. At the beginning of the twenty-first cen- drugs.61,62
tury, the behavioral approach has become popular in A few researchers and educators more recently
health education programs, and the use of the mass have suggested a rather different drug education and
media has increased dramatically. drug prevention approach in which drug taking is
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Fundamentals of pharmacy practice | 363

Table 10.3 Reasons/motivations for drug use

For drug’s effects (therapeutic or otherwise)

Accessibility and availability of drugs

Peer pressure/modeling/social acceptance

Genetic predisposition

Suggestibility

Curiosity

Information, instructions, and accounts of drug effects and experiences (including other users, mass media and advertising)

Meanings of drug effects

Inherent behavior in humans

Rituals of preparation, administration, use

Religious reasons

Social and communication networks

Group/social interaction dynamics

Symptom sensitivity

Coping response

Physical and social setting

Social–cultural background of user

Political and social control

Escape

‘‘I don’t know’’& ‘‘As an excuse’’ (for other behavior)

considered a natural behavior.63 In this context edu- of peers in educational programs also increased in the
cational programs focus on the need to alter one’s 1990s. Much of the effort started in the field of alco-
state of consciousness in an acceptable way and to hol education as attempts were made to move away
use drugs in a responsible manner consistent with from authoritarian, moralistic programs with absti-
one’s lifestyle. The drug taker is alerted additionally nence as a goal to peer-facilitated strategies based on
to the importance of values and the influence of soci- the concept of self-discovery and the fact that alco-
etal attitudes on drug taking. These two notions are hol use is socially approved and engendered in most
extremely important in presenting programs or for societies, even if it is an illegal activity for certain
counseling patients with regard to drug use. The use segments (e.g., by age) of the population.
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364 | An Introduction to Pharmacy

Professional communications from a nurse, a drug dosing question from a physician,

or a request about the adverse effects of a medica-
Introduction tion from a patient; all of these interactions require
excellent verbal communication skills. The most com-
Communication is a vital skill, necessary for suc-
mon verbal communications that pharmacists engage
cess in personal and professional settings. Pharmacists
in involve responding to drug therapy questions and
often serve as the guardians of appropriate drug ther-
receiving verbal drug orders.
apy. Therefore, communicating effectively is key to
reinforcing the value of the pharmacist within the
healthcare system. Pharmacists communicate with a Receiving drug-related questions
wide variety of healthcare professionals on a daily A major challenge in responding to requests for
basis. The type of information that is communicated drug therapy recommendations is determining the
may be the same. However, the knowledge level and unique situation that prompted the request. Often, the
expectation of the audience dictate the delivery of the original request posed by a requestor does not rep-
message. Regardless of knowledge or expertise, phar- resent the actual information needed.64 Requestors
macists cannot actively participate in patient care of information are sometimes unclear when asking
unless they can communicate effectively. questions pertaining to specific-patient needs. This
Pharmacy career options have expanded into most likely occurs because they are not aware of
multiple, distinct settings, including institutions, the specific information that pharmacists need to
community, managed care, academia, regulatory, and provide a comprehensive response. Therefore, phar-
industry. In all of these settings, professional com- macists should recognize this potential challenge and
munication is critical. Whether verbally responding use appropriate listening and questioning skills to
to a physician’s question during patient care rounds, collect pertinent background information to deter-
providing an educational program to nursing staff, or mine the exact context of the question. Questions
publishing results of a research project in a biomed- that often appear simplistic in nature at first glance
ical journal, communication skills are paramount
may actually be more complex when all appropriate
to effective pharmacy practice. This section will
background information is considered. If pertinent
discuss appropriate professional communication
background is not determined and the pharmacist
skills related to communications with healthcare
does not have a clear understanding of why the ques-
professionals, highlighting verbal and written skills,
tion is being asked, patient care could be jeopardized.
formal presentations, formulary communications,
For example, if a physician asks a pharmacist a ques-
personnel communications, and communicating with
tion regarding the dose of a medication, inaccurate
administrators, and the media.
and potentially harmful information may be provided
if patient-specific factors such as age, weight, and
Communicating with healthcare renal or hepatic function, are not considered.64
professionals Consider the example of a middle-aged man who
Verbal communications approaches a community pharmacist and asks the
Regardless of the practice setting, verbal communica- question ‘‘Is Advil good for muscle pain?’’65 At
tion is the most common type of communication that first glance this appears to be a relatively simple
pharmacists utilize. It is common for a pharmacist to question. Advil contains ibuprofen, which is a com-
be approached by several different individuals (with mon over-the-counter (OTC) analgesic. Therefore, it
varying backgrounds), regarding a multitude of situ- would appear that a reasonable answer to the man’s
ations, in a single day. As practitioners, pharmacists request would be ‘‘yes.’’ However, what if the phar-
should be encouraged to remember that any type of macist further questions the man about his medical
question or interaction, regardless of how informal history to determine why he was asking this question?
it may seem, is an important method of professional After further questioning, the pharmacist realizes that
communication. Whether responding to a question the man had recently started lovastatin therapy. This
concerning compatibility of intravenous medications additional background information suggests that the
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Fundamentals of pharmacy practice | 365

patient may be experiencing symptoms of lovastatin- and in these situations pharmacists must be espe-
induced myopathy. Instead of answering the question cially skilled in gathering background information.
at face value, the pharmacist in this situation is able It is very important to ask for clarifications when
to identify a potential drug-related adverse event necessary to ensure a complete understanding of the
by collecting important background information to situation. Finally, an important last step to collecting
determine ‘‘why’’ the man was asking the question. appropriate background information is to repeat the
The previous example illustrates the importance question or request to verify the inquiry. This will
of questioning strategies to collect pertinent back- help clarify any discrepancies between the requestor
ground information and determine the true informa- and pharmacist. Pharmacists should remember that it
tion need. Pharmacists should apply the appropriate is their professional responsibility to collect pertinent
skills to ask logical background questions in a rea- background information to fully understand the true
sonable sequence to clarify each question. This is information request. Providing drug therapy recom-
especially important when confronted with an impa- mendations without a complete understanding of the
tient requestor who may not realize the value of pertinent background is simply negligent. Table 10.4
gathering background information. When receiving provides a list of important background questions
drug-related information requests from healthcare to consider when receiving a drug-related request.
professionals, it is particularly useful to ask the infor- These questions allow the pharmacist to formulate
mation requestor if his or her question is about a the most appropriate response. Care also should be
specific patient.64 This allows the pharmacist to ascer- taken to identify when a response is needed. Providing
tain key patient data immediately and usually prompts timely and accurate responses establishes the value of
the requestor to describe more information about the pharmacists as drug therapy experts.
patient. Another helpful questioning strategy is to
use open-ended questions.65 Open-ended questions Responding to drug therapy questions
cannot be answered by one-word, short answers,
After a complete and accurate response to the request
but require responses with detailed descriptions, and
is developed, communicating the information clearly
enhance information exchange about the context of
and concisely is critical. Utilization of appropriate
the question. In the previous example about Advil and
information resources, data analysis, and formulation
muscle aches, an appropriate open-ended question
of responses is beyond the scope of this section. How-
could be, ‘‘Please describe your muscle pain to me.’’
ever, the reader is referred to Drug Information: A
This allows the patient to provide more details about
the circumstances surrounding his question. There are
situations, however, when the pharmacist will need to
ask direct questions to obtain certain types of factual
Table 10.4 Questions to consider when
information like patient age, weight, or current medi-
collecting pertinent background information
cations. For pharmacists to gain a clear understanding
of the actual question, a mixture of different types of What is the requestor’s name, profession, and affiliation?
questioning strategies should be used. Does the question pertain to a specific patient?
In addition to asking appropriate questions, it Do I have a clear understanding of the question or problem?
Do I know if the correct question is being asked?
is important to have strong listening skills. Phar-
Do I know why the question is being asked?
macists should avoid all possible distractions when
Do I understand the requestor’s expectations?
gathering background information. If the interaction Do I know pertinent patient history and background
is in person, the pharmacist may use non-verbal cues information?
such as facial expressions, eye contact, and other Do I know what unique circumstances generated the question?
Do I have insight about how the information I provide will actually
forms of body language to interpret the requestor’s
be used?
response to his or her background questions. Racial
and cultural differences are also important issues to (Data from Calis KA, Sheehan AH. In: Malone PM, Kier KL, Stanovich JE
consider during in-person interactions. Communicat- eds. Drug Information: A Guide for Pharmacists, 4th edn. New York, NY:
ing over the telephone is inherently more difficult, The McGraw-Hill Companies, 2012.)
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366 | An Introduction to Pharmacy

Guide for Pharmacists for more information on this is not forgotten and that the information is communi-
topic.64 cated in a clear and concise manner. Once the response
In the clinical pharmacy practice setting, verbal has been communicated verbally, verification should
communications may be more common than written be made to make sure that the information provided
communications. Therefore, it is very important for to the requestor was sufficient to meet his or her
pharmacists to have the necessary skills to communi- needs. An offer to provide written documentation of
cate information verbally in an effective manner. Oral the response should also be made.66 Proper methods
responses are generally preferred because they are for documenting drug therapy recommendations will
more personal than written responses, and they allow be reviewed later in this section.
for prompt clarification of information that may be Displaying confidence is obviously very important
unclear. Verbal responses may also be favored in situ- during the delivery of the response. If the pharmacist
ations that are of high priority (emergency situations does not appear confident in his or her response, the
when a prompt response is needed) or when a sensi- requestor may certainly have reservations about the
tive issue is being discussed. It is important to note information provided. Additionally, the vocabulary
that when pharmacists effectively communicate drug and terminology that is used should be appropriate
information in a face-to-face manner, they promote for the given audience. For example, when commu-
nicating with a physician, professional terminology
the profession of pharmacy by being recognized as
should be used and all medical terms should be
valuable members of the healthcare team. However,
pronounced correctly. Finally, follow-up questions
when information is communicated orally, the risk for
should be expected and addressed in advance to save
misinterpretation exists.66 Factors that may poten-
valuable time.
tially increase the risk for misinterpretation during
Follow-up is extremely important to maintain-
oral communication include differences in vocabu-
ing professional practice. This allows pharmacists
lary, pronunciation, accent, and speaking pace.
to verify if their recommendations were taken and
When communicating important drug therapy
to investigate patient outcomes while demonstrating
information, the pharmacist should always make sure
dedication to patient care. Additionally, pharmacists
to identify him- or herself professionally. This pro-
can learn from their experiences and develop more
vides the requestor with confidence that a professional
confidence when they conduct regular follow-up to
with appropriate educational background and train-
drug therapy recommendations.64
ing is responding to their request. If responding to a Although verbal recommendations do not always
question that was posed during a previous interaction, include a formal written response, it is important to
it is recommended to review briefly what the initial document oral drug therapy recommendations for
drug therapy question was for the purpose of refresh- several reasons, including in the event that legal
ing the memory of the requestor. For questions that questions arise. Documentation also reinforces the
are specific to a certain patient, the patient should be usefulness of pharmacists to other healthcare pro-
identified to avoid any potential confusion.66 When fessionals and contributes to pharmacist workload
verbally communicating the specifics of the response, assessment. Proper methods for documenting drug
the pertinent facts should be stated, limitations to the therapy recommendations in patient medical charts
literature should be acknowledged, and a final con- are reviewed in the written communications section.
clusion and recommendation should be provided.64,66
Pharmacists should make sure to focus on the key Using the telephone for communications
points in a clear and concise manner and reinforce the Pharmacists are often asked to respond to questions
major point again at the end of the conversation. All and provide drug therapy recommendations using the
relevant information should be presented. However, telephone. Therefore, all pharmacists should be famil-
describing large amounts of minor details should be iar with professional phone etiquette. Face-to-face
avoided. It may be helpful to write a brief outline using interactions are preferred, as they are more personal;
bullet points with the major issues to be communi- however, in many situations telephone interactions
cated. This helps to ensure that pertinent information are necessary. Regardless of the professional setting,
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Fundamentals of pharmacy practice | 367

the telephone should always be answered by provid- the complete order, read it back to the prescriber,
ing a greeting that identifies the pharmacist’s name and receive verification from the prescriber that the
and affiliation (e.g., ‘‘Pharmacy Department, this is information is correct. It should also be documented
John, a pharmacist, speaking’’). It is also helpful for that the verbal order was repeated back to the pre-
pharmacists to have a pen and paper readily avail- scriber. For words that the pharmacist may not be
able before answering the telephone to document familiar with, repeating the word back to the pre-
any notes that are necessary during the conversation. scriber by spelling the word, using phrases such as
Many pharmacists find it helpful to write down the ‘‘S as in Sam’’ and ‘‘T as in Thomas’’ may be par-
exact date and time that a call is received. The hold ticularly helpful. Verbal drug orders are not the ideal
option should always be used when asking someone means of communicating drug therapy orders, but
to wait on the telephone line. This maintains a pro- this method is sometimes employed for urgent insti-
fessional setting and avoids the potential for the caller tutional orders or as a means of convenience in
to overhear background conversations while waiting community settings. Verbal drug orders emphasize
for the pharmacist to return to the telephone line. the importance of excellent communication skills to
Repeating information to clarify any discrepancies is allow accurate and rapid decision-making processes.
also especially important to avoid any confusion.
Written communications
Receiving verbal drug orders
The most critical written communications between
Pharmacists may be asked to receive medication
pharmacists and other healthcare professionals are
orders over the telephone. A licensed prescriber, or an
undoubtedly the prescription, in community practice,
agent of the prescriber, can communicate a patient-
and medication order, in institutional practice. Other
specific order directly to the pharmacist. This process
important types of written communications, including
challenges the pharmacist to dictate the information
documentation of patient care, electronic communi-
necessary to accurately fill the prescriber’s order, as
cations, professional correspondence, manuscripts for
well as quickly ascertain if the prescription will be
publication, and poster presentations are discussed in
an appropriate medication for the patient. Many
this section.
institutions have limits on the types of orders (e.g.,
chemotherapy) that may be received verbally in order
to improve medication safety. Documentation of patient care in the permanent
medical record
The pharmacist should ask the prescribing party
to identify him or herself and to provide the appro- The Omnibus Budget Reconciliation Act of 1990
priate contact information to verify authenticity and (OBRA-90) set forth the requirements for patients’
to ensure a method of contact in case follow-up ques- education and maintenance of records; under this
tions are necessary. Asking questions and directing the legislation, pharmacies must maintain records of
conversation can assist the pharmacist in controlling patients’ name, age, gender, contact information,
the rate and extent of information exchange. Patient- significant medical, known medication allergies and
specific information must be obtained along with intolerances, and all concurrent medications and
a complete and accurate description of the medica- medical devices. Records must also reflect the thought
tion regimen. The patient’s medication order should process of the pharmacist as it relates to patient
always be verbally repeated back to the prescriber care. For practitioners who previously did not for-
to verify accuracy and reduce the risk for a med- mally document their therapeutic recommendations,
ication error. Repeating information to clarify any OBRA-90 formalized the requirement for completion
discrepancies is especially important when taking ver- of that task. The OBRA-90 legislation requires that
bal medication orders from a prescriber over the pharmacists maintain a database of documentation
telephone. All verbal orders and telephone prescrip- regarding input into patient care which may be
tions should be repeated back to the prescriber to located such that review by an impartial, external
reduce the likelihood of medication errors. Ideally, reviewer will clearly identify the intent of the
pharmacists receiving verbal orders should document pharmacist’s actions in terms of patient care.
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368 | An Introduction to Pharmacy

The American Society of Health-System Phar- formalized documentation program because of the
macists (ASHP) endorses guidelines on documenting belief that most patients require some type of edu-
pharmaceutical care in patient medical records.67 In cational support to optimize therapy and because
developing these guidelines, it was emphasized that pharmacists often provide recommendations without
recommendations made by pharmacists on behalf of identifying the desired specific endpoint in terms of
their patients should be documented in a permanent outcomes. Addition of the latter component serves as
manner, such that information is accessible to all a mechanism for follow-up to determine whether or
healthcare professionals caring for the patient. not therapeutic goals have been met. It also provides
These recommendations may include the patient’s a basis for understanding when care is passed from
medication history, allergies, consultations to other one pharmacist to another. Figure 10.2 contains an
healthcare professionals regarding drug therapy example SOAPEO note.
management, verbal orders, order clarification, An alternative method to SOAP charting is
drug-related problems, drug-therapy monitoring Focused Documentation. Focused Documentation
findings, and patient education. It is stressed that is a simplified method of charting, which reduces
documentation by pharmacists should incorporate repetition, using components reflective of Focus,
a standard format and be written in a legible, clear, Data, and Action. In the authors’ practice, Focused
and complete manner. Documentation is the preferred method for charting
The Weed method of documentation has been except in situations where the physician requests
utilized and accepted by healthcare professionals or the pharmacist initiates a comprehensive review
including pharmacists. The Weed method consists of a patient’s medication regimen. This may be the
of the development of a patient problem list and case for documenting medication reconciliation, if
SOAP note, which organizes written patient care polypharmacy is an issue, or if a patient demonstrates
communications into subsections related to Subjec- symptoms consistent with sub- or supra-therapeutic
tive, Objective, Assessment, and Plan components response(s) to medications and/or an adverse drug
for the identified problem(s).68,69 In addition to the event. An example of Focused Documentation for the
components, each chart note should be appropriately above scenario is included in Fig. 10.3.
titled (e.g., Pharmacy Note), dated, timed, and signed Whether documented in SOAPEO, or another
with the appropriate professional designation of the format, maintaining a record of pharmacist recom-
pharmacist (e.g., PharmD) along with the method for mendations and interventions in the patient medical
follow-up contact from the recipient (e.g., pager or record is essential to the practice and advancement
telephone number). The components of each of the of pharmacy as a profession. One such advancement
sections of a SOAP note are included in Table 10.5. of the profession is Medication Therapy Manage-
The authors have expanded this methodology to ment (MTM).70 The rules for MTM outline specific
include two additional components, Education and requirements for documentation of care. MTM is a
Outcomes. These were incorporated into the authors’ structured form of pharmacist-managed care entailing

Table 10.5 Components of the SOAP note68,69

S – Subjective: Patient’s complaints or symptoms; data provided by family members should be characterized as such.
O – Objective: Patient data including age, sex, race, height, weight, vital signs, results of laboratory and diagnostic tests, and
physical exam findings.
A – Assessment: The pharmacist’s evaluation of therapeutic alternatives or resolution of drug-therapy problems which may
define the necessity for all drugs in the patient’s regimen, evaluate the potential for drug interactions, document the
appropriateness of the drug regimen and/or evaluate the patient’s previous response to pharmacotherapy.
P – Plan: The plan should include specific drug therapy recommendations (drug, dose, route, frequency, duration),
monitoring parameters and the necessity for further studies or tests.
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Fundamentals of pharmacy practice | 369

Scenario: AW is a 38 YOWM with duodenal ulcer diagnosed this admission

following extensive work-up. PMH is significant for epilepsy, controlled since
childhood with phenytoin. AW weighs 68 kg and is 5'10" tall. He is employed
as a financial analyst in a high-stress, demanding firm. AW reports NKDA.
The physician has ordered ranitidine 150 mg PO BID. Ranitidine is a
nonformulary drug.

Pharmacist Documentation:

3/9/03 Pharmacy Note

1100
S: AW is a 38YOWM with duodenal ulcer. Dr Jones has ordered ranitidine,
a nonformulary drug.
O: AW receives daily maintenance therapy with phenytoin, to control a
seizure disorder.
A: Ranitidine is a nonformulary item. In light of concurrent phenytoin
therapy, cimetidine is not considered a viable alternative. Suggest
initiating therapy with famotidine.
P: Begin famotidine 20mg PO BID
E: Educate patient that ranitidine is not available and famotidine has been
prescribed as an alternative. Therapy should be administered BID, with a
12-hour dosing interval being most desirable.
O: Control and resolution of patient’s duodenal ulcer while avoiding
drug–drug interactions.

Figure 10.2 Example of a SOAPEO note.

Table 10.6 Components of medication therapy

3/9/03 Pharmacy Note management (MTM) documentation
1100

Focus: Ranitidine, a nonformulary drug, has been prescribed for Prescription medications (current and discontinued)
AW. Nonprescription medications (current and discontinued)
Dietary supplements (current and discontinued)
Data: AW receives daily maintenance therapy with phenytoin, to
control a seizure disorder. Therefore, cimetidine is not a viable Medication-related action plan (MAP):
alternative. Patient name
Action: Begin famotidine 20mg BID. Educate patient regarding Primary care physician (including name and phone number)
alternative therapy and monitor response. Pharmacy (including pharmacist name and phone number)
Date prepared
Action steps for patient
Figure 10.3 Example of focused documentation. Notes for patient
Follow-up information
Interventions (possibly including SOAP or SOAPEO note with
or without a cover letter)
at least an annual complete medication review fol- Education materials
lowed by creation of a medication-related action plan Correspondence with other healthcare professionals
(MAP), a patient-specific plan designed to provide the Billing information

patient with a list of actions to complete in order

to optimize their self-management. The MAP can
also be used by patients to assess their progress over elements for MTM and the components of a MAP.
time. The MAP, in addition to several other pieces of The primary purpose of the extensive documentation
information, must be documented (ideally electron- required for MAP is to facilitate pharmacist com-
ically) through the maintenance of a chronological, munication with other healthcare professionals while
patient-specific record that allows for longitudinal resolving drug-related problems; the documentation is
patient evaluation and billing submission. Table 10.6 also designed to improve outcomes, demonstrate the
provides a detailed list of suggested documentation value of MTM services, and ensure legal compliance.
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370 | An Introduction to Pharmacy

Electronic communication information not intended to be viewed by other pro-

Electronic mail fessionals or patients is not available on the Internet.
A general guideline to follow is not to post anything
While the introduction of e-mail has greatly facilitated
online that would not be appropriate to send in a
contact, this type of communication must be appropri-
professional e-mail. Pharmacists should be careful to
ately utilized in the professional environment. Within
present themselves through social networking sites in
this environment, e-mail should be for professional
the same manner that they represent themselves in the
use only. Attention should be given to one’s cho-
professional setting.
sen e-mail sign-on. If a pharmacist’s given name is
not utilized for e-mail communication, care should
Professional correspondence
be taken to choose a name that reflects positively
Memoranda
on the character of the pharmacist as a professional.
Professional e-communication should be utilized in Most pharmacists will find a need to communi-
situations where the messenger has concluded that a cate with other healthcare providers via memos,
face-to-face meeting or telephone (i.e., direct) com- whether or not they have administrative positions.
munication would not communicate the message Written memos are frequently used to communicate
more effectively. When communicating by e-mail, drug information, policy changes, or in the evalua-
it is important to remember that any message may tion/discipline of employees. Memos should be formal
be either saved or forwarded for viewing by others. in format and should be addressed to a specific indi-
Accordingly, close attention should be paid to content vidual or group of individuals, whenever possible. The
and format. For example, use of capital letters could format for a professional memorandum is included in
be interpreted as ‘‘yelling.’’ The subject line should Fig. 10.4.
clarify the intent of the message. The content of mes-
sages should be concise but thorough enough to be Cover letters
understood. Given that messages may be printed or Cover letters should accompany applications for
shared, one should refrain from including confidential employment. As such they offer a written ‘‘first
or controversial information. E-mail users are advised impression’’ to the recipient. Much like e-mail and
to compose professional communications with a word memos, cover letters should be addressed to a specific
processing program initially, to facilitate spelling individual whenever possible. The cover letter should
and grammar checks. All messages should end with be written in standard business format, as referenced
a professional closing and contain the individual’s in any primary or secondary school English text.
name, title, affiliation, and contact information. When The first paragraph of the cover letter should include
e-communication is utilized, it is most appropriate to the purpose for writing the letter. For example, the
respond within the same business day, but a goal letter may be written to introduce a pharmacist as a
would be to respond in no longer than 24 hours. It candidate for employment. The content would then
is recognized that this may be a challenge, depending reflect the pharmacist’s background and training and
on the setting. his or her current position. The middle paragraph
should contain a brief summary of the key strengths,
Social media
Social media sites such as Facebook and Twitter have
recently become a popular source of communication.
Although access to social networking sites may pro- To: Jane A. Doe, PharmD, RPh
Director of Pharmacy
vide a valuable venue for professional interaction
and information dissemination, they could jeopar- From: Samuel T. Smith, PharmD, RPh
Pharmacy Manager
dize one’s professional reputation. Pharmacists should
Re: Staffing Patterns for Ambulatory Pharmacy
always be vigilant to present themselves as trusted
Date: September 4, 2011
professionals. Therefore, all photos that are view-
able to the public should be appropriate in nature.
Privacy settings should be carefully chosen so that Figure 10.4 Example of memo header.
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Fundamentals of pharmacy practice | 371

which make the pharmacist a strong and/or unique

candidate for a particular employment opportunity. Name (centered top)

The last paragraph should close with identification Business Address Permanent Address (if desired)
of the mechanism for follow-up. For example, Employment objective
the author may wish to indicate that if the letter Education (may include skills)
recipient does not provide follow-up contact within
Licensure/certification
a two-week timeframe, the author will initiate such
Professional experience (perhaps selected, most relevant)
contact. The letter should also specify the preferred
Other work experience (as applicable)
mechanism for contact (e.g., e-mail, telephone with
specific number). Activities, honors, and/or awards (most relevant)

Resumé Figure 10.5 Content of the resumé.

The resumé should serve as a one-page summary or
snapshot of an individual’s education and work expe-
rience. Frequently the resumé contains a professional Name (centered top)
objective as it is often used to facilitate an employ- Business Addres Permanent Address (if desired)
ment opportunity. Resumés are designed to highlight Education (post high-school, chronological order)
professional accomplishments and entice the recipient
Licensure/Certification
to make an offer for interview. Within today’s profes-
Professional Experience (list most current first)
sional environment, resumés are frequently requested
Other Work Experience (as applicable)
at the initial point of contact, particularly in com-
munity pharmacy and the pharmaceutical industry. Organizational and Committee Appointments (where
applicable)
Following the screening of applicants, those invited
Affiliations (e.g., professional organizations, includes offices
for interviews in these and other settings (academic, held)
hospital pharmacy) are often asked to submit a cur- Awards/Honors
riculum vitae. Typical resumé contents are described
Service (e.g., professional, community)
in Fig. 10.5.
Grants (where applicable)

Curriculum vitae Presentations

The curriculum vitae is intended to be a comprehen- Publications (by category, e.g., refereed articles, book chapters)

sive chronology of the education, training, and work

experience which also reflects professional presenta- Figure 10.6 Content of the curriculum vitae.
tions and publications. The healthcare professional
should maintain a curriculum vitae that is inclusive of for this reason, preparing a manuscript for publica-
all types of professional activities. Potential categories tion can sometimes appear to be an overwhelming
for a curriculum vitae are included in Fig. 10.6. Some task. However, publishing is a very fulfilling accom-
accomplished professionals maintain an abbreviated plishment that can lead to professional advancement
curriculum vitae that represents the most recent 5 to and recognition.
10 years of accomplishments.
Preparation
Manuscripts for publication Preparation is the first step to any project. Because
Pharmacists may be involved in writing a wide variety writing an article for publication is typically a long
of manuscripts for publication. These include book process, the first hurdle to overcome is the anxi-
chapters, editorials, case reports, review articles, and ety associated with the project. Because anxiety can
clinical research studies. Publishing these types of sometimes lead to procrastination, it is very important
manuscripts is essential to enhance communication to overcome any apprehensions as soon as possible.
among peers and advance/promote the profession. A good way to deal with this is to begin the ini-
Generally, pharmacists are not trained to be writers; tial preparation process by conducting background
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372 | An Introduction to Pharmacy

research, gathering all necessary resources, and devel- Writing the first draft
oping an outline for the manuscript.71 It is also helpful Once the outline has been prepared and all informa-
to develop a working plan for completion of the tion resources have been gathered, the next step is
project.72,73 The writing project should be divided to begin writing. Professional writing is a skill that
into small sections with attainable deadlines. Time requires continued practice. Because most pharma-
for working on each section should be planned, simi- cists are not trained writers, this step is often quite
larly to other scheduled daily activities. This strategy difficult. One potential difficulty is finding the time
can help avoid postponing the writing process due to necessary to devote to writing. As stated above, a
an already busy schedule. helpful strategy to manage this problem is to reserve
After all necessary resources have been collected short blocks of time each day that are devoted to writ-
the items should be organized in a systematic fashion. ing the manuscript. This approach may be easier for
This will enable the writer to locate references quickly a busy practitioner than to reserve an entire day for
when they are needed during the writing process. An completing the project. Progress can be made using
outline should also be developed to define the project short blocks of time, even if the daily goal is to write
clearly. When developing an outline, it is best to con- only one or two paragraphs. During this time, it is
sider the primary objective of the manuscript and the helpful to use a technique known as freewriting.72,73
target audience. Knowing this information will help Freewriting involves taking about 20 to 30 minutes
determine which topics or sections should be included to write your ideas continuously without stopping
in the manuscript. An effective outline should help to check grammar, spelling, or references.72 Once a
make the writing process easier because it determines few paragraphs have been written in this manner,
focus areas. With computer word-processing pack- then content revisions and clarifications can made.
ages, the outline can be used as a working template In general, is it best to complete a first draft in
for the final manuscript. If the manuscript is intended its entirety before beginning the editing process.71
for a specific medical journal or book, the publishers However, it is sometimes difficult to avoid becoming
will customarily have requirements for the various engaged in the minor details of correcting grammati-
sections that must be included. This will allow orga- cal and typographical errors in paragraphs that have
nization and provide a framework to follow during already been written. This habit can lead to frus-
the writing process. Many biomedical journals follow tration and slow down the entire writing process.
The Uniform Requirements for Manuscripts Submit- Strategies such as disabling the spelling and gram-
ted to Biomedical Journals.74 This is a document mar check programs of the word-processing program
prepared by a group of editors to provide guide- and turning the computer screen off have been recom-
lines for manuscripts that are submitted to medical mended to avoid the temptation of making corrections
journals for publication. Table 10.7 lists the general instead of writing new paragraphs.72,73 Professional
sections that should be included in the publication of writing also follows a certain set of rules that are
a research project.72 different from other types of writing. General rules

Table 10.7 Basic sections of a research project publication72,74

Introduction: Background information to support ‘‘why’’ the project was conducted (written in present tense)

Methods: Detailed description of all study procedures (written in past tense)

Results: Detailed description of study findings (written in past tense)

Discussion: Description of the clinical implications and limitations of the study findings (written in present tense)

Conclusions: A statement of the final conclusions (written in present tense)

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Fundamentals of pharmacy practice | 373

work, quotation marks should be used around the

Table 10.8 General rules for professional
material and the appropriate authors should be cited.
writing
A good general rule to follow is to use quotation
Use proper grammar and spelling marks around three or more words in a row that are
Keep sentences simple and direct taken directly from a source without modification. If
Avoid writing in the first person (e.g., I, we, us) paraphrasing another author, the original publication
Avoid using the passive voice
should always be cited. Specific instructions for cit-
Avoid using contractions
ing various types of publications can be found in the
Avoid using abbreviations or acronyms
Proofread Uniform Requirements for Manuscripts Submitted to
Biomedical Journals.74
(Data from Malone P. In: Malone PM, Kier KL, Stanovich JE, eds.
Drug Information: A Guide for Pharmacists, 4th edn. New York, NY: Formal presentations
The McGraw Hill Companies, 2012.)
Verbal presentations
Pharmacists are routinely involved in the delivery
for professional writing are listed in Table 10.8.71 of formal presentations, including continuing educa-
An excellent reference for general stylistic considera- tion and in-service programs. The pharmacist should
tions including the rules of proper punctuation and evaluate the specific needs of the audience and tar-
grammar, and avoiding commonly misused words is get the level of the educational program accordingly.
The Elements of Style, written by William Strunk and Pharmacists who know their audience can then pre-
EB White.75 pare specific objectives that include content consistent
with the expectations of the recipients. Presentations
Editing should be organized based upon the objectives and
After the first draft has been completed, editing is the should not include excessive information that detracts
final critical step. When a manuscript is submitted from the key points. Because pharmacists frequently
for publication, or any type of written communica- present to other healthcare professionals, provision
tion for that matter, it represents an image of the of examples, stories, or analogies that include appli-
writer. If a written manuscript is full of typographi- cation of the information shared may facilitate the
cal and grammatical errors, this reflects poorly upon learning process for the participants. Although there
on the author. Because is it sometimes difficult for is not one approved method for formal presentations,
the author to identify noticeable errors, it is espe- it is clear that ‘‘practice makes perfect.’’ The presen-
cially useful to ask colleagues to help proofread one’s ter should be certain to prepare his/her talk well in
manuscript. Other strategies that have been suggested advance of the presentation date, to allow ample time
to aid the editing process include reading sentences for practice.
out loud slowly, reading sentences in reverse chrono- In most settings, it is recommended that the pre-
logical order, and enlarging the font on the computer senter use some type of visual aid, which would
screen.72 It is also useful for the author to put the include slides, overheads or transparencies, or flip
manuscript away from view for several days, and charts. Given current technology, the development
then come back to it at a later date. of a Microsoft PowerPoint presentation is common,
as slides can quickly be converted to handouts for
Referencing program participants. Whether using slides or trans-
It is very important for authors to be familiar with parencies, several formatting recommendations exist
proper referencing techniques to give credit when that have been summarized in Table 10.9.76
appropriate and avoid committing plagiarism. Pla- When properly developed, visual aids should serve
giarism is defined as using the ideas or words of as a prompt for the speaker, which should minimize
another in a way that represents them as one’s own. the need for note cards or a complete presentation
Authors should always be vigilant of the potential for text. Presenters should be cautioned to speak from
plagiarism when writing manuscripts for publication. their slides or visual aids, but not to read. Other
If copying words verbatim from another authors’ keys to effective presentation include the use of voice
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374 | An Introduction to Pharmacy

audience who may know the answer. If questions

Table 10.9 Characteristics of the ideal
do not relate to the presentation topic, the speaker
slide/transparency text
should respond to the best of his or her ability and
Horizontal with 2:3 ratio redirect the conversation to a point that does relate.
Content limited to main point The authors recommend the text Writing, Speaking,
Black or dark blue background and Communication Skills for Health Professionals
Title all in capitals
to any pharmacist who wishes to strengthen his or
Outline format in lower case
Maximum of seven lines of text
her presentation skills.76
No more than seven words per line
Readable font such as Helvetica or Arial Poster presentations
Limited use of capitals and italics
Graphic slide will have no more than 5–7 bars, columns, or Poster presentations are a common method for shar-
pieces of a pie chart; clear labels or legends in corresponding ing information at national meetings. At most national
colors pharmacy meetings, there is an opportunity to present
research ideas in a poster format. The basic compo-
(Data from Casella PJ. In: Writing, Speaking, and Communication Skills
nents of a scientific poster are similar to the basic
for Health Professionals. The Health Care Communication Group.
London: Yale University Press, 2001.) sections of a written research project. These sections
include background, methods, results, limitations,
and conclusions (see Table 10.7). Posters differ from
inflection to maintain listener interest, incorporat- written manuscripts in the amount of detail presented.
ing gestures which accentuate voice inflection, and With the exception of the background and conclusion
allowing a pause when emphasizing key points. It sections, posters should not contain full sentences.73
is important to dress consistently with the audi-
Information should be presented in at least 18-point
ence. Thus, a formal presentation requires formal
font and bullet points and boxes should be used
(e.g., business suit) attire. Nonverbal communication
to emphasize the main points. This makes it eas-
enhances the relationship with the audience. If pos-
ier for passersby to read and interpret. There are
sible, the speaker should try to move away from the
two different methods to make a poster. The first is
lectern or walk about the front of the room, to make
to use separate slides (or panels) for each section.
a connection with a greater portion of the audience.
This can be done using Microsoft PowerPoint slides.
Eye contact brings the audience into the presentation.
Alternatively, some word-processing programs allow
If uncomfortable looking directly at individuals, the
presenters to make single page posters. These posters
speaker should try looking at the top of heads. In a
still contain different slides for each section, but can
large room, participants will still feel the presenter is
be printed as a one-page sheet. This can make the
making contact with them. In a smaller setting, speak-
poster easier to transport and arrange at the meeting.
ers can try to identify three or four ‘‘friendly’’ faces
The general rules of professional writing discussed
throughout the audience and use them as a gauge to
above and the importance of proofreading also apply
the presentation as well as a link to the audience.76
to the preparation of poster presentations. A sug-
Most presentations will include time for questions
gested format for a poster presentation is shown in
and answers. If time allows, in some settings, it is more
Fig. 10.7.
effective to allow the audience to interrupt the formal
presentation and ask questions instead of waiting
until the end. This can enhance the presentation, but Formulary communications
the speaker must be careful not to allow excessive Written communication skills are extremely impor-
time for discussion. Effective presenters should repeat tant for pharmacists who participate in formulary
questions to ensure that everyone in the audience has management. A formulary can be defined as a con-
heard and understands the inquiry. As in all aspects tinually revised compilation of medications that are
of healthcare, if one does not know the response to readily available for use within an institution and
a question, it is best to admit this freely and offer the policies addressing their use; a formulary typi-
to follow-up or defer to an expert colleague in the cally is determined by the institution’s medical staff
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Fundamentals of pharmacy practice | 375

TITLE OF PROJECT
Authors’ names
Name of Institution

Background Results Discussion

Unsure
35
(12%) Yes Yes
80 (28%) 75 (60%)

No
No No
175 (60%)
200 (71%) 260 (90%)

Objective 40
35 Students
30
Faculty
25
Percent

Study Methods 20 Conclusions

15
10
5
0
Very minor Minor Moderate Severe Very severe

References

Figure 10.7 Suggested format for poster presentation.

and should be tailored for the needs of that spe- Drug evaluation monographs
cific population.72,73 Medication formularies serve A drug evaluation monograph is an objective, written
the purpose of decreasing inventory and allow prac- appraisal of a medication (or class of medications
titioners to gain familiarity with certain drug prod- in the case of drug class reviews) under consid-
ucts. Formularies also promote a decreased risk for eration for formulary addition that allows for an
medication errors and help the institution provide organized assessment.78 Drug evaluation monographs
cost-effective therapy. Ideally, a formulary should are almost always prepared by pharmacists. In 2009,
contain the most cost-effective medications to treat the Food and Drug Administration (FDA) standard-
all disease states likely to be encountered within an ized the expected components of the FDA-approved
institution, given its expected patient population. A labeling (i.e., package insert) to the list of headings
comprehensive review of the issues related to formu- presented in Table 10.10.79 Drug evaluation mono-
lary management is beyond the scope of this section; graphs should use similar sections as a general tem-
however, the most common ways that pharmacists plate. The following sections describe the suggested
use professional communication skills to contribute components of a drug evaluation monograph in detail;
to formulary management are through the prepara- however, the specific template used by an institution
tion of drug evaluation monographs (or drug class may be modified to meet the institution’s needs.77,78
reviews), medication-use evaluations, clinical practice
guidelines and pathways, medication alert notifica- Title
tions, newsletters, and medication use policies. Basic This section includes basic information such as generic
guidelines for the preparation of these documents are and trade names, manufacturer, available dosage
listed below. forms, and the corresponding national drug code
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376 | An Introduction to Pharmacy

metabolism, excretion), including information about

Table 10.10 FDA-required prescribing
potential pharmacokinetic changes in specific popu-
information
lations (e.g., geriatrics, patients with hepatic and/or
1. Indications and Usage renal dysfunction, pediatrics). For these data, a chart
2. Dosage and Administration format is often preferred. This is especially helpful for
3. Dosage Forms and Strengths drug class reviews when several agents within a given
4. Contraindications
drug class are being compared.
5. Warnings and Precautions
6. Adverse Reactions
Indications
7. Drug Interactions
8. Use in Specific Populations A list of all the FDA-approved indications and any sig-
9. Drug Abuse and Dependence nificant differences between the monograph drug and
10. Overdose
similar products within the same drug class should be
11. Description
12. Clinical Pharmacology
provided. Because many medications are used for indi-
13. Nonclinical Toxicology cations that are not officially approved by the FDA,
14. Clinical Studies it is also important to list pertinent off-label uses of
15. References the medication as well, particularly when these uses
16. How Supplied/Storage and Handling
are supported by the primary medication literature. It
17. Patient Counseling Information
is also helpful to note these potential uses when they
are under-studied and/or use of the medication could
(NDC) numbers, the American Hospital Formulary potentially decrease patient safety.
Service (AHFS) Pharmacologic-Therapeutic Clas-
Clinical efficacy
sification, and any important storage instructions.
The AHFS Pharmacologic-Therapeutic Classification A thorough review of available primary literature per-
number is found in the classification index of the tinent to the efficacy and safety of the requested drug
AHFS Drug Information reference book. AHFS Drug as it relates to the FDA-approved and off-label indi-
Information is published by the American Society cations should be presented. Studies that are reviewed
of Health-System Pharmacists and is commonly should include placebo-controlled and comparative
used as an important reference book for practicing trials, with emphasis on comparative trials when
pharmacists. The AHFS Pharmacologic-Therapeutic available. It is important to note that clinical trials
Classification method indexes medications by that do not assess the safety and efficacy of the drug
pharmacologic and therapeutic effects by assigning product should not be included. For example, phar-
numerical values to each drug class. Many institutions macokinetic evaluations in healthy subjects or animal
use the AHFS Pharmacologic-Therapeutic Classifica- toxicology studies are not appropriate for inclusion
tion system to index the medications available on the in the clinical efficacy section of a drug evaluation
drug formulary. Use of a classification system helps monograph. These types of studies may be referenced
organize an institution’s formulary list. in other sections of the monograph (such as the phar-
macokinetic section or the safety section), but they do
Description and pharmacology not provide clinical efficacy information.
This section includes a description of the compound Typically, it is best to follow a general tem-
including the therapeutic mechanism of action. Impor- plate when abstracting clinical trial data within a
tant advantages and disadvantages in the pharmaco- drug monograph evaluation. This improves readabil-
logical effects of the monograph drug as compared to ity, ensures consistency, and allows comparisons to
current formulary agents of the same class should be be made between different clinical trials in a rela-
discussed as well. tively simple format. The citation, objective, and study
design should always be stated in a clear and concise
Pharmacokinetics
manner. Detailed information describing the inclu-
This section includes a brief review of the available sion/exclusion criteria, randomization process, study
pharmacokinetic data (i.e., absorption, distribution, treatments, and the efficacy and safety assessments
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Fundamentals of pharmacy practice | 377

should be included in the description of the methods. Dosing and administration

Within the results section, the writer should report The recommended doses for specific indications and
specific numbers to describe the efficacy and safety of patient populations (e.g., geriatric, pediatric, obese,
the drug. For example, instead of simply reporting a renal failure) should be clearly listed. If applicable, a
‘‘statistically significant difference between groups,’’ description of dosage titration should be included. For
the writer should report the quantitative difference parenteral medications, it is important to list infor-
in the outcome measure between study groups (e.g., mation about reconstitution techniques, appropriate
160 mg/dL versus 110 mg/dL). This allows the reader diluents, long-term stability and sterility, and compat-
to interpret the potential clinical significance of the ibility with other medications. Special administration
results. In addition to a short conclusion, the writer issues such as infusion rate or the need for in-line
should provide a brief commentary regarding the filters should also be addressed in this section.
potential strengths and limitations that should be
considered when interpreting the results of the study. Patient monitoring parameters and patient information
An example of a clinical trial summary that would Information regarding recommended patient mon-
be appropriate for inclusion in a drug evaluation itoring parameters with suggested time intervals for
monograph is shown in Fig. 10.8 assessments should be presented. Additionally, patient
information written in lay terms for the monograph
drug should be provided.
Safety and tolerability
This section should include information regarding Budget impact
manufacturer-labeled contraindications, warnings, This section should provide a quantitative description
and precautions (including pregnancy and lactation of the health system’s cost for the new product based
information); additionally, review of safety data on the typical dosage regimen (e.g., Q8h for 10 days).
from additional clinical trials and tertiary medication The cost per bottle (or package) is not always helpful,
references may be helpful. Adverse event data should because it does not take into account the typical
be presented in a manner that emphasizes the most dosage regimen. It is best to provide these data in
common and most serious adverse events, with a tabular format that compares the new product to
suggested strategies to prevent or manage these currently available agents. Additionally, it is helpful
events if they occur; it is also helpful to present these to include projected use and how the item will affect
data as specifically as possible, highlighting the exact the health system’s total drug budget.
portion of a specific population who experienced
the adverse event (i.e., ‘‘in Phase III clinical trials, Summary and recommendations
47% of patients over 65 years of age receiving The summary should briefly review the pertinent data
nitroglycerin ointment experienced headache’’). presented throughout the document including a con-
Potential drug–drug, drug–food, drug–laboratory, cise discussion of the drug class and information
and drug–herb interactions should also be presented regarding the efficacy, safety, and cost of the new
with suggested management approaches. As with all drug product in comparison to currently available
sections of the drug monograph, comparative data formulary agents. Any important advantages of the
should be presented when available. new drug should also be highlighted in this section.
Finally, the recommendation should be stated with
appropriate rationale. Additional secondary recom-
Medication error possibility mendations, such as deletion of alternative agents
Information should be included about potential med- from the drug formulary, restrictions of use to certain
ication errors that could occur in dosing, medication patients or practitioners, or follow-up medication use
preparation, medication administration, or concerns evaluation, should also be included in this section. In
with look-alike/sound-alike names. If potential risks some institutions, the summary and recommendation
exist, methods for preventing medication errors are listed on the front page of the drug evalua-
should be introduced. tion monograph to make it easier for reference and
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378 | An Introduction to Pharmacy

Objective Assess the safety and efficacy of fidaxomicin compared to vancomycin for the treatment of non-complicated C. difficile
infection.
Design Prospective, multicenter, double-blind, randomized, parallel-group, noninferiority trial
Methods Patients included in the study were at least sixteen years of age and diagnosed with C. difficile infection. Diagnosis was
based on greater than three unformed bowel movements (i.e., diarrhea) within 24 hours prior to randomization and presence
of C. difficile A and/or B toxin in the stool within 48 hours prior to randomization. Patients were excluded if they received
greater than four doses of metronidazole and/or vancomycin within 24 hours prior to randomization, any other treatment for
C. difficile infection (e.g., rifaximin), and symptoms of complicated C. difficile infection (e.g., life-threatening infection, toxic
megacolon, second recurrence). Patients were randomized to fidaxomicin 200 mg PO every twelve hours or vancomycin
125 mg PO every six hours for ten days; patients were stratified according to whether the case was a first or second occur-
rence. The primary endpoint assessed was clinical cure at the end of therapy. Secondary endpoints included recurrence of
C. difficile infection within four weeks following completion of therapy and global cure. Clinical cure was de ned as three or
fewer unformed stools for two consecutive days and no need for continued treatment. Clinical cure with no recurrence was
defined as a global cure. Safety was assessed from study entrance through last dose of study drug or visit if the patient
received at least one dose of study medication and was evaluated.
Results A total of 629 patients underwent randomization (327 to vancomycin and 302 to fidaxomicin); of these, 309 and 283 van-
comycin patients were included in the modified intention to treat population and the per-protocol population, respectively.
Of the 302 fidaxomicin patients, 287 and 265 were included in modified intention to treat and the per protocol population.
Baseline characteristics were similar between groups; in the modified intention to treat population, the mean age was 61.6
± 16.9 years, 55.9% of patients were female, 59.4% of patients were inpatient. Few patients (17.1%) had experienced
previous C. difficile disease, or contracted the virulent BI/NAP1/027 strain (38.1%). Approximately 39% of patients received
treatment for C. difficile during the 24 hours prior to randomization. In the modified intention to treat population, 88.2% of
fidaxomicin patients and 85.8% of vancomycin patients experienced clinical cure; fidaxomicin was found to be noninferior to
vancomycin. Fidaxomicin clinical rate was also found to be noninferior to vancomycin in the per-protocol population (92.1%
vs. 89.8%). The fidaxomicin group also had a lower rate of recurrence (15.4% vs. 25.3%; p=0.005) and a higher rate of
global cure (74.6% vs. 64.1%; p=0.006) compared to vancomycin. Fidaxomicin patients also had a higher rate of diarrhea
reolution without recurrence (74.6% vs. 64.1%) and a shorter median time to diarrhea resolution (58 hours vs. 78 hours)
compared to vancomycin. Rates of clinical cure did not differ between clinically relevant subgroups. Rates of recurrence
tended to be lower in patients with no previous C. difficile disease (14.2% vs. 24%; p=0.01), no C. difficile treatment 24 hours
prior to enrolment (13.9% vs. 25%), mild (11.9% vs. 29.4%; p=0.02) and severe (13% vs. 26.6%; p=0.02) baseline disease,
non-NAP1/BI/027 strain type (10.3% vs. 28.1%; p<0.001), and no concomitant antibiotics (14.5% vs. 24%; p=0.03). Safety
outcomes were similar between groups with 62.3% of fidaxomicin patients and 60.4% of vancomycin patients experiencing
an adverse event; 25% of fidaxomicin patients experienced a severe adverse event compared to 24.1% of vancomycin patient.
Fidaxomicin patients had a higher rate of laboratory abnormalities compared to vancomycin patients (4.7% vs. 1.2%).

Conclusions Fidaxomicin and vancomycin are both highly effective in achieving clinical cure of uncomplicated C. difficile disease.
Fidaxomicin may be more effective in preventing recurrence of disease within four weeks compared to vancomycin. Both
agents were similarly effective in achieving clinical cure with the virulent NAP1/BI/027 strain but vancomycin may be more
effective in preventing its recurrence.
Comments • Study population: Patients were not stratified at randomization according to disease severity, limiting the ability to identify
the most appropriate patients who should receive fidaxomicin. Additionally, it is difficult to quantify the severity of
disease in relation to the treatment guidelines as various baseline data (e.g., white blood cell count, serum creatinine
trends) were not provided.
• Control group: The medication (vancomycin) and dose used for the comparator are indicated in the treatment guidelines
for severe C. difficile infection; it is unclear if this was a severe population. The authors did quantify patients by disease
severity in subgroup analyses but did not elaborate as to how these distinctions were made. Additionally, the study
does not provide a comparison to metronidazole.
• Disease definitions: Recurrence was only measured for 28 days following study drug completion. Recurrence of C. difficile
infection typically occurs for up to 60 days. No data was provided as to differences in timing of recurrence between
treatment groups.

Figure 10.8 Example of a clinical trial summary for a drug evaluation monograph. Louie TJ, Miller MA, Mullane KM et al..
Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364(5): 422–31.

discussion during the Pharmacy and Therapeutics within the text. References should be cited using the
(P&T) Committee meeting.78 Uniform Requirements of Manuscripts Submitted to
Biomedical Journals.74
Authorship
The pharmacist who prepared the monograph should Other
be listed along with the date that the final document Additional sections may be included in drug formulary
was completed. Additionally, pharmacists who served monographs to fit the needs of individual institutions.
as document reviewers should be listed. These may include information pertaining to risk eval-
uation and mitigation strategies (REMS) required by
References the FDA, patient education materials, updated poli-
All references should be footnoted and listed at the cies and procedures, and hazardous drug precautions
end of the document in the order that they appear for healthcare workers.
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Fundamentals of pharmacy practice | 379

The use of a standard drug evaluation monograph, pharmacist assume accountability for completion of
including the sections noted above, can help stream- this process, in its entirety.
line the P&T review process. Additionally, some P&T The following sections provide a general template
Committees use a one-page executive summary in lieu to follow when reporting results of an MUE.
of the entire drug evaluation monograph. Pharmacists
typically present the executive summary of the drug Background
evaluation monograph or drug class review verbally This section should provide background information
during the P&T Committee meeting.78 about why the MUE was conducted. For example, the
reason may be that the medication being evaluated has
Medication-use evaluation been associated with medication errors, or because the
Medication-use evaluation (MUE) is a continuous medication may be associated with a serious adverse
improvement method used to evaluate the use of event. Pertinent literature or national guidelines that
medications within a health system to identify areas support the need for an MUE should also be reviewed.
for improvement in medication-related quality out- This section should end with a statement describing
comes and aid in formulary management.77,80 MUE the primary objective of the MUE.
is frequently completed based upon evidence-based
clinical practice guidelines and clinical pathways. In Methods
addition, MUE may be based upon approved use A detailed description of exactly how the MUE
criteria of an individual drug or drugs within a thera- was conducted should be included. Typically, a
peutic class or designed to assess cost-effectiveness of retrospective cross-sectional, case–control, or cohort
medication therapy. MUE should focus on high risk, study design is used, although some MUEs may be
highly complicated, or expensive medications and is performed prospectively. The methods for patient
often based on preliminary internal data (e.g., a high selection, identification, and data collection should
rate of errors with a particular medication). While be listed; as well as the study time period and sample
MUE is no longer required by regulatory agencies size. Justification for the selected sample size should
such as the Joint Commission, it is completed as an be provided. It may be helpful to list the types of
ongoing indicator of continuing quality improvement. data that were collected. For example, if the MUE
There are several key communication issues assessed appropriate use of a particular medication
related to MUE. First, it is imperative that the criteria with regard to renal function, serum creatinine would
for MUE are approved by the medical staff and/or any be recorded for all patients.
other group of healthcare providers who are expected
to apply the criteria in the care of their patients. Results
Following completion of an MUE, results should Detailed results for each type of data that was
be shared through appropriate channels. Within collected should be presented in a tabular format
healthcare organizations, MUE is often a function that directs the audience’s attention to the most
of the Pharmacy and Therapeutics Committee or important findings. The presentation of results should
an associated subcommittee. The most common include patient demographics and numerical values
communication-related problems in the MUE process for all data. If statistics were performed, investigators
generally occur after results have been discussed should clearly state whether results were statistically
by the committee. Discussion frequently culminates significant.
in recommendations for the improvement of care.
These recommendations are often not shared with Summary
practitioners, nor is there subsequent assessment The results of the MUE should be briefly summarized,
to determine the results of the recommended highlighting the most important findings. As with
improvements. Thus, the 360-degree cycle associated any investigation, authors should comment on any
with study completion and process improvement is potential limitations of the study, whether results
not completed, and recommendations for improved were clinically significant, and potential impact on
care are not implemented. It is essential that the practice.
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380 | An Introduction to Pharmacy

Recommendations Medication alert notifications

Finally, the recommendations to improve medication In many cases, there may be situations that require the
use should be presented. These should be specific to pharmacy department to alert the medical and nurs-
the health system. Recommendations and plans for ing staff of an important medication-related issue.
improvement should be specific, measureable, and Recently, one of the most important examples of
achievable in the context of the particular health these types of issues has been medication shortages.
system. When a commonly used or critically important med-
ication is unable to be obtained, it is vital that
Clinical practice guidelines and pathways the pharmacy communicate with key stakeholders
Evidence-based clinical practice guidelines have been (e.g., medical specialties, nursing areas) to notify
defined as ‘‘systematically developed statements those individuals of the shortage and present a plan
to assist practitioner and patient decisions about of action. Additional examples requiring drug alert
healthcare for specific circumstances.’’82 Clinical notifications include change in pharmacy procedures,
practice guidelines may also be used as tools to formulary updates, or withdrawal of a drug from
promote appropriate medication used based on the market. Typically, pharmacists are responsible
Pharmacy and Therapeutics Committee approval for developing these types of communications. The
requirements. Guidelines and pathways should be most effective method is generally the preparation
based on widely-endorsed clinical practice guide- of a one-page communication that clearly states the
lines and primary medication literature. Guidelines problem or issue and provides a recommendation for
should include specifications for care, which may be managing the problem. The notification should pro-
disease-based (e.g., hypertension, asthma, diabetes) vide contact information for potential questions or
or process-focused (e.g., guidelines for the use of concerns. An example of a drug alert notification is
serum levels in monitoring aminoglycoside therapy). shown in Fig. 10.9. It is important that medication
Clinical pathways reflect the details that support alerts take into account the perspective and level of
practice guidelines using clear inclusion and exclusion understanding of the intended audience and provide
criteria. For example, guidelines which focus on sufficient detail while maintaining readability.
the use of serum levels in monitoring gentamicin
therapy might include patients with an elevated serum Newsletters
creatinine of greater than 2 mg/dL or those receiving Most health systems have a pharmacy newsletter
daily dosages in excess of 6 mg/kg but exclude or website that is published on a regular basis to
patients less than 2 years of age. The corresponding communicate important formulary decisions that
clinical pathway would state the exact manner in have been made by the Pharmacy and Therapeutics
which the serum levels should be monitored, such as Committee. Newsletters may also be used to commu-
obtaining the trough level within 30 minutes prior to nicate important current events in pharmacy practice,
the infusion of a gentamicin dose, and the peak 30 educational information for healthcare professionals
minutes after the end of a one-half hour infusion. and/or patients, medication shortages updates, and
Clinical practice guidelines and pathways should changes in policy and/or procedure. As drug therapy
be specifically and succinctly written, such that there specialists, the main writers and editors of pharmacy
is no confusion regarding the intent of the guideline newsletters are pharmacists. When preparing a phar-
or the exact process for application of the guideline. macy newsletter the primary factors to consider are
Healthcare organizations with sophisticated informa- the target audience, the primary goal of publication,
tion systems (including computer-generated physician and professional appearance.71 The specific format
order entry) frequently incorporate guidelines and used varies greatly depending on these primary
pathways into their software to provide guidance to factors. Potential limitations to newsletters and/or
practitioners in the care of their patients; this method websites to be considered include time required for
of enforcement is thought to contribute to increased preparation, financial burden, and accessible equip-
adherence to guidelines and subsequent improved ment resources. Professional writing strategies are
patient outcomes. discussed in detail elsewhere in this section. Pharmacy
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Fundamentals of pharmacy practice | 381

MEDICATION ALERT
PHARMACY AND THERAPEUTICS COMMITTEE
IU Health

March 10, 2011

CALCIUM CHLORIDE INJECTION SHORTAGE
Calcium chloride 1 gram vials are currently on national shortage. It is unclear how long this shortage is expected to
continue. Clinicians are advised to use calcium gluconate for the duration of the shortage.

Orders for the following products: Will be dispensed as:

Intravenous calcium chloride Intravenous calcium gluconate
dosed in grams at three times the ordered calcium chloride dose

Example: Calcium chloride 1 gram IVPB now Example: Calcium gluconate 3 gram IVPB now
Intravenous calcium chloride Intravenous calcium chloride
dosed in mEq at the same ordered calcium chloride dose

Example: Calcium chloride 13.7 mEq IVPB now Example: Calcium chloride 13.7 mEq IVPB now

For more information, contact a pharmacist or the Drug Information Service.

Figure 10.9 Example drug alert notification.

newsletters serve a valuable purpose for communi- Service

cating important information to the medical staff and Individuals involved with equipment and/or building
provide visibility for the pharmacy department. maintenance.

Medication use policies Administrative

Medication use policies and procedures are vital writ- Individuals who may complete some clerical func-
ten communications that are generally written and tions, with the addition of budgeting/financial
implemented by pharmacists practicing in formulary management or supervision of clerical staff.
management and/or drug information.
Technical
Personnel communication
Individuals involved with product procurement and
Position description preparation, along with certain levels of customer
Pharmacists, particularly those in management posi- interaction
tions, are frequently required to write position descrip-
tions for other pharmacists, technicians, and/or other Professional
supportive personnel. The position description should Including pharmacists, nurses, etc.
delineate the required qualifications, experience, and Educational requirements may include the ability
an overview of job responsibilities. Most position to read/write English or another language, high school
descriptions also include an overview of the required diploma, vocational training, certification, college
competencies for successful job performance. course work, associate degree, BS degree, advanced
The types of positions for which pharmacists degree, or postgraduate training. Required experience
might prepare position descriptions include: should include the number of years and type of expe-
rience (i.e., directly related to the position). Other
Clerical related skills might include word processing, account-
Individuals who complete tasks including word ing, supervision, prescription processing, and perhaps
processing, filing, bookkeeping, and serving as a work with automated dispensing systems, to name a
receptionist. few. The position description should include essential
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382 | An Introduction to Pharmacy

Position Description
Ambulatory Care Pharmacist

Professional Pharmacy Systems

300 North Carleton Bldg
Indianapolis, IN 44444-4444
Qualifications:
1. Doctor of Pharmacy (PharmD) degree and/or BS in Pharmacy with equivalent experience
2. Minimum of 3 years experience in progressive pharmacy practice
3. Eligibility for and attainment of pharmacy licensure in the State of Indiana
4. Involvement with medication therapy/disease state management programs (e.g., diabetes, asthma, hyperlipidemia, anticoagulation)
preferred
5. Strong organizational and interpersonal skills
6. Ability to communicate effectively with patients of varying educational and ethnic backgrounds

Position Responsibilities:
1. Assist with prescription processing and patient education
2. Under scope of practice and prescribing protocols, provide direct medication therapy/disease state management for patients with
chronic diseases (described above)
3. Assist in the development and marketing of additional disease management programs to support community-based physician practices
4. Serve as a preceptor for PharmD students completing advanced pharmacy practice experiences (APPE) within the practice site

Required Core Competencies:

Knowledge
1. Knowledge of procedures and laws pertaining to the processing and dispensing of prescriptions
2. Knowledge of medication therapy/disease state management for chronic diseases (described above)
Skills
1. Ability to modify disease state recommendations based upon scope of practice and prescribing protocols
2. Ability to individualize education for each patient
Behaviors
1. Monitor indicators of response including disease-based parameters
2. Provide individualized follow-up for patients to optimize outcomes
It is anticipated the ambulatory care pharmacist will have responsibilities that mirror the following:
Prescription Processing (20%)
The ambulatory care pharmacist will assist with prescription processing for clinic patients.This function includes managing and modifying
therapy based upon scope of practice and prescribing protocols and educating patients regarding recommended therapy including use of
over-the-counter and alternative therapies.

Medication Therapy/Disease State Management (60%)

The ambulatory care pharmacist will provide direct medication therapy/disease state management for patients with chronic diseases through a
scope of practice and prescribing protocols
Program Development/Marketing (10%)
In conjunction with practice management, the ambulatory care pharmacist will assist with the identification program development and marketing
of additional medication therapy/disease state management programs.
Experiential Learning (10%)
The ambulatory care pharmacist will assist with supervision of APPE students from state colleges of pharmacy.

Figure 10.10 Example of position description.

duties and the percent of effort that is designated to should include contact information for the individual
each duty. Figure 10.10 contains an example position responsible for recruitment and should also reflect the
description for a pharmacist. status of an equal opportunity employer, where appli-
cable. An example position description is included in
Job postings Fig. 10.11.
Once a position description has been developed,
job postings reflecting abbreviated qualifications and Interviewing
responsibilities for the successful applicant are pre- Interviewing is an essential skill for pharmacists,
pared. Job postings are commonly used to advertise whether they serve in administrative positions and
for candidates in local newspapers, professional jour- are responsible for hiring staff that will enhance their
nals, and/or via the Internet. Position descriptions services or apply their skills in obtaining a fulfilling
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Fundamentals of pharmacy practice | 383

Ambulatory Care Pharmacist

Professional Pharmacy Systems
Professional Pharmacy Systems invites applications for a full-time pharmacist position in its Indianapolis, IN ambulatory clinic site. Applicants
should possess a PharmD or BS in Pharmacy with equivalent experience. Candidates should have a minimum of three years experience in
progressive pharmacy practice. Involvement with medication therapy/disease state management programs (e.g., diabetes, asthma, hyperlipi-
demia, anticoagulation) is preferred. T he candidate should be able to demonstrate strengths in organization and communication with both
patients and other healthcare professionals. Fluency in a second language (preferably Spanish) is highly desirable. Salary commensurate with
qualifications and experience. Review of applicants will begin upon receipt and continue until the position has been filled. Applicants should send
a letter of intent with curriculum vitae and the names and contact information for three professional references to:
Steven R.Abel, PharmD, FASHP
Pharmacy Director
Professional Pharmacy Systems
300 North Carleton Bldg.
Indianapolis, IN 44444-4444
sabel@professionalpharmacysx.org

Figure 10.11 Example job posting.

professional position. It is important for pharma- (A) taken in the situation and the result (R). As
cists to be aware of the different types of interviews noted, this type of interview may also be termed the
in which they might participate. These include the STAR format. The interviewer wishes to understand
following: how a candidate reacted in certain situations and
what they learned or might do differently as a result.
Structured interview
The interviewee’s past experiences are the focus
An interview that utilizes a predetermined list of for specific examples which offer the interviewer a
questions designed to facilitate comparison among chance to determine strengths and weaknesses based
the candidates. This format is good for a naı̈ve inter- on ‘‘lessons learned.’’
viewer because it provides a ‘‘script’’ for the interview
process, but it may not offer enough flexibility to Regardless of the interview technique, interview-
allow complete assessment of a candidate’s strengths ers and interviewees alike should be prepared to
and liabilities. discuss topics including personal interests, educa-
Unstructured interview tion, experience, and career goals. Skills related to
interpersonal interactions, communication, and tech-
An interview that is unorganized, spontaneous, and
nical/practical competence will also be evaluated.
flexible. This format tests the listening skills of the
Topics that may not be discussed in an interview
interviewee while challenging the interviewer to
are included in Table 10.11.
remain on task and ascertain pertinent information
from the candidate. Performance appraisal
Stress interview Pharmacists will have the responsibility to provide
input into or prepare performance appraisals. The
An interview designed to determine the emotional
primary purpose of the performance appraisal is
stability of the interviewee. Questions are asked in
a direct, sometimes offensive manner in an effort to
strike an emotional chord and evaluate the candidate’s
Table 10.11 Inappropriate interview topics
response.
Age
Behavioral interview
Arrest or conviction record
An interview focused on identifying how the intervie- Credit rating
wee reacted in certain situations. Questions may focus Disabilities
on stressful, frustrating, or positive scenarios. The Marital/family status
Military record
interview asks the candidate to describe a situation
Name, national origin, or religion
(S) with which they were involved, explain their tasks Request for a photograph
(T) associated with the situation, describe the action
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384 | An Introduction to Pharmacy

to enhance employee development. Performance verbal counseling of the employee by the super-
appraisals are also frequently utilized to distribute visor, with written documentation that the verbal
rewards (e.g., salary increases). When communicating counseling occurred. The written documentation
with the employee regarding performance, the dis- simply serves as a record for the employee’s file. The
cussion should focus on four characteristics of good second step in progressive discipline is provision of a
performance criteria. Performance criteria should written warning. Should performance not improve,
be achievable, measurable, unbiased, and significant there is a follow-up to the written warning issued,
to the work of the individual. It is suggested that which may subsequently lead to suspension and
performance criteria be developed jointly by the finally discharge. Supervisors should be aware of the
supervisor and employee, including the method for process for progressive discipline and should carefully
assessment. This approach should make the review document all events. Without documentation, the
process most valuable for the involved parties. poor performer may not be able to be terminated.
Several general guidelines exist for conducting the When communicating with an employee through-
appraisal interview. Appraisals should be conducted out the progressive discipline process, the supervisor
in a quiet setting that is removed from the general should describe the problem(s) specifically, including
workplace and other employees. The frequency and the implications of why the problem(s) are of concern
timing of performance evaluations should be known to the supervisor and/or within the workplace. The
to the employee. In most settings, evaluations occur employee should be given a chance to provide his or
on an annual basis (e.g., at the end of each year) or on her explanation, and the supervisor should actively
the anniversary of employment. Presentation of the listen during this process. The employee should be
appraisal is critical to its success. Managers should asked for input on problem resolution. When com-
begin their assessment by citing specific examples or pleted effectively, the act of progressive discipline
instances in which the employee made positive contri- should put the onus for improvement on the indi-
butions to the site. Criticism is acceptable, but should vidual employee. At each step within the progressive
be offered as opportunities for employee develop- discipline process, specific action should be agreed
ment and should always be presented after at least upon, and a date identified for follow-up to review
some positive statements are made. The evaluation progress. In general, no more than two weeks should
should be offered as the manager’s interpretation of pass between discussions. Supervisors should express
the available facts. If opportunities for improvement confidence that the employee can improve, except at
are recommended, these should be delivered in a discharge. Again, the importance of documentation
tactful, but direct manner. throughout this process cannot be overemphasized.
Verbal evaluations should always be supported by
Policies and procedures
paper documentation of performance. The employee
and manager should sign the written document. This Policies and procedures are required in virtually all
does not imply that the employee agrees with the business settings; the most important types of poli-
assessment, but rather simply that they have read cies and procedures for pharmacists are intended for
and understand its content. Evaluations should not personnel or medication management.77 When writ-
be changed, but the employee should be offered ten properly, policies and procedures should serve as
the opportunity to prepare a written addendum or the basis for completion of each function or activity
response that can be appended to the written docu- within the workplace. Essentially, a policy statement
ment and retained in the employee record. describes an outcome an organization expects to
achieve (e.g., ‘‘The pharmacy implements strategies to
Progressive discipline safeguard the use of high-alert medications.’’) and the
Unfortunately, the process of progressive discipline procedures describe a stepwise approach to achieve
is a necessary component of most professional work compliance with the policy (e.g., separating storage,
environments. Progressive discipline occurs when restricted distribution, alert labels).
there are identified problems with an individual’s Policies and procedures should be written such
work habits or performance. There are five steps in that a naive employee should be able to read the pol-
the progressive discipline process. The first involves icy and procedure and successfully complete a given
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Fundamentals of pharmacy practice | 385

task; it is virtually impossible for policies and proce- appropriate use of a medication or medications in
dures to be too detailed. For example, if a particular a particular patient: an individual plan of care to
task requires use of a computer, the procedure should remedy a medical problem. It may be communicated
begin by instructing the participants to turn on the in writing, verbally, or transmitted electronically but,
computer using the green switch on the side of the regardless, the prescription is the framework for the
processor. The participant might next be instructed processes involved in pharmaceutical care running
that, once the screen is visible, the cursor should be through, and facilitating, all areas of clinical and dis-
used to select the appropriate icon for execution of pensing operations for medications. The prescription
the task, etc. It is common for policies and proce- may also be the means for the patient to obtain neces-
dures to be prepared by managers or individuals most sary medical equipment or services such as diagnostic
familiar with the individual activity. New employ- tests or clinical referrals. The prescription connects the
ees or individuals from other areas within the work pharmacist with prescribers, other healthcare profes-
environment are frequently utilized to test the depth sionals, and, most importantly, the patient.
and detail of written policies and procedures. Policy A prescription is issued by a physician or other
authors should make efforts to use active voice and licensed medical practitioner. Individual states have
ensure grammatical agreement when writing these the authority to determine which medical professions,
documents. For example, instead of ‘‘high alert med- in addition to licensed physicians, have prescribing
ications will be defined by the Medication Safety authority. This authority is granted to correspond
Committee,’’ a stronger policy statement would be only with the provider’s scope of practice (i.e., a
‘‘the Medication Safety Committee defines high alert veterinarian may prescribe only for animals; a podia-
medications.’’ trist can prescribe only for conditions of the human
When developing a policy and procedure structure foot; optometrists only prescribe drugs for disor-
specific to medication management, it is important to ders of the eye, etc.). Some additional examples of
consider the scope of these documents.77 Medications medical professionals that may have full or limited
and/or processes that have been shown to be high risk prescribing authority are dentists, nurse practitioners
and complex may warrant a policy and procedure and physician assistants, depending on current state
to help guide clinicians. Additionally, the Joint Com- and federal laws. Pharmacists can issue prescriptions
mission requires development of policies regarding under a physician approved protocol or with certain
specific procedures (e.g., investigational medications, state-mandated restrictions.
self-administered medications) to maintain accredita- The prescription can facilitate the professional
tion. In health systems, the role of policy development relationship between the prescriber and the pharma-
and approval is frequently given to the Pharmacy and cist for the delivery of quality pharmaceutical care
Therapeutics Committee. to meet patient needs. The pharmacist will often
advise the prescriber related to drug product selec-
tion based on clinical protocols, drug formularies or
Summary and conclusion
patient financial considerations. The pharmacist may
Professional communication, which is utilized multi- also consult with the prescriber based on other patient
ple times each day regardless of practice setting, is specific knowledge such as patient drug sensitivities,
a vital skill for pharmacists. This section provides a previous adverse drug reactions (ADRs), concurrent
broad overview of the most common types of written medication therapies, and previous treatment suc-
and verbal communication skills that are necessary cesses or failures. In order to accomplish this for the
for successful pharmacists. best possible patient outcomes, the pharmacist must
maintain a high level of practice competence, keep
accurate and updated patient records, and always pur-
The prescription sue the best working relationships with other health
professionals.
Introduction
The prescription is the basis for the pharmacist–
The prescription is a set of specific directions issued patient relationship as well. It conveys the necessary
by a medical practitioner to a pharmacist for the information about how the patient should utilize the
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386 | An Introduction to Pharmacy

prescribed medication. This information, when com- minors). Licensed prescribers may issue prescriptions
bined with the pharmacist’s knowledge of medications for nonprescription drugs, but it is predominantly the
and dosage forms, allows for a dialogue between the pharmacist who is responsible for the implied pre-
patient and pharmacist where conditions for optimal scription by reviewing directions for appropriate use
use of the medication and concerns specific to an with the patient.83,84
individual patient can be accommodated for the best
patient outcomes. The prescription itself is such an Inpatient medication orders
integral part of this exchange that often patients will
Medication orders for inpatients in hospitals and
refer to their medication as their ‘‘prescription’’ as
other institutions are written by the physician on
well. Just as pharmacists must establish and maintain
forms called the Physician’s Order Sheet or are
the trust of the physician, the trust of the patient is
entered directly into the institution’s computer system.
equally important if the pharmacist is to be assured of
These orders are then sent, on paper or electronically,
the patient’s adherence after the visit to the pharmacy.
directly to the pharmacy serving that institution to
The vast majority of prescriptions are written for
be screened for potential problems, processed and
medications that can only be obtained after being
dispensed through the institution’s medication dis-
prescribed by a licensed practitioner and are referred
tribution system. If the medication order is written,
to as prescription or legend drugs. In some instances,
the exact form used varies between institutions and
a prescription will be generated for a medication
even within an institution, depending on the unit
that can be obtained without such a prescription,
rendering the care. Because these orders are writ-
for example, based on payor necessity or a desire by
ten in a controlled environment and the medications
the prescriber for the medication to appear on the
are administered by trained healthcare professionals,
patient’s medication profile. These medications are
many of the requirements and restrictions placed on
termed nonprescription or over-the-counter (OTC)
prescription orders for outpatients do not apply in
drugs. Legend or prescription drugs are recognizable
the institutional setting. The balance of this section is
by the statement ‘‘Caution: Federal Law Prohibits
focused on outpatient medication orders, or prescrip-
Dispensing Without Prescription’’ or ‘‘RX only’’ that
tions, intended for use by patients in the community
must, by law, appear on the label of the product as it
who administer their own medications without inter-
is provided to the pharmacist by the manufacturer.82
vention by a healthcare professional.
OTC medications can be further divided into drugs
that are available for patients without consulting
Form of the prescription order
any healthcare professional (traditional OTC med-
ications), and drugs the patient must request from the Prescriptions usually are written on printed forms
pharmacist (behind-the-counter, BTC, or restricted that contain blank spaces for the required informa-
OTC medications). BTC medications may be catego- tion. These forms are called prescription blanks and
rized as such by state or federal agencies and although are supplied in the form of a pad to be filled in by the
they do not require a prescription, they are not read- prescriber or may be printed, already completed, from
ily available to the public without consulting with a the prescriber’s computer. Most prescription blanks
pharmacist. Drugs in the BTC category often receive are imprinted with some basic contact information
this designation because of their potential for patient about the prescriber or their practice site should
harm or misuse. The pharmacist is typically required additional professional communication be required.
to obtain proof of the patient’s identification and age This information usually includes the prescriber’s
and may need to maintain appropriate documenta- name, address, and telephone number at a minimum
tion with the patient name and quantity at the time (Fig. 10.12).
of purchase. Examples of BTC medications include Although most prescribers use specially imprinted
pseudoephedrine (sold only in limited quantities to prescription blanks, it is not universally a legal
prevent abuse or its use in the manufacture of the ille- requirement for prescriptions; any paper or other
gal and highly addictive methamphetamine) or Plan B writing material may be used. There are some
(sold without a prescription only to patients 17 years situations where more stringent requirements are
of age or older to assure appropriate oversight in necessary to increase patient safety or prevent
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Fundamentals of pharmacy practice | 387

Figure 10.12 Example of a physician’s prescription showing typical form and content. (Courtesy of Dawn Pearson.)

unlawful drug diversion. For example, a healthcare In addition to paper prescriptions transported
system such as the Veterans Health Administration from the prescriber to the pharmacy by the patient,
(VHA) may provide prescription forms for use most states allow prescription orders to be trans-
only in their facilities. Medicaid prescriptions must mitted electronically from the prescriber by fax or
be written on tamper-evident paper, (e.g., possess direct computer-to-computer transmission. Electronic
a ‘‘COPY’’, ‘‘ILLEGAL’’ or ‘‘VOID’’ pantograph submission often eliminates the safety and security
evident on any prescription photocopies or utilize measures outlined for handwritten prescriptions,
erasure revealing backgrounds) if the prescription is such as security paper, especially when they are trans-
to be transported to the pharmacy by the patient or mitted via secure computer networks. The Institute
their designee.
for Safe Medication Practices (ISMP), has advocated
Controlled substances require specialized pre-
that electronic prescribing – with proper systems
scription blanks. Controlled substances are drugs
design, implementation, and maintenance – should
that, because of their potential for abuse, are placed
completely replace handwritten prescriptions as a
in specific schedules, I–V, by the federal government
way to reduce or eliminate the medication errors
based on their relative potential for abuse. Specialized
and risk to patient safety associated with illegible
prescription blanks for these controlled substances in
handwriting.85 Other potential advantages associated
all or specific controlled substance schedules (such as
C-II) are often required to include certain security with direct computer-to-computer prescribing (often
features for the prevention of tampering or diversion. referred to as ‘‘e-prescribing,’’ ‘‘physician order
Specific modifications for controlled substance pre- entry,’’ or POE) are prescriber access to the patient’s
scription forms could include, in addition to security medical record, prescription history, and third-party
paper: triplicate prescription forms, watermarks, drug formularies. The prescriber can also, while
sequentially numbered blanks, check-off boxes for entering the prescription, receive on-screen warning
quantities or refills, a serial number or bar code for prompts with drug-specific dosing information or
tracking, the statement ‘‘Prescription is void if more potential drug interactions.
than one (1) prescription is written per blank’’, or the Prescriptions may also be received into the phar-
printed, stamped, or handwritten name and license macy verbally by a phone call from the prescriber or
number/DEA registration number of the practitioner. their designee. In the interest of patient safety, these
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388 | An Introduction to Pharmacy

prescriptions should be immediately reduced to writ- Patient information

ing or entered into a prescription processing computer The full name and address of the patient are necessary
by the pharmacist and repeated back, for verification on the prescription for identification purposes. Names
from the prescriber that the repeated order is accurate. and addresses written illegibly should be clarified on
The component parts of a prescription are acceptance of the prescription.
described as follows and are identified in Fig. 10.12. The patient’s date of birth and allergy information
may be included as well for both identification and
1. Prescriber information
safety purposes. Some prescription blanks used by
2. Patient information
medical specialists, particularly pediatricians, include
3. Date
a space for insertion of the patient’s age, weight,
4. Symbol or superscription (not shown on
or body surface area. This information is placed on
Fig. 10.12)
the prescription by the physician when medication
5. Medication prescribed or inscription
dosing is dependent on patient age or weight. This
6. Dispensing directions to pharmacist or
information assists the pharmacist in interpreting the
subscription
prescription and verifying the dose prescribed, espe-
7. Directions for patient or signatura
cially for a pediatric patient.
8. Refill number
9. Prescriber’s signature Date
Prescriptions are dated at the time they are written
In practice, some of the above information (such as the
and also when they are received and filled in the
patient’s address) may be absent when the prescription
pharmacy. The date is important in establishing the
is received by the pharmacist. In these instances the
treatment history for the patient. An unusual lapse of
pharmacist obtains the necessary information from
time between the dates a prescription was written and
the patient or physician, as is required by state law,
when it is brought to the pharmacy may be questioned
to complete the prescription.
by a pharmacist to determine if the intent of the
physician and the needs of the patient can still be met.
Prescriber’s information and signature
For controlled substance prescriptions, the date of
The prescription should include sufficient information
issue by the prescriber carries additional significance
to identify and, if necessary, contact the prescriber.
since federal and state laws govern the time period
The top of the prescription usually includes the pre-
after which a controlled substance prescription is no
scriber’s name, address, and telephone number. This
longer valid.
may be specific to an individual prescriber or may be
the name of the institution (i.e., hospital or clinic) or Symbol or superscription
office where all or none of the names of prescribers The symbol generally is understood to be a contrac-
in that group are listed. If the prescription header tion of the Latin verb recipe, meaning take thou or you
is specific to the prescriber, state license or Drug take. Some historians believe this symbol originated
Enforcement Agency (DEA) registration numbers may from the sign of Jupiter, employed by the ancients in
be present. In instances where the prescription form is requesting aid in healing. Gradual distortion through
preprinted with more generic institution information, the years has led to the symbol currently used. Today,
the prescriber may include their own state license or the symbol is representative of both the prescription
DEA registration numbers by the signature lines. The and the pharmacy itself.
prescription form should also include the prescriber’s
signature, often on one of two lines indicating the pre- Medication prescribed or inscription
scriber’s wishes related to drug product substitution. The body or principal part of the prescription order
A prescriber may have allowed a designee to write contains the names, dosages, and quantities of the
the prescription or telephone a prescription into a prescribed medications or ingredients. The majority
pharmacy. In these cases, the name or initials and cre- of prescriptions are written for medications already
dentials of the individual designated by the physician prepared or prefabricated into dosage forms by regu-
should also be present. lated pharmaceutical manufacturers. The medications
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may be prescribed under their trademarked (man- and pharmacists express quantities can have a signifi-
ufacturer’s proprietary) name or by their generic cant impact on patient safety. Pharmacists need to be
(nonproprietary) name. Prescribers, generally, have attentive not only to these dangers in the expression
the ability to indicate on the prescription if they of quantities, but also make a conscious effort to edu-
would like the patient to receive the specific trade- cate other healthcare professionals on these inherent
marked drug as written or if they will allow for dangers to patient safety.
substitution. This preference is generally communi-
Dispensing directions to pharmacist
cated to the pharmacist by the prescriber signing on or subscription
a ‘‘Dispense as Written’’ or ‘‘May Substitute’’ sig-
In the majority of prescriptions where a commercially
nature line, or utilizing similar check-boxes. When
manufactured product is dispensed, the subscription
substitution is permitted by the prescriber, pharma-
serves merely to designate the dosage form (e.g.,
cists, using their professional judgment, will determine
tablets, capsules, inhalers, and transdermal patches)
with the patient’s consent if substitution is appropri-
and the number of dosage units to be dispensed.
ate. Health Maintenance Organizations (HMOs) and
For compounded prescriptions, specific directions for
prescription benefit plans may have formularies for
preparing the compound may be included in this part
which only certain drug products within a therapeutic of the prescription.
class may be dispensed. In these cases, the pharmacist Examples of prescription directions to the phar-
may be directed by the prescription plan to dispense macist include:
a generic product or a different drug product within a
therapeutic class which was prescribed for the patient. • Disp #100 tabs (Dispense 100 tablets)
How the pharmacist handles these payor or contrac- • M ft caps dtd no xxiv (Mix and make capsules.
tual substitutions is governed by state and federal Dispense 24 such doses)
law. Most insurance companies and prescription plans • Ft supp No xii (Make 12 suppositories)
require on-line verification and authorization prior to • M ft ung (Mix and make an ointment).
dispensing prescription products.
Directions for patient or signatura
Prescription orders requiring the pharmacist to
mix ingredients are termed compounded prescrip- The prescriber indicates the directions for the patient’s
tions. Prescriptions requiring compounding contain use of the medication in the portion of the prescription
the names and quantities of each ingredient as part termed the Signatura (commonly abbreviated Signa or
of the inscription. The names of the ingredients gen- Sig and meaning mark thou). The directions in the
signa are frequently abbreviated forms of English or
erally are written using the nonproprietary names
Latin terms or a combination of the two. A list of
of the materials, although occasionally proprietary
some common prescription abbreviations is presented
names may be employed.
in Table 10.12. These directions are interpreted by
Dosages or quantities for commercially available
the pharmacist and then conveyed verbally to the
products or listed ingredients for prescriptions requir-
patient to ensure understanding as well as transcribed,
ing compounding may be expressed as a concentration
using layman’s terms, onto the prescription label of
or unit of measure using the metric or Apothecary sys-
the dispensed medication container for the patient’s
tem of weights and measures. The ISMP has published
continued reference.
‘‘Medication Safety Alert’’ articles encouraging pre- Examples of prescription signa along with the
scribers to use the metric system. Another significant appropriate interpretation for the patient include:
danger outlined by the ISMP related to the expression
of quantities is the use of trailing zeros (resulting in • ‘‘ii tabs po q4h’’ translates to ‘‘Take two tablets by
a medication ordered in a 1.0 mg dose being inter- mouth every 4 hours’’
preted and administered as a 10 mg dose) and the • ‘‘i cap po TID pc’’ translates to ‘‘Take one capsule
failure to use leading zeros (resulting in a .1 mg dose by mouth three times a day after meals’’
being interpreted and administered as a 1 mg dose). • ‘‘ii gtts right eye q12h’’ translates to ‘‘Place two
These simple, yet critical, changes to how prescribers drops into the right eye every 12 hours’’
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390 | An Introduction to Pharmacy

Table 10.12 Commonly used abbreviations in prescriptions and

medication orders

Abbreviation Meaning

aa of each

ac before meals

ad to, up to

a.d.** right ear

ad lib at pleasure, freely

AM morning

amp ampule

APAP acetaminophen

aq water

a.s.** left ear

ASA aspirin

ATC around the clock

a.u.** each ear

BCP birth control pill

bid two times a day

BM bowel movement

BP blood pressure

BPH benign prostatic hypertrophy

BS blood sugar

BSA body surface area

C with

CAD coronary artery disease

CAP community acquired pneumonia

caps capsule

cc** cubic centimeter [milliliter]

(continued overleaf)
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Table 10.12 (continued)

Abbreviation Meaning

CHF congestive heart failure

COPD chronic obstructive pulmonary disease

CP chest pain

DAW dispense as written

DC or D/C** discontinue

disp dispense

div divide

DM diabetes mellitus

DOB date of birth

d.t.d. give of such doses

Dx diagnosis

elix elixir

EtOH ethanol

Ft make, let it be made

g gram

GERD gastroesophageal reflux disease

GI gastrointestinal

GU genitourinary

gr grain

gtt a drop

h hour

HA headache

HCTZ** hydrochlorothiazide

HR heart rate

HRT hormone replacement therapy

(continued overleaf)
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392 | An Introduction to Pharmacy

Table 10.12 (continued)

Abbreviation Meaning

hs** at bedtime

HTN hypertension

inj injection

IV intravenous injection

IM intramuscular injection

ID intradermal injection

IU** international units

kg kilogram

L liter

lb pound

mcg microgram

MDI metered dose inhaler

mEq milliequivalent

mg milligram

mL milliliter

mOsmol milliosmole

MOM milk of magnesia

MS** morphine sulfate

MTX** methotrexate

MVI multivitamin

M mix

NV nausea and vomiting

NKDA no known drug allergies

NPO nothing by mouth

NMT no more than

non rep/NR do not repeat

(continued overleaf)
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Table 10.12 (continued)

Abbreviation Meaning

NS normal saline

NSAID non-steroidal anti-inflammatory

NTE not to exceed

NTG nitroglycerin

OA osteoarthritis

OC oral contraceptive

OCD obsessive compulsive disorder

OJ** orange juice

O2 oxygen

o.u.** each eye

o.d.** right eye

o.s.** left eye

OTC over-the-counter

oz; fl oz ounce; fluid ounce

P pulse

pc after meals

PCN penicillin

PM evening

po by mouth

post-op after surgery

pr or rect rectally

prn when necessary

pulv powder

pv or vag vaginally

PVCs premature ventricular contractions

PVD peripheral vascular disease

(continued overleaf)
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394 | An Introduction to Pharmacy

Table 10.12 (continued)

Abbreviation Meaning

q every

qd** every day

qid four times daily

qod** every other day

qs a sufficient quantity

qs ad a sufficient quantity up to

q __h every ___ hour

RA rheumatoid arthritis

ss without

ss one-half

SC,SQ,SubQ** subcutaneous injection

Sig write on label

SL sublingual

SOB shortness of breath

sol or soln solution

sq m, m2 square meter

stat immediately

supp suppository

susp suspension

Sx symptom

syr syrup

T temperature

tab tablet

TCN tetracycline

TIA transient ischemic attack

(continued overleaf)
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Table 10.12 (continued)

Abbreviation Meaning

tid three times a day

tiw** three times a week

tbsp tablespoon

TMP-SMX trimethoprimsulfamethoxazole

tsp teaspoon

top topically

TUD take as directed

Tx treatment

U** unit

UA uric acid, urinalysis

UC ulcerative colitis

ud or ut dict as directed

ung ointment

URTI upper respiratory tract infection

UTI urinary tract infection

WA while awake

wk week

y or yr year

yo years old

∗∗ These abbreviations are included on the Institute for Safe Medication Practices List of Error-Prone

Abbreviations (http://www.ismp.org)

Just as it has been noted that the ISMP has iden- • Abbreviation of drug names – an order writ-
tified expressions of quantity which are error-prone ten for HCT which could easily be filled with
and compromise patient safety, there is also a sig- hydrochlorothiazide instead of the intended
nificant number of literature reports and other ISMP hydrocortisone
Safety Alerts related to the dangers of abbreviations • Abbreviation of administration routes – a medica-
in the prescription order and documentation pro- tion direction abbreviated AU intended for both
cesses. Examples of problematic abbreviations are as ears is administered into both eyes or only the
follows: right ear
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396 | An Introduction to Pharmacy

• Abbreviation of administration frequency – a dating, preparing, packaging, labeling, rechecking,

once daily medication is abbreviated q1d or even dispensing, documenting, pricing, and refilling.
a handwritten order for qd dosing which is mis- Patient compliance or adherence with prescribed
interpreted as four times daily (qid) resulting in a therapies is a source of concern for physicians as
fourfold overdose. well as pharmacists. The pharmacist must be vigilant
during the processing of prescription orders for indi-
Whether an abbreviation is handwritten on a pre- cations of patient noncompliance and work with both
scription or typed into an electronic prescription, all the prescriber and patient for appropriate resolutions.
healthcare practitioners need to be cognizant of, and
avoid the use of, the error-prone abbreviations, sym- Receiving the prescription
bols, and dose designations listed by the Institute It is desirable that the patient present the prescription
of Safe Medication Practices and available on their order directly to the pharmacist because this initiates
website, http://www.ismp.org. Pharmacists are a cru- and enhances the pharmacist–patient relationship as
cial part of the solution to eliminating the use of well as facilitates the gathering of essential disease
these error-prone abbreviations and designations in and drug information from the patient. This is crit-
order forms, protocols, prescription labels, and any ical for the provision of quality medication therapy
other print material through editorial intervention management and can significantly increase patient
and provider education. safety. In the case of electronically or verbally submit-
ted prescriptions where the patient does not present
Refills the prescription order directly to the pharmacist, this
The number of authorized refills should be indicated same exchange can be accomplished when the patient
on each prescription by the prescriber. In the event arrives at the pharmacy to pick up the prescription.
that no refill information is provided, it is understood The timing is not crucial as long as the interaction
that no refills have been authorized; however, it is between patient and pharmacist occurs prior to the
advised that the label state such to avoid confusion. patient receiving the medication. In a situation when
Most prescription blanks include a section where the pharmacist is unavailable to receive a prescrip-
this information may be indicated (Fig. 10.12). Most tion, other pharmacy personnel should be trained to
states limit refills on a prescription to one year after the accept it in a professional manner and obtain the
prescription was written. When a prescriber indicates correct name, address, and other pertinent patient
that a prescription can be refilled prn, ‘‘as needed,’’ information.
the pharmacist should refill it only with a frequency Patients having a prescription filled for the first
consistent with the directions and, again, only for one time at a pharmacy may be asked to provide a brief
year from the origination date. Controlled substance health and medication history. The patient should be
prescriptions are an exception; they are typically lim- provided with an estimate of the time required for
ited to six months rather than one year and no refills filling the prescription and, if possible, the anticipated
are permitted for Schedule II controlled substances. cost associated with the medication. Some pharma-
cists make it a practice to price prescriptions before
dispensing, especially in the case of an unusually
Processing the prescription order
expensive medication, to avoid potential conflict
The manner in which pharmacists process a prescrip- and allay patient concerns about the cost of their
tion order is important not only in fulfilling their medication.
professional responsibilities but also in enhancing
their relationships with the physician and the patient. Reading and checking the prescription
The pharmacist must be precise in all aspects from Once all appropriate patient information has been
receipt of the prescription order through care of added to the prescription order, the pharmacist must
the patient for the duration of the therapy, and first review the prescription completely and carefully.
often beyond. Proper procedures are given below There should be no doubt as to the ingredients,
for receiving, reading and checking, numbering and quantities prescribed, directions for the patient or
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Fundamentals of pharmacy practice | 397

appropriateness for this specific patient at this time. If or drug–disease interactions may exist. Most pre-
something is illegible or if it appears that an error has scription processing computer software programs
been made, the pharmacist should consult a colleague readily identify these possible interactions. In the
or the prescriber. A pharmacist should never guess at absence of computer software to screen for these
the meaning of an indistinct word or unrecognized interactions, many specialized print and on-line
abbreviation. Especially in the case of ISMP identi- references are available to assist pharmacists in
fied error-prone abbreviations, pharmacists must be clinical decision making. However, these software
especially vigilant and seek clarification from the pre- programs and references do not always identify
scriber whenever necessary to ensure patient safety. the relative significance of the interaction, and are
Another concern in the interpretation of the pre- generally incapable of determining the interaction’s
scription order is drugs with names that look alike magnitude for the specific patient. Only pharmacists,
or sound alike. These similar names are a potential using their best clinical judgment combined with
source for errors. Knowledge of the patient’s medical the right information solicited from the patient,
problems and diagnoses can often provide the phar- can ascertain if the interaction is insignificant in
macist with insight into which one of the look-alike or this patient, can be managed through consultation
sound-alike drugs is actually intended for the patient. and intervention with the patient (e.g., cautioning
In 2001, the FDA Branch Office of Generic Drugs a patient against taking the medication with dairy
requested manufacturers to ‘‘voluntarily revise the products or to avoid sun exposure during treatment),
appearance of established names’’ of certain drugs or requires contacting the prescriber when a true and
that had similar names. Drugs with similar names unavoidable contraindication exists.
started using TALL MAN lettering to highlight the In reviewing and interpreting all of these areas of
portion of the drug name that is different from the the prescription medication order, pharmacists must
other similar drug name. An example is the differ- take great care and use their broad knowledge of drug
entiation between NIFEdipine and NiCARdipine.86 products to prevent dispensing errors. In each situa-
Other examples of drugs with similar names are listed tion, the prescriber may be consulted by a confidential
in Table 10.13. telephone call, e-mail, or electronic instant message
The amount and frequency of a dose must be noted to clarify the prescriber’s intentions. These clarifica-
and checked carefully. The age, weight, and condition tions can also enhance the professional reputation of
of the patient (e.g., liver function and kidney func- the pharmacist as a careful practitioner and valuable
tion) as well as the dosage form prescribed must often member of the healthcare team. Prior to contact-
be considered in determining the safety of the dose ing the prescriber, pharmacists must be thoroughly
for a prescribed medication. Many printed references, prepared to clearly and concisely explain their con-
on-line references and embedded databases within the cerns, recommend alternative drug products or doses
software of prescription processing computer systems, (including available strengths and dosage forms), and
are available as resources for the pharmacist evaluat- have citations for the appropriate references used
ing the safety of a prescribed dose. In the case of a in assimilating these recommendations. This informa-
suspected error in the prescribed therapy, appropriate tion is necessary to assist the prescriber in determining
references should be checked thoroughly prior to con- the best therapeutic options for the patient. The same
sulting the prescriber. Omissions, such as the failure logic applies when a medication is prescribed for a
to specify the desired strength of a medication or its patient who has a known drug allergy or sensitivity
dosage form, must also be corrected prior to dispens- to the prescribed drug or other drugs of the same
ing. The pharmacist should never make assumptions chemical class and the prescriber must be contacted.
such as electing to dispense the ‘‘usual’’ dose or dosage
form but instead should consult the prescriber. Numbering and dating
From the pharmacy’s paper or electronic records, It is a legal requirement to number the prescription
the pharmacist determines the compatibility of order and to place the same number on the medi-
the newly prescribed medication with other drugs cation when dispensed to the patient. This serves to
being taken by the patient or if any drug–food identify the dispensed product and to connect it with
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398 | An Introduction to Pharmacy

Table 10.13 Examples of look-alike and/or sound-alike drug names

AcetaZOLAMIDE AcetoHEXAMIDE MS Contin OxyCONTIN

Actos Actonel Mucinex Mucomyst

Advair Advicor Neulasta Lunesta

ALPRAZolam LORazepam NexIUM NexAVAR

Ambisome Amphoterecin B OxyCODONE OxyCONTIN

Amicar Omacor Paregoric Opium Tincture

Amphotericin B Abelcet Plavix Paxil

Amphotericin B Ambisome PriLOSEC PROzac

Avandia Coumadin Retrovir Ritonavir

AVINza INVanz SEROquel Serzone

AVINza Evista SEROquel SINEquan

Cardura Coumadin Singulair SINEquan

CeleBREX CeleXA SitaGLIPtin SUMAtriptan

CeleBREX Cerebyx Solu-CORTEF Solu-MEDROL

CeleXA Cerebyx SulfADIAZINE sulfiSOXAZOLE

CloNIDine KlonoPIN SUMAtriptan Zolmitriptan

Cymbalta Symbyax TEGretol TRENtal

DAUNOrubicin DOXOrubicin TiaGABine TiZANidine

DAUNOrubicin IDArubicin Ticlid Tequin

Diabeta Zebeta TOLAZamide TOLBUTamide

Diflucan Diprivan Topamax Toprol XL

Diovan Zyban TraMADol TraZODone

Enbrel Levbid Tricor Tracleer

ePHEDrine EPINEPHrine Ultracet Duricef

folic acid folinic acid Viagra Allegra

heparin Hespan VinBLAStine VinCRIStine

(continued overleaf)
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Fundamentals of pharmacy practice | 399

Table 10.13 (continued)

HumaLOG HumuLIN Wellbutrin SR Wellbutrin XL

HumaLOG NovoLOG Xanax Zantac

HumuLIN NovoLIN Xenical Xeloda

HydrALAZINE HydrOXYzine Yaz Yasmin

HYDROcodone OxyCODONE Zantac Zyrtec

HYDROmorphone morphine Zestril Zetia

KlonoPIN CloNIDdine Zestril ZyPREXA

LamiVUDine LamoTRIgine Zocor ZyrTEC

Lantus Lente Zocor Cozaar

Lexapro Loxitane ZyPREXA CeleXA

Lipitor Loniten ZyPREXA ZyrTEC

Lipitor ZyrTEC Zyvox Vioxx

MetFORMIN MetroNIDAZOLE Zyvox Zovirax

(Data from Institute of Safe Medication Practices List of Confused Drug Names (http://www.ismp.org))

the original order for reference or when renewing require extemporaneous compounding by the phar-
the prescription. Consecutive numbers are assigned macist or other trained pharmacy personnel prior
by prescription processing computer software pack- to dispensing. The extemporaneous compounding of
ages but, in the absence of such automation, can be prescriptions is an activity for which pharmacists
numbered manually by use of numbering machines. are qualified uniquely by virtue of their education,
Indicating on the prescription the date filled is also training, and experience.
a legal requirement. This information is important in Pharmacists must exercise care to make certain
determining the appropriate refill frequency or patient that the product dispensed is of the prescribed dosage
compliance. This task is easily completed by utilizing form, strength, and number of dosage units. Unless
prescription processing software or manually writing a single unit is dispensed (e.g., an inhaler or a single
the date on the prescription blank. compliance package of tablets) solid, prefabricated
dosage forms generally are counted in the phar-
Preparing the prescription macy using a counting tray such as the one shown
After thoroughly reviewing the prescription order, the in Fig. 10.13. Such a device facilitates the rapid
pharmacist should decide on the exact procedure to be and sanitary counting and transferring of medication
followed in compounding, if necessary, and dispens- from the stock packages to the prescription con-
ing the prescription product. Most prescriptions can tainer while preventing touch contamination. Because
be prepared using prefabricated dosage forms pro- manipulating products across this tray can generate
cured from regulated pharmaceutical manufacturers. aerosolized or surface particles of the drug product
Some prescription medications, because the formula- which are left behind on the counting tray, measures
tion or dosage form is not commercially available, may be necessary to prevent cross-contamination
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400 | An Introduction to Pharmacy

(a) (c)

(b) (d)

Figure 10.13 Steps in the hygienic counting of solid dosage units with the Abbott Sanitary Counting Tray: (A) placing units
from the stock package onto the tray, (B) counting and transferring the units to the trough, (C) returning the excess units to the
stock container, and (D) transferring the counted units into the prescription container. (Courtesy of Dawn Pearson.)

between products, especially when counting uncoated or deterioration, and within the stated expiration
tablets. Wiping the counting tray between prod- date. The manufacturer’s product should undergo a
ucts and periodic cleaning will minimize the risk of ‘‘triple check’’ system against the prescription order
cross-contamination. Many high volume pharmacies by comparing them first, before preparation at the
use automated counting machines (e.g., Baker Cell, time of product selection; second, during product
Kirby-Lester, Drug-O-Matic, Auto-Script III). These preparation by checking both against the computer
systems allow for manual addition of medications or hand generated label; and a third time after the
to be counted, or on a larger scale, the medications preparation process is complete to make certain of
are stored within the counting machines and auto- its correctness. Computer software programs can be
matically counted and packaged, without pharmacist very useful in the quality control step by providing
intervention, through an interface between the count- actual photographs of the expected product or by
ing machine and the pharmacy’s prescription process- using bar-coding or radio frequency identification
ing software when the prescription is processed. technologies. Any technologies available to the
Of all the activities involved in prescription pharmacist should be utilized to the fullest and never
processing, product selection and preparation carries viewed as an impediment to prescription processing
a significant risk of error resulting in increased patient leading to the generation of ‘‘work-arounds’’ to
morbidity or mortality. For this reason, quality con- circumvent this quality control process.
trol in prescription processing activities is extremely The pharmacist should determine a beyond-use
important and deserves significant attention from date to the prescribed product prior to dispensing
the pharmacist. In preparing prescriptions using pre- which takes the method of prescription preparation
fabricated products, the pharmacist should carefully into consideration. This should not be confused with
inspect the manufacturer’s container to be assured the the expiration date of a medication which is ‘‘the time
original container is intact, free from contamination during which the article may be expected to meet the
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Fundamentals of pharmacy practice | 401

requirements of the pharmacopeial monograph pro- • Prescription bottles or ovals – Used for dispensing
vided it is kept under the prescribed conditions.’’87 liquids of low viscosity
It is also not to be confused with the expiration • Wide-mouth bottles – Used for bulk powders,
date of the prescription order which is typically, for large quantities of tablets or capsules, and vis-
non-controlled substances, the duration of therapy cous liquids that cannot be poured readily from
including refills, or one year, whichever comes first. the narrow-necked standard prescription bottles
The beyond-use date is intended to limit the patient’s • Dropper bottles – Used for dispensing ophthalmic,
use of the medication within an appropriate period nasal, otic, or oral liquids to be administered by
determined using the pharmacist’s professional judg- drop
ment and is based on all of the following: • Applicator bottles – Used for applying liquid med-
ication to a wound or skin surface
• The prescriber’s intent – as outlined on the pre-
• Ointment jars and collapsible tubes – Used to dis-
scription order. pense semisolid dosage forms, such as ointments
– The product expiration.
and creams
– For all commercially available products it is
• Sifter-top containers – Used for topical powders to
determined by the manufacturer, clearly printed
be applied by sprinkling
on the manufacturer’s label, and valid as long
as stated storage and handling procedures are
• Hinged-lid or slide boxes – Used for dispensing
suppositories and powders prepared in packets.
followed.
• For extemporaneously compounded products, it is
The vials, bottles, and jars are typically colorless
assigned by the pharmacist based on the expiration
or tinted and composed of glass or plastic. Tinted
date of individual ingredients and the available
containers, the most prevalent tint being amber,
stability information on the specific formulation.
provide the maximum protection of their contents
In the absence of such stability information, the
against photochemical deterioration. Additional outer
pharmacist can use the beyond-use dating guide-
wrappings or cartons also may be used to pro-
lines published in Chapter <795> of the United
tect light-sensitive pharmaceuticals packaged in non-
States Pharmacopeia.
tinted containers. Glass containers are generally used
• The type of packaging and anticipated storage con-
in situations where drug products are exceptionally
ditions for the dispensed product.
moisture sensitive or have the potential for chemical
• The expiration date of the prescription – total
or physical interaction with plastic. A variety of mate-
days of therapy up to one year for non-controlled
rials, polystyrene being the most common, are used to
substances.
manufacture plastic prescription containers to allow a
Packaging minimum reactivity while still providing appropriate
product protection. Polyethylene is typically added to
When dispensing a prescription, pharmacists may
plastics when the container requires flexibility such
select a container from among various shapes, sizes,
as when the medication is to be administered in a
colors, and composition. Selection is based primarily
on the dosage form, quantity of medication to be dis- dropwise manner (e.g., nose or eye drops and throat
pensed, and the intended method of administration. sprays) or more viscous liquids and semisolids (e.g.,
Containers must provide protection from ‘‘contami- lotions, medicated shampoos, or creams). Tinted plas-
nation by extraneous liquids, solids, or vapors; from tic containers are the most widely used because these
loss of the article; and from efflorescence, deliques- provide increased product protection and durability
cence, or evaporation under ordinary or customary with less weight. Examples of pharmacy containers
conditions of handling, shipment, storage, and distri- are shown in Fig. 10.14
butions, and is capable of tight re-closure.’’87 When determining the appropriate container
The containers generally used by pharmacies are: for a specific prescription product, the pharmacist,
although not an expert, is expected to be knowl-
• Round vials – Used primarily for solid dosage edgeable about the materials used for packaging
forms as capsules and tablets medications to make the best container selections for
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402 | An Introduction to Pharmacy

Figure 10.14 Examples of prescription containers used for packaging small numbers of solid dosage forms, such as tablets and
capsules; liquid preparations administered by drops or spray; liquid preparations; powders; and semisolid preparations, such as
ointments and creams. (Courtesy of Dawn Pearson.)

specific prescription products.88 The pharmaceutical printed medication information right on the prescrip-
manufacturer’s packaging can often provide insight as tion container to prevent inadvertent loss; and color
the manufacturer has already selected a container that coding which allows products for different patients in
will not adversely affect the composition or long-term the same household to be easily identified preventing
stability of their product. Similar types of containers mix-ups. See example in Fig. 10.14.
The closure on a prescription container is an
should be used by the pharmacist in dispensing the
essential component in protecting the product from
medication to the patient. Also, FDA regulations
contamination and loss. An additional consideration
require pharmaceutical manufacturers to include
for closures is that they be child-resistant. The high
in their prescription–product labeling the type of
number of accidental poisonings after ingestion of
container to be used by the pharmacist when dis-
medication and other household chemicals by children
pensing the prescription drug to preserve its identity, led to the passage of the Poison Prevention Packaging
strength, quality, and purity. For example, sublingual Act in 1970 which requires childproof closures for
nitroglycerin tablets are always dispensed in their both legend and OTC medications. The Consumer
original glass bottles to minimize exposure to air and Product Safety Commission has ruled that manufac-
moisture. If a drug product is intended to be dispensed turers must place prescription drugs in child-resistant
in the manufacturer’s original container, the regula- packages if the original package is intended to go
tion does not apply and this packaging information directly from the pharmacist to the patient. However,
will likely not be available to the pharmacist. manufacturers need not place drugs in safety pack-
The increased attention given to patient safety ini- aging if the drugs are intended to be repackaged by
tiatives has led to innovations in design and shape for pharmacists. Other exceptions to the requirement for
prescription packaging by some pharmacies. Some childproof closures include:
of these modifications include: shapes that provide
• Drugs that are used or dispensed in inpatient insti-
flat surfaces for labeling so that the label can be tutions, such as hospitals, nursing homes, and
read without turning the container; special surfaces extended-care facilities, unless they are intended
for highlighting the most important drug informa- for patients who are leaving the confines of the
tion items on the container; ability to store expanded institution
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Fundamentals of pharmacy practice | 403

• Specific prescription drugs which are highly dose, to give the patient visual cues for administra-
reactive to common plastic containers such tion to assure compliance with the prescribed regimen.
as nitroglycerin, medroxyprogesterone, and Examples of compliance packaging include oral con-
pancrealipase preparations traceptives and some antibiotics (i.e., dos-paks). In
• Specific prescription drugs where the importance some instances, single unit, unit dose or compliance
for direct and immediate access in an emergency packages are labeled and dispensed as received from
supersedes concerns over potential pediatric poi- the manufacturer (Fig. 10.15). These innovations can
soning such as nitroglycerin sublingual tablets or dramatically streamline the drug packaging and dis-
epinephrine syringes pensing process.
• Unique packaging designed to improve patient Medications may come from regulated pharma-
compliance such as oral contraceptives ceutical manufacturers in unit-dose form or may be
• Specific requests by the prescriber or patient to use repackaged in the pharmacy into unit-dose contain-
non-childproof closures on individual prescription ers. Regardless of where the drug product is unit-dose
orders. packaged, the FDA requires that each individual unit
be labeled with the drug name, strength, dosage form,
A patient may request non-child-resistant containers expiration date (revised from the manufacturer’s
for a single prescription or for all of the patient’s expiration date to reflect handling of the medication),
dispensed medications. If the patient is making the lot or control number, and the name of the busi-
request that all of their prescription medications are ness responsible for the packaging or distribution.
dispensed without child-resistant containers, the phar- Controlled substances must also be labeled with the
macist should have this request in writing and verify schedule designation such as C-II. The label may also
this blanket waiver with the patient periodically in contain national drug codes (NDC) or utilize bar
case circumstances have changed.89 coding technology. When the unit-dose packaging is
Other forms of medication packaging come under completed in the pharmacy, the pharmacist must give
the broader heading of unit-dose or single-unit enclo- adequate attention to the packaging materials used to
sures. Most often, unit-dose packaging places individ- ensure the medication will not be adversely affected
ual dosage forms, a single tablet or capsule, in its own by being in contact with the packaging materials and
sealed package. Less frequently, each sealed package that any necessary precautions such as protection
will contain a single dose which may consist of one from light, excess handling, or protection from high
or more units, such as when two tablets make up temperatures (when mechanical packaging machines
a single dose. This system was originally developed are used) are adequately considered. Sufficient
for inpatient prescription processing as it allowed for controls should exist within the pharmacy to prevent
simplified drug distribution and inventory control. product package labeling mix-ups such as only
This type of packaging is now sometimes seen in allowing one drug product to be repackaged at a time
the outpatient setting due to advantages for patient with cleaning, inspection, and use of independent
safety including being able to easily visualize the prod- double checks between products. Control logs should
uct, provide complete protections from environmental be kept to document medication repackaging. Some
hazards until administration (e.g., orally dissolving states also have regulations related to repackaging
tablets), prevent product manipulations which could of medications by the pharmacy and all applicable
compromise therapy when performed incorrectly (i.e.,
state laws should be consulted prior to initiating
cutting unscored tablets for a half a tablet dose),
repackaging processes.90,91
provide evidence of entry, and aid in compliance.
Common types of unit-dose packaging include the
strip package, the blister package, unit-dose cups and Labeling
modified disposable syringes for oral, as opposed to Each packaged drug product for dispensing must
injectable, use. Compliance packaging is typically blis- be appropriately labeled by the pharmacist with a
ter packaged medications on a card where the blisters prescription label. This label, different from the med-
are arranged, usually with instructions next to each ication label applied to manufactured products, is
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404 | An Introduction to Pharmacy

(a) (c)

(b) (d)

Figure 10.15 Examples of unit-dose packaging, including (A) for oral solid dosage forms, (B) for liquid dosage forms, (C) for
topical semisolid preparations, and (D) compliance packaging. (Courtesy of Dawn Pearson.)

primarily intended to provide the necessary informa- in appearance, the patient may conclude that the
tion for optimal patient compliance. There is also prescription medication itself was also prepared in a
information on the label related to the dispensing careless manner potentially damaging the relationship
pharmacy where the original prescription documen- between the pharmacist or pharmacy and the patient.
tation is stored. This label is typically generated by The content of the label is legislated at both
a computer using prescription processing software, the federal and state levels, but there is still sig-
but may be typewritten or handwritten, if neces- nificant diversity in labels depending on the phar-
sary. Figure 10.16 demonstrates a computer-prepared macy or software used. Organizations such as the
prescription, including the label, additional printed Institute of Medicine, the ISMP, the National Asso-
medication information, and receipt. ciation of Boards of Pharmacy (NABP) and the
Readability, both initially and for the lifespan United States Pharmacopeia have all recommended
of the dispensed therapy, is of primary importance. standardizing prescription labels to a more patient-
The quality of the computer printer, the font selected centered format for increased patient safety. Legisla-
(a minimum of 11-point sans serif such as ‘‘arial’’), tive efforts nationwide are under way to accomplish
the use of white space, highlighting, ink color and these changes and pharmacists must stay abreast
the type of paper or adhesive labels used by a of these changes. Examples of these recommended
pharmacy can have a major effect on the readability patient-centered standardized labels can be found in
of a prescription label. Prescription tape should be the NABP report on uniform prescription labeling
used to cover and protect a label if the ink used is requirements.92 The types of information typically on
prone to rubbing off or if use of the drug product prescription labels are:
itself (e.g., an oily ointment the patient will apply
using their hands) may decrease the readability of • Patient name – The patient’s legal name is
the label over time. A prescription should have an required. In the case of veterinary medications,
aesthetic and professional-appearing label. If the the last name of the owner and the animal species
label and the container are not neat and professional should be included.
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Fundamentals of pharmacy practice | 405

Figure 10.16 Example of a computer-prepared prescription record, label, patient receipt, and patient-counseling information.
(Courtesy of Dawn Pearson.)
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406 | An Introduction to Pharmacy

• Directions for use – A simplified, concise transla- such as the original manufacturer’s lot number
tion of the directions for use as indicated by the or expiration date. This information is generally
prescriber along with the medication’s indica- considered superfluous and only clutters the
tion (when provided by the prescriber) without prescription label and diverts patient attention
unfamiliar terms or medical jargon facilitates the from the critical information. The manufacturer’s
best patient outcomes. Directions should clearly information is better suited for prescription
separate the dose itself, or the number of dose documentation and not labeling.
units to be taken, from the frequency of doses. • Beyond use date – This is the date by which the
To assist patients with low literacy skills, doses medication should be used and should not be con-
should be described using numeric rather than fused with the expiration date of the drug product
alphabetic characters (e.g., ‘‘Take 2 tablets’’ rather or the prescription.
than ‘‘Take two tablets’’). Also, vague instruc- • Pharmacy name, address, and telephone number
tions such as ‘‘twice daily’’ should be replaced – Regardless of corporate names or the use of cen-
with more explicit terms (i.e., ‘‘in the morning and tral ‘‘filling’’ pharmacies, the information for the
again at bedtime’’) as appropriate. Following these dispensing pharmacy, which may include details
basic guidelines will translate a prescribed signa such as the store number, must be included on the
of ‘‘ii po bid’’ to ‘‘Take 2 tablets by mouth in the prescription label. Although current recommenda-
morning and 2 tablets in the evening’’ rather than tions suggest the pharmacy address may only serve
‘‘Take two tablets twice daily’’ which has been as a distraction on the prescription label, and is
misunderstood by even highly literate patients. unnecessary in the presence of the telephone num-
The challenge for pharmacists is when the pre- ber, it is currently a legal requirement.
scriber’s instructions will not fit on the prescription • Prescription number –This number is assigned by
label or are ambiguous such as ‘‘take as directed.’’ the pharmacy and correlates the dispensed product
In these cases, clear and unambiguous supple- to the original prescription records.
mental materials and verbal counseling must be • Date of dispensing –Because the ‘‘fill date’’ pro-
provided. A clear statement referring the patient vides a better indication of the timeframe for the
to these materials should be included on the pre- dispensed medication and can be useful in recon-
scription label. In certain circumstances, it may be ciling the product with pharmacy documentation,
necessary for the pharmacist to clarify ambiguous it is recommended for the prescription label to use
instructions with the prescriber, especially when, in the dispensing date instead of other dates such as
the judgment of the pharmacist, additional direc- the date the prescription was generated by the pre-
tions for the patient are imperative for appropriate scriber.
dosing and patient care. In these cases, the phar- • Quantity dispensed.
macist may add the clarified directions to those • Number of refills – Whole numbers should be used
indicated by the prescriber on the original prescrip- to indicate the number of refills remaining on the
tion (with documentation of how, when, and by original prescription order after the current dis-
whom the clarified directions were obtained) and pensing or ‘‘No refills’’ as appropriate. This field
subsequently, to the prescription label. on the prescription label should not be used to
• Drug name and strength – The drug name must manage partial fills.
accurately represent the specific product dispensed. • Prescriber name.
If the name differs from the prescribed name, such • Other items which may appear on the prescrip-
as when a generic drug is dispensed, a phrase tion label include bar code and radio frequency
indicating the substitution should be present (i.e., identifications for the use of technology to elimi-
‘‘generic for [prescribed name]’’). The dosage nate human error in dispensing, and the dispensing
form is typically included in this notation as well, pharmacist’s initials, although specific pharmacist
although it is not imperative. Some states require identification is typically part of the pharmacy’s
that the name of the manufacturer be included and prescription documentation and is not necessary
some pharmacies choose to include information on the label itself.
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Fundamentals of pharmacy practice | 407

• The label of any drug listed as a controlled sub- prescription medications to ensure that the patient is
stance in Schedules II, III, or IV of the Controlled apprised of proper use, benefits and risks, and signs
Substances Act must, when dispensed to a patient, of adverse reactions. Examples of PPIs are shown in
contain the following warning: ‘‘CAUTION: Fig. 10.18. For certain high risk medications, this
Federal law prohibits the transfer of this drug to printed information is not only responsible profes-
any person other than the patient for whom it was sional practice, but may be required by federal or
prescribed.’’ state law. Prescription processing computer software
typically interfaces with drug databases to provide
The current evidence-based recommendations
this supplemental information upon dispensing
related toward more patient-centered prescription
(Fig. 10.16). PPIs may be used by pharmacists to
labels and associated materials are intended to
reinforce individualized patient counseling efforts.
address problems associated with nonadherence and
Pharmacists may need to customize these materials to
patient misunderstanding of prescribed therapies.
These recommendations also include designating the fit the individualized patient needs or to assist patients
critical information on a prescription label and giving in understanding and applying the information to
it emphasis through highlighting, font selection, font their prescribed therapy. This is especially important
size and the use of increased white space in these when dealing with patients who have low health
areas. The prescription label items designated as literacy, impaired cognitive function, or take many
critical information include: patient name, directions different medications.
for use, drug name and strength, and beyond use date. Despite all the attention given to recommended
The pharmacist must also give special attention legislative changes related to the prescription label and
to the associated materials provided with the dis- associated materials, the NABP Report of the Task
pensed product to all patients (i.e., the auxiliary Force on Uniform Prescription Labeling Require-
labels and the printed medication information). Aux- ments points out that ‘‘The prescription label can-
iliary labels are used to emphasize important aspects not and should not replace critical pharmacist care
of the dispensed medication and provide cautionary responsibilities, such as appropriately identifying the
statements from the pharmacist including the medica- patient at the time of dispensing and providing patient
tion’s proper use, handling, storage, administration, counseling.’’93
and potential adverse effects. A ‘‘shake-well’’ label
is indicated for a prescription containing ingredients Rechecking
that may physically separate on standing (e.g., sus-
The importance of this step cannot be overempha-
pensions, lotions, and emulsions). The use of labels
sized. Every prescription should be rechecked and the
such as ‘‘For the Ear’’, ‘‘For the Eye’’, and ‘‘External
ingredients and amounts used verified by the phar-
Use’’ is recommended because of the added safety
macist. All details of the label should be rechecked
these offer, even when the primary directions indicate
their proper use. Other auxiliary labels may be used against the prescription order to verify directions,
to warn that the medication should not be swallowed, patient’s name, prescription number, date, and pre-
used internally or left within the reach of children. scriber’s name. The ISMP recommends dedicating an
Auxiliary labels are available in various colors to area of the pharmacy as a ‘‘sterile cockpit’’ in reference
give them special prominence but should complement to safety standards first implemented by the aviation
the prescription label. They should be placed in a industry highlighting, as with pilots, a pharmacist’s
conspicuous spot on the prescription container; the need for focused, uninterrupted attention. This cre-
number used should be minimized to avoid distract- ates a visual cue reminding pharmacy workers that
ing patients with nonessential information; and only the pharmacist should not be interrupted during the
evidence-based auxiliary information, both text and crucial rechecking process. If another worker needs
icons, should be utilized. Examples of some auxiliary the pharmacist, they should use a non-verbal method
labels in English and Spanish are shown in Fig. 10.17. of making their need known (e.g., placing a placard at
Printed medication information, or patient the station) and waiting patiently for the pharmacist’s
product information (PPI) is often provided with attention. Even errors that would not result in patient
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408 | An Introduction to Pharmacy

Figure 10.17 Examples of pharmacy auxiliary labels in English and Spanish. Actual labels available in color.

Figure 10.18 Example of manufacturers’ patient package inserts used to enhance patient understanding of the medication
prescribed. (Courtesy of Dawn Pearson.)

injury can still jeopardize the pharmacist–patient rela- Dispensing

tionship. Something as basic as an incorrect spelling Whenever possible, the pharmacist personally should
of a patient’s name on a prescription label might present the prescription medication to the patient
cause concern for the patient as to the accuracy of the (or family member, caregiver). Unfortunately, in too
prescribed medication. many organizations, this is not how the workflow
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Fundamentals of pharmacy practice | 409

processes are designed. The interaction between the the patient an opportunity to share vital information
pharmacist and patient each time the patient receives with the pharmacist that would not be available by
a prescription medication provides crucial measures any other means. The pharmacist must also use these
for increased patient safety and compliance. There is discussions to ensure that patients know how to mea-
heightened awareness that labeling instructions alone sure their prescribed dose and have any necessary
are inadequate to ensure patients’ understanding of devices (e.g., calibrated dosing cups or spoons for
their medication, including administration instruc- liquids as seen in Figs. 10.19 and 10.20).
tions, potential side-effects, monitoring parameters When the pharmacist is not able to personally
and general safe and effective use of their therapy. interact with the patient or caregiver (i.e., the phar-
Even if the patient has been on the prescription medi- macist is temporarily unavailable or the medication is
cation in the past, or for a period of time (i.e., when being delivered to the patient’s home), the pharmacist
a prescription order is being refilled), there is no cer- should make every attempt to personally interact with
tainty that the patient understands how to best use the patient in a different manner such as the telephone
their therapy or that there has not been a change in or e-mail.
the patient’s status that could affect their therapy. The patient or caregiver should always be reas-
Reinforcement of not only the labeled instructions sured that the pharmacist welcomes their questions
but also any additional printed medication informa- both at the time of dispensing and at any time during
tion (see Fig. 10.16 and Fig. 10.18) through verbal the therapy by making sure contact information is
communication between the pharmacist and patient is clear and readily accessible for the patient.
key. This should not be merely a listening exercise for
the patient, but should involve a dialogue between the
pharmacist and patient to ensure understanding of the Documenting prescription process
therapy. During this exchange, pharmacists have the A record of the prescriptions dispensed is maintained
opportunity to review the labeling information and in the pharmacy through the use of computer and hard
drug product itself for accuracy as they review it with copy prescription files. The use of computers in phar-
the patient. These discussions also frequently allow macy practice has significantly eased the burden on

Figure 10.19 Examples of medicinal spoons of various capacities, calibrated medicine droppers, an oral medication tube, and a
disposable medication cup. (Courtesy of Medi-Dose.)
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410 | An Introduction to Pharmacy

system is beneficial to the pharmacist and helps to

avoid misunderstandings from patients.
The charge applied to a prescription should cover
the costs of the ingredients, including the container
and label, the time of the involved pharmacy staff,
the cost of inventory maintenance and other opera-
tional costs of the department, as well as providing
a reasonable margin of profit on investment. Pricing
structures may be based on a ‘‘cost + % markup’’,
‘‘cost + set fee’’ or a combination of the two.
Another source of funding currently available to
pharmacies is fees for professional services that may or
may not be associated with dispensing activities. One
example is Medication Therapy Management Ser-
vices (MTM) where the pharmacist’s time and clinical
expertise related to management of chronic diseases
(i.e., asthma, diabetes, or hypertension) are billable.

Refilling and renewal

Instructions for refilling a prescription are provided by
the prescriber as part of the original prescription. For
non-controlled substances, most states limit the life
Figure 10.20 An oral liquid dispenser for the accurate of a single prescription to one year from the date the
delivery of small doses of liquid medication to infants. prescription was written. The logic behind such legis-
(Courtesy of Baxa.) lation is to prevent patients from using legend drugs,
which require the oversight of a licensed prescriber,
pharmacists to maintain and retrieve important infor- indefinitely without being under the care of their
mation related to prescription dispensing activities. physician. No prescription for a Schedule II controlled
Computers have the ability to store when, how often, substance may be refilled. Prescriptions for Schedule
by whom, quantities and the specific products used III or IV controlled substances may be refilled, if so
in processing prescription orders and quickly retrieve authorized. These prescriptions may not be filled or
that information to meet patient needs, respond to refilled more than 6 months after the date issued.
drug recalls, etc. Newer centralized computer systems When a prescription order has expired or the
used by many chain drug stores allow pharmacists prescribed number of refills has been exhausted,
from any workstation in the specific company’s sys- physicians and pharmacists must work together so
tem to access a patient’s records for a prescription that prescriptions are renewed in a frequency that
previously dispensed at another store, whether in is consistent with the directions for use. Pharmacists
another part of town or a totally different state. should check with the prescriber (in person, over
the telephone, utilizing e-prescribing software, etc.)
Pricing the prescription as is prudent and reasonable to be assured the pre-
For a pharmacy to be financially stable, the phar- scriber’s intent is being met and the patient’s therapy
macist must be an effective manager of the financial is uninterrupted. No prescription should be renewed
aspects of the operation. To maintain the types of indefinitely without the patient being reevaluated by
pharmaceutical services necessary for quality patient the prescriber to assure that the medication as origi-
care, the pharmacy must make a fair and equi- nally prescribed remains the medication of choice.
table profit. A pricing method should be established Renewals should be noted on the reverse side of
to ensure the profitable operation of the prescrip- the prescription order or in the prescription com-
tion department. A uniform and consistently applied puter with the date, the quantity dispensed if different
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Fundamentals of pharmacy practice | 411

from the original, number of additional refills if dif- date of last refill, number of refills remaining, and full
ferent from the original, and the name or initials of name of transferring pharmacist.
the pharmacist procuring the renewal. When verbal Additional rules are in place related to the transfer
authorization has been obtained from the prescriber, of controlled substances. Prescriptions for Schedules
it should be recorded as such. III, IV and V drugs may be transferred between phar-
The maintenance of accurate records of renewals macies for refill purposes. The transfer of original
is important for following federal and state laws and prescription information for a controlled substance
providing an accurate patient medication history. listed in Schedules III, IV or V for the purpose of refill
For a variety of reasons, patients will occasion- dispensing is permissible between differently owned
ally request that the balance or refills remaining on pharmacies on a one time basis only.
a prescription order for a non-controlled substance
be dispensed by another pharmacy. This transfer of Drug product safety reporting
a prescription order could be due to a change in programs
the patient’s insurance plan or a temporary or per-
manent change in the patient’s location. For safety Monitoring drug product quality and preventing harm
reasons, patients should be discouraged from ‘‘price to the public is an important function of the practicing
shopping’’ where they may have prescriptions at a pharmacist. The medications dispensed subsequent to
variety of pharmacies based on the price of individual prescription orders and those sold directly to patients
medications. (If the patient is determined to do this, from behind- or over-the-counter should meet high
each pharmacy should ensure they have a record of standards of manufacturing quality to assure safety
all medications and supplements the patient is taking and efficacy when used properly. Any encounter of
and not just the ones obtained from their pharmacy.) a significant medication problem related to serious
State pharmacy law will dictate the specifics related to adverse events, product quality problems, product
prescription order transfers, such as if a prescription use errors, therapeutic inequivalence/failure or a sus-
may be transferred across state lines or the number of picion of product counterfeits for any FDA-regulated
times a single prescription order can be transferred. drug, biologic, medical device, dietary supplement or
Chain pharmacies that have centralized computer sys- cosmetic should be reported to the FDA immediately
tems can access a patient’s prescription records from through the MedWatch Program.93 This reporting is
any of their pharmacies throughout the United States voluntary for consumers and healthcare professionals
and can easily transfer any remaining refills on the and is completed using Form FDA 3500 (Fig. 10.21)
by telephone (1-800-FDA-1088), fax (1-800-FDA-
original prescription order. When a prescription is
0178), US mail (using the postage-paid addressed
being transferred without benefit of a centralized
form), or electronically through the FDA’s website
computer system, it requires a phone call between
(http://www.fda.gov). The FDA 3500 may also be
licensed pharmacists at the patient’s request.
embedded in some pharmacy prescription processing
Appropriate documentation of the transfer, as
software packages which can assist in completion and
indicated in state pharmacy law, is necessary. The
distribution to the FDA. Reporting of these prob-
pharmacist transferring the prescription must void
lems is mandatory for investigators, manufacturers,
the balance on the original prescription and document
distributors, and medical facility personnel associated
the date of the transfer, the pharmacy and pharmacist with investigational new drugs in clinical trials. These
receiving the prescription, as well as the transferring events are reported using Form FDA 3500A. Death
pharmacist’s signature. If the original prescription of a patient also results in mandatory reporting to the
order is part of an electronic record keeping system, FDA or the medical product manufacturer by facilities
just the name of the transferring pharmacist will such as hospitals or nursing homes. Although the FDA
suffice in place of the actual signature. The transferred also requests reports on vaccines, veterinary medicines
copy should include the original prescription number, and suspected unlawful sale of medical products on
the name and address of the transferring pharmacy, the Internet, separate reporting mechanisms are in
original date of prescription, date of initial dispensing, place for these categories and the Form 3500 is not
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412 | An Introduction to Pharmacy

Figure 10.21 FDA MedWatch reporting form.

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Fundamentals of pharmacy practice | 413

used. If a patient or caregiver would like to initiate the FDA website, through e-mail updates, RSS news
a quality complaint, the FDA will accept complaints feeds to your computer or wireless device, or even
directly but encourages them to file their complaint via social networking tools such as Twitter so that
through a healthcare professional with access to their healthcare professionals can stay informed.
medical record in order to provide the most accurate
clinical information.
Regardless of the source or nature of the Providing a framework for ensuring
complaint, all the information collected during the medication use safety
reporting process is shared between the FDA and
the manufacturer for evaluation whether corrective Introduction
action, by either organization, is required. The person
The US healthcare system is paradoxical, offering at
filing the report is always given the option by the FDA
once the promise of state of the art care, and also
to remain anonymous in subsequent communication
the threat of injury, and even death, resulting from
with the product manufacturer or distributor.
flawed and sometimes dysfunctional performance. In
Complaints or concerns specifically related to
1998, the Institute of Medicine sponsored National
drug product quality may relate to any factor of qual- Roundtable on HealthCare quality, published a report
ity or effectiveness, including dosage form integrity, that called attention to an alarming problem:94
authenticity, stability, contamination, appearance,
odor, taste, color, device malfunction, packaging Serious and widespread quality problems
(or product mix-up), and labeling. Regardless of exist throughout American medicine. These
whether the problem occurred during manufacturing, problems . . . occur in small and large
shipping, storage or administration, the MedWatch communities alike, in all parts of the country,
program can still be utilized for reporting. and with approximately equal frequency in
The postmarketing surveillance of pharmaceuti- managed care and fee-for-service systems of
cals for adverse reactions is essential in establishing care. Very large numbers of Americans are
a complete safety profile for marketed drugs. Once harmed as a result.
marketed, the number and diversity of patients
This realization was brought sharply to public and
receiving a new drug is far greater than during
professional attention with the publication in Novem-
the controlled clinical trials. Thus, some adverse
ber 1999, of To Err is Human: Building a Safer Health
drug reactions (ADRs) or adverse drug experiences
System, the first report of the Institute of Medicine
(ADEs) and drug interactions that escape detection
(IOM) Committee on Quality. This benchmark report
during the clinical trials are only seen after the drug
reframed medical error as a chronic threat to public
product is marketed through routine surveillance
health and galvanized media attention to the issue.
by healthcare professionals or during postmarketing
Some startling findings included95 .
clinical studies. Serious reactions (including the
detection of rare but potentially lethal ADRs or drug • 98 000 Americans die annually as a result of pre-
interactions), observations of events not described in ventable medical errors
the package insert, and reactions to newly marketed • National costs (including lost income, lost house-
products are of particular importance. hold production, disability, and healthcare costs)
Regardless of the type or magnitude of the of preventable adverse events – medical errors
reported concern, MedWatch reports are taken very resulting in injury – are estimated between $17 and
seriously. Data collected have resulted in changes $29 billion, of which healthcare cost represents
to product labeling, warning letters to healthcare over half
professionals regarding safe conditions of use, • More Americans die of medication errors annually
requirements for further clinical or safety studies or, than from workplace injuries
in some instances, withdrawal of the product from • Even medication errors that do not result in
the market. Reports of safety alerts and other changes actual harm have a cost, calculated at as much as
as a result of MedWatch surveillance are available on $2 billion annually.
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414 | An Introduction to Pharmacy

Because these hospital-based studies do not even

Patient self-care
account for errors in other settings, where they may
occur with at least equal frequency, the figures offer
only a modest estimate of the real target of actual Microsystems of care delivery
errors. Err recommended a comprehensive approach
to improving patient safety, which would demand
Macro-organizations
a broad-based response. There was no magic bullet,
no single solution, and no single recommendation as
the answer. Preventing errors means designing the Social and public policy

healthcare system to build in safety at all levels.

Figure 10.22 Levels of quality-focus in healthcare. (Data
Err offered a similar conclusion relative to safety:
from Berwick DM. A user’s manual for the IOM’s ‘‘quality
flaws are unacceptable and common. The effective
chasm’’ report. Health Aff (Millwood) 2002; 213: 80.)
remedy is not to brow-beat the healthcare workforce
by asking them to try harder to give safe care, when microsystem level. This team of people, with
in fact, the courage, hard work, and commitment of their information system, client population of
healthcare workers are the only real means to stem patients, and a defined set of work processes,
the tide of errors latent in the healthcare system.95 represents where work or care happens. Care at
Unfortunately, workers rely on outmoded systems the microsystem level must be knowledge-based,
and poor workflow design that sets them up to fail, patient-centered, and systems-minded. The quality
despite efforts to the contrary. of a microsystem is its sustained ability to provide
One realizes that knowledge of best practice is not ever-improving levels of care: safe, effective,
applied systematically or rapidly; in fact, the diffusion patient-centered, timely, efficient, and equitable.
of innovation of best practice is frustratingly slow.
• Healthcare organizations (or macrosystems) –
An average of 17 years is required for new evidence- The quality of an organization lies in its ability
based knowledge to be incorporated into common
to support microsystems’ ability to sustain ever-
practice.96 The IOM committee set forth six Aims for
improving care levels. Through their culture, poli-
Improvement, establishing what should be attainable
cies, and the tools provided for work, healthcare
common goals: care should be safe, effective, timely,
organizations frame the capacity for microsystems
patient-centered, efficient, and equitable. Yet Chasm
to achieve care improvements. Organizations need
reports that, as it exists, the American healthcare
to develop more robust and persistent systems for
system is incapable of providing the public with the
identifying, diffusing, and adopting best practice.
quality it expects and deserves, offering only few of
Access to information and decision support
these basic aims consistently. Quality problems occur
systems must be available to create a supporting
typically, not because of failure of goodwill, knowl-
network of knowledge at the microsystem level.
edge, effort, or resources, but rather because of funda-
Because human assets are a fundamental differ-
mental shortcomings in the way care is organized.96
entiating factor, organizations need to invest in
If, as Err suggests, exhortation, blaming, and trying
recognition and development in the persistent
harder cannot get the necessary job done, what system
improvement of knowledge, skills, and compe-
redesign considerations must be considered?
tency within the workforce. Beyond individual
Chasm called for change at four levels (Fig. 10.22):
knowledge, skills, and competency, effective and
• Experience of patients and communities – The collaborative teams and teamwork will be essential
focus for improvement must shift from the health- to achieving improvement goals, as will coordina-
care system itself to being patient-centric, tying tion of care among services and departments and
quality issues more closely to patient’s values and across the continuum of care, particularly with
expectations, actual experiences, cost, and social respect to patients with chronic illnesses. Finally,
justice. organizations need to commit philosophically
• Microsystems of care – The small work units and in practice to a data-driven measurement and
that actually give care to patients represent the assessment of performance and outcomes.
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Fundamentals of pharmacy practice | 415

• Healthcare environment – Sweeping and difficult it has to set the standards for national healthcare
changes will be necessary in the external envi- quality.99 Specifically, the report indicates that
ronment, including capital and operating financ- clinical data reporting requirements, purchasing
ing, regulation, accreditation, litigation and tort strategies, standardized performance measures, and
reform, professional education, and social policy. quality reports should be developed to accelerate
Who would pay for telemedicine or e-mail care? the development of knowledge and tools that have
What will be the source of capital for much needed been demonstrated to improve quality. An additional
information technologies? A safety culture func- report, Patient Safety: Achieving a New Standard
tions on the basis of openness, transparency, and For Care, outlines the IOM recommendations for
trust, but without tort reform to ease pressures enhancing knowledge, developing tools, disseminat-
of litigation and in an environment of blame and ing results in order to build the necessary health data
shame, can that be a reality? The quality of the interchange and work plan to develop data standards
healthcare environment may determine how well applicable to the collection, coding, and classification
organizations and microsystems can achieve their of patient safety information.100
quality goals. The IOM also identified that to provide safe
and effective care, health professional education
Err and, to an even greater extent Chasm, reflect
requires a major overhaul to address changing health
a solid base in systems thinking. Solidly tying expe-
system expectations, evolving practice requirements,
riences of patients to the fundamental definitions of
new information and technologies, and staffing
quality, judgments of performance, delivery systems,
arrangements. The first report released by the IOM,
organizations, and policies and procedures can only
Health Professions Education: A Bridge to Quality
be made in the context of health status, satisfaction,
provides a mix of approaches necessary to improve
and reduction of morbidity and mortality. Improving
patient safety relies on an understanding of systems training environments, research, public reporting and
thinking, complex adaptive systems, and learning in leadership.101 The focus of this report identifies the
complex systems. need to integrate a core set of competencies – patient-
While Chasm has provided the framework for centered care, interdisciplinary teams, evidence-based
improvement, additional work by the IOM, through practice, quality improvement, and informatics – into
the Quality Chasm Series continues to build the health professions education. A second report,
body of evidence, understanding, and necessary addressed nursing workforce issues, Keeping Patients
action steps to keep patients safe. In January 2003, Safe: Transforming the Work Environment of Nurses,
the IOM released the report entitled Priority Areas identifies necessary safeguards for safe and effective
for National Action Transforming Health Care care.102 While specifically focused on an evaluation
Quality that clearly identified 20 priority areas of nursing practices, resources, and environment,
that collectively address preventive measures, care the report highlights changes that could impact all
coordination, patient self-management, and health care professionals and patient safety efforts: effective
literacy issues that cross acute, chronic, and palliative leadership, adequate staffing, organizational support
care domains.97 A subsequent report, Fostering Rapid for ongoing learning, interdisciplinary collaboration,
Advances in Health Care: Learning from System appropriate work design, and organizational support
Demonstrations identified the need for primary through governance and culture that supports safety
care redesign, improved information and technology as a priority.
infrastructures, insurance coverage changes, and The IOM published a report in 2006, titled Pre-
malpractice reform strategies necessary to make care venting Medication Errors,105 which expanded upon
patient-centered and safety focused.98 their earlier reports. This book set an agenda for
In Leadership by Example: Coordinating Gov- improving the safety of medication use, by providing
ernment Roles in Improving Health Care Quality, an overview of the system for drug development, reg-
the IOM goes further to recommend a multi-pronged ulation, distribution, and use. Preventing Medication
approach to care improvement by suggesting that the Errors also examined the peer-reviewed literature on
federal government take advantage of the influence the incidence and the cost of medication errors and
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416 | An Introduction to Pharmacy

the effectiveness of error prevention strategies. The • Gather and use evidence to define the path and to
report provided action agendas, detailing the mea- persuade others to follow it.
sures needed to improve the safety of medication use • Realize that if you build it, they may not come.
in both the short- and long-term. Patients, primary People always do want what makes sense to them
healthcare providers, healthcare organizations, pur- in their own context, in their own time. The con-
chasers of group healthcare, legislators, and those text cannot be overlooked because it is believed
affiliated with providing medications and medication- that content is impressive and persuasive. Allow
related products and services will benefit from this some time for sense-making and learning to occur,
guide to reducing medication errors.103 but remember to front-end-load the learning with
The IOM and other groups continue to build vision, direction, and feedback.
the body of evidence necessary to identify strate- • Wanting to do the right thing is not the problem.
gies for sustainable and effective care improvement. The aggregated consequences of how things are
What has been identified to date? There are clear done creates the outcomes, morbidity, mortality,
conditions and priorities for care improvement action and cost experienced. Redesign will be essential.
that require attention. A need exists for leadership to Make it easy to do the right thing, not harder. Sim-
be passionate and engaged for safety improvement to plification is a key.
occur. Comprehensive strategies must be implemented • Engage the culture. Do not wait for it to change.
to develop the workforce to provide the sustainable Miracles happen when knowledge and context are
change needed to improve care delivery. The findings shared through feedback. Build on best knowl-
in the Quality Chasm Series to date highlight the edge to engage the culture, with the realization that
breath and diversity of issues that must be addressed culture changes when knowledge shifts occur.
to improve local as well as natural healthcare quality. • Knowledge is sticky. Without a systematic process,
enablers, and system supports, it doesn’t move eas-
Conclusion ily. Posters, senior leaders’ speeches, newsletters,
and slogans typically do not cause knowledge to
The IOM reports titled To Err is Human,97 Cross-
blow. Use data, make personal connections, and
ing the Quality Chasm98 and Preventing Medication
use champions to move knowledge to influence
Errors105 paint a vivid landscape of the crisis in the
culture to create change.
American healthcare system and offer recommenda-
tions to point to a path for change. Mindful that • Think about absorptive capacity. What issues
might compete or conflict with the priority of the
the Chinese word for crisis contains two elements,
safety issue? Consider timing and how full individ-
danger and opportunity, we are reminded that that
the edge of chaos is where change occurs and where ual plates are, and craft a compelling message to
systems unfreeze and reform with renewed capacity engage people in the process.
to respond to environmental forces and to adapt. • Consider ways to increase the dialog about
The path to safer medication use and improve- safety. Communities of practice and successful
ments in patient safety is not about a destination. microsystems are powerful tribes. When they
This is a journey that must involve iterative work, knowledge flows, and best practices can be
learning. There are no absolute solutions, no mystical replicated. Dialog is the key to effective informa-
pronouncements that will tell the profession of tion flow and to uncovering tacit knowledge that
pharmacy what to do to fix the system. The problems holds keys to success strategies.
it faces will not be solved by the level of thinking that
created them. The profession is forced to consider Clearly, a new approach is needed within health-
new approaches, and new knowledge and to consider care organizations to improve the safety of medication
ways of thinking, acting, and being that are outside use. Building the required safer medication use sys-
our traditional approaches. tem will mean redesigning processes of care to ensure
Some hard lessons learned from other transfor- patients are safe from accidental injury. A number of
mational change initiatives in healthcare and other practices have been shown to reduce error in the med-
industries provide insight and wisdom for the journey: ication process and are recommended to be in place
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Fundamentals of pharmacy practice | 417

in healthcare settings. Recommendations for build- system, exposing them to life-threatening infections.
ing a safer medication use system include redesigning The negative and undesirable effects of drug therapy
processes that govern medication use, involving all are adverse drug reactions (ADRs).
members of the medication use team, and creating All medical products, whether drugs, biologicals,
a new culture that identifies medication safety as a diagnostic agents (e.g., radiocontrast dye), natural
priority for the organization. products, or nutritional agents can cause adverse
Ultimately, the judge of the quality of work, the reactions. These reactions may be caused by: the drug
services delivered, and the outcomes of care is an itself or one of its metabolites; interaction between
increasingly well-informed patient, as well as payors two or more drugs or between a drug and food; an
and regulators from the public and private sectors. excipient in the product, such as a dye or preservative.
Focus on patients’ needs and wants and less on ‘‘how Some reactions occur with most or all drugs in the
we do it around here.’’ class (a drug class is made up of medications with
identical or very similar mechanisms of action; for
example, penicillin antibiotics, beta-adrenergic block-
Adverse drug reactions ing agents, tricyclic antidepressants, etc.). An example
of a so called ‘‘class effect’’ is cough from angiotensin
Introduction converting enzyme (ACE) inhibitors. Other reactions
are unique to the drug. Among antibiotics, chloram-
Drug availability and use have risen steadily for
phenicol causes aplastic anemia, a reaction rarely seen
the past several decades. In 1961, only 656 drugs
with other antimicrobials. Some drugs can affect mul-
(prescription and over-the-counter (OTC)) were mar-
tiple organ systems; for example, amiodarone may
keted in the United States. By 1989 this number had
cause pulmonary fibrosis, dermatological reactions,
increased to 8000 and by 2011 well over 11 000
hyper- or hypothyroidism, ophthalmologic changes
drugs were marketed in the United States.104,105 The
and arrhythmias. Adverse effects from other drugs
United States drives drug development, with almost
can be highly specific; for example, toxicity from
45% of the world’s new medicines originating in
aminoglycoside antibiotics is limited primarily to the
the United States.106 Since 2000, an average of 24
kidney and vestibular/cochlear systems. And while
new molecular entities or biological license appli-
drugs and biologicals marketed in the United States
cations (i.e., new products marketed for the first
are required to be proven safe and effective, safe does
time) have been approved each year in the United
not mean risk-free. Thus, the decision to use any
States.107 Physician office visits result in over 2.3
medicinal product is always the result of examining
billion prescriptions or drug samples supplied annu-
its risk to benefit ratio.
ally, and although the US population grew by 9%
between 1999 and 2009, the number of prescrip-
tions increased by 39%.108,109 In 2009, prescription Defining an adverse drug reaction
drug sales topped $300 billion, nearly eight times the Although there are many definitions of an
amount spent in 1990.109,110 This is in addition to ADR,111 – 113 an internationally accepted description
OTC medicines, dietary supplements, and ‘‘natural’’ is that of the World Health Organization (WHO):
or alternative products consumers commonly use. ‘‘A response to a drug that is noxious and unintended,
Medications unquestionably have provided and that occurs at doses normally used in humans
tremendous benefits to society. Whether preventing for the prophylaxis, diagnosis, or therapy of disease
childhood illness through vaccination, treating or or for the modification of physiological function.’’114
preventing infections with antimicrobials, or forcing Notably, this definition tacitly excludes the failure of
cancer into remission with antineoplastic agents, the a drug to have its intended effect (i.e., a therapeutic
benefits of modern drug therapy are immense. How- failure), and situations of drug abuse, drug overdose
ever, such therapy is not without risk. Encephalitis or poisonings.
has been associated with vaccines; allergic reactions It is important to distinguish an ADR from an
to antimicrobials are well documented; and antineo- adverse drug event (ADE). While the two terms
plastic agents can severely impair a patient’s immune have been used interchangeably, the differences
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418 | An Introduction to Pharmacy

are important. An ADE is an injury resulting from improvements including active surveillance and risk
taking a drug.115 ADEs encompass all steps that can mitigation strategies have been implemented to make
go wrong with drug therapy including preventable drug use safer.
mistakes in prescribing, administering, dispensing,
monitoring, and documenting (that is, medication
errors), and non-preventable ADRs. That is, an ADR
Drug interactions
is the result of the intrinsic properties of the drug and
cannot be prevented.
Introduction
Tremendous attention has been paid to adverse Although some drug-related problems develop unex-
medical events and medical errors, which include pectedly and cannot be predicted, many are related to
ADEs, largely as a result of the Institute of Medicine known properties and actions of the drugs and can
publication To Err is Human: Building a Safer Health reasonably be anticipated. However, as drug therapy
System.116 This report reviewed and summarized the becomes more complex and because many patients
literature on medical errors in the US healthcare sys- are being treated with two or more drugs, the ability
tem and concluded that between 44 000 and 98 000 to predict the magnitude of a specific action of any
deaths occur annually as a result of preventable med- given drug diminishes. These circumstances point to
ical mistakes. Drug-related errors account for an a need not only for maintenance of complete and
estimated 7000 of these deaths. current medication records for patients but also for
As progress is made toward better assessment and closer monitoring and supervision of drug therapy so
management of drug risk, the line between ADRs and problems can be prevented or detected at an early
ADEs blurs. While much of the research in recent stage in their development. The pharmacist is in a
years has been on identifying risk factors for ADEs unique position to meet these needs, and opportuni-
and ADE prevention, much of what is learned can ties exist for greater involvement in the provision of
apply to ADRs as well. Indeed, comprehensive man- drug therapy that is both efficacious and safe.
agement of drug risk requires that ADRs and ADEs Many drug-related problems are caused by drug
be considered equally. To this end, FDA has iden- interactions. As a basis for this discussion, a drug
tified four sources of risk from medical products: interaction may be considered a situation in which
known side-effects (both avoidable and unavoidable), the effects of one drug are altered by prior or concur-
medication errors, product defects, and ‘‘remain- rent administration of another drug (i.e., drug–drug
ing uncertainties,’’ which include side-effects not yet interactions). The concept of drug interaction often is
known or reported, long-term effects, and unstudied extended to include situations in which
uses and unstudied populations.117
1. Food or certain dietary items influence the activity
Summary of a drug (i.e., drug–food interactions), or
2. Herbs or other natural products influence the
Medication use continues to increase in the United activity of a drug, or
States and, while offering tremendous benefits, it does 3. Environmental chemicals or smoking influence the
so with the potential for patient harm. ADRs are activity of a drug, or
a significant cause of morbidity and mortality and 4. A drug causes alterations of laboratory test results
have a significant financial, emotional, and societal (i.e., drug–laboratory test interactions), or
impact. There are numerous risk factors for develop- 5. A drug causes undesired effects in patients with
ing ADRs; the role genetics plays in drug response is certain disease states (i.e., drug–disease interac-
being increasingly recognized and is having an impact tions).
on drug development, testing, dosing, and prescribing.
Postmarketing safety monitoring of drugs is essential, Considerable attention has been focused on the
as not all reactions a drug may cause are known subject of drug interaction, and information per-
at the time of its approval. Although the passive taining to these occurrences has been widely publi-
postmarketing surveillance system in place for sev- cized. Several comprehensive references, such as Drug
eral decades has functioned as intended, significant Interaction Facts,118 Drug Interactions Analysis and
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Fundamentals of pharmacy practice | 419

Management119 , and Pocket Guide to Evaluation of pharmacokinetics, opposing or additive pharma-

Drug Interactions120 deal exclusively with this sub- cologic effects, multiple prescribers; the addition
ject. Computerized references such as Micromedex® of OTC medications, or even drugs of abuse, may
and Lexi-Comp™ also provide drug interaction infor- cause adverse drug reactions because of a drug–drug
mation and are widely used. interaction. Since there are many avenues of entry for
One of the most important consequences of a drug a drug interaction to occur, pharmacists can play a
interaction is an excessive response to one or more proactive role in identifying an otherwise unidentified
of the agents being used. For example, a significantly potential for interactions.
enhanced effect of agents like digoxin and warfarin
can result in serious adverse events. Not as well recog- Pharmacokinetic alterations
nized, but also very important, are those interactions Situations that interfere with the absorption, distri-
in which drug activity is decreased, resulting in a loss bution, metabolism, or excretion of drugs have the
of efficacy. These interactions are especially difficult potential to significantly alter the pharmacokinetic
to detect since they may be mistaken for therapeutic profile and result in drug interactions. Such inter-
failure or progression of the disease. actions have the potential to reduce the efficacy or
Despite the fact that some drug interactions are increase the risk of toxicities of affected agents.
well documented and recognized, the drugs are still
given concomitantly, resulting in adverse outcomes. Multiple pharmacological effects
Digoxin and a diuretic often are given concurrently, Most drugs used in current therapy have the capa-
and rationally so, in treating patients with congestive city to influence many physiological systems. There-
heart failure. It is well known that most diuretics can fore, two drugs concomitantly administered will often
cause potassium depletion that, if uncorrected, could affect some of the same systems. When considering the
become excessive and lead to an increased action of potential for interactions between drugs, there often
digoxin and adverse events. Yet problems continue to is a tendency only to be concerned with the primary
occur as a result of this interaction. effects of the drugs involved and to overlook the sec-
Even with the extensive publicity that drug ondary activities they possess. Combined therapy with
interactions have received, it is still often difficult a phenothiazine antipsychotic (e.g., chlorpromazine),
to determine their incidence or clinical significance. a tricyclic antidepressant (e.g., amitriptyline), and an
However, numerous studies have demonstrated that antiparkinson agent (e.g., trihexyphenidyl) is initiated
many patients receive multiple drug therapy with in some patients. Each of these agents has a consid-
agents of recognized potential for interaction. As the erably different primary effect; however, all three
number of drugs in a patient’s therapeutic regimen possess anticholinergic activity. Even though the anti-
increases, the greater becomes the risk of occurrence cholinergic effect of any one of the drugs may be
of a drug interaction. Although there are only limited slight, the additive effects of the three agents may be
data regarding many of the potential drug interactions significant.
that have been suggested, considerable progress has
been made in defining the level of risk associated with Multiple prescribers
the use of a number of combinations of drugs. Indeed, It is necessary for some individuals to see more than
the risk of serious interactions involving the use of one physician, and it is very common for a patient
astemizole, cisapride, mibefradil, and terfenadine to be seeing one or more specialists in addition to
was sufficiently important for these drugs to be a family physician. Some individuals also are seeing
withdrawn from the market in the United States. other health professionals (e.g., dentists, podiatrists)
who may prescribe medication. It is difficult for
one prescriber to be aware of all the medications
Factors contributing to the occurrence of
that have been prescribed by others for a particular
drug interactions
patient, and complications could arise from such sit-
A number of factors contribute to the occurrence uations. For example, one physician may prescribe
of drug interactions, ranging from alterations in a medication capable of causing tiredness/sleepiness
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420 | An Introduction to Pharmacy

(e.g., certain antihistamines, opioid analgesics) for a making identification of potential problems extremely
patient for whom another physician has prescribed difficult for the pharmacist as well as the physician.
an antianxiety agent, with the possible consequence For this reason, patients should be encouraged to
of an excessive depressant effect. obtain both their prescription and nonprescription
Even though the patient is seeing different physi- medications at a pharmacy. Such advice is justified,
cians, he or she often will have the prescriptions however, only when the pharmacist personally super-
dispensed by the same pharmacy. Therefore, the phar- vises the sale of nonprescription medications while
macist has an important role in the detection and simultaneously reviewing the patient’s complete med-
prevention of drug-related problems. ication profile.
The precautions observed with respect to poten-
Use of nonprescription products tial interactions involving products that are typically
Many reports of drug interactions have involved the designated as nonprescription drugs also apply to the
concurrent use of a prescription drug with a nonpre- use of herbal products, dietary supplements, and other
scription drug (e.g., aspirin, antacids, decongestants) related products that are available without a prescrip-
or herbal (St John’s wort) or other natural product. tion. Although much is still to be learned about the
When a physician asks patients about medications properties of these products, many have a potential to
that they are taking, the patients often will neglect interact with prescription medications, and patients
to mention the nonprescription products they use. should be asked whether they are using such products.
Many patients have been taking preparations such as
antacids, analgesics, laxatives, dietary supplements, Patient noncompliance
and herbal products for such long periods and in For a variety of reasons, many patients do not take
such a routine manner that they do not consider them medication in the manner intended by the prescriber.
to be drugs or to be important with respect to the Some have not received adequate instruction from the
effectiveness and safety of medications. Patients also prescriber and pharmacist as to how and when to
may think that since a drug is nonprescription, it is take their medication. In other situations, particularly
safe, and thus, the importance placed on mentioning involving patients who are taking several medica-
it diminishes. This information often may be missed tions, confusion about the instructions may develop
when interviewing a patient, and some physicians and even though the patient may have understood them
pharmacists prefer to use a list of symptoms that might initially. It is understandable that older patients who
ordinarily be treated with nonprescription products may be taking five or six medications several times a
in trying to obtain this information from the patient. day at different times can become confused or forget
Interactions also may result from the concurrent to take their medication, although these occurrences
use of two or more products available without a are by no means unique to the geriatric population.
prescription. In some situations two nonprescription Although the situations involving noncompliance
products promoted for different purposes contain the usually would result in a patient not taking enough
same active ingredient(s), increasing the risk of an medication, some circumstances could lead to
excessive response to these agents. Acetaminophen is excessive use of certain medications, thereby increas-
included in many products for its antipyretic and anal- ing the possibility of drug interaction. For example,
gesic actions and is included in many nonprescription some patients, if they realize they have forgotten a
sleep-aid formulations. Patients often are unaware dose of medication, double the next dose to make up
that products they purchase for different conditions for it. Some other patients may act on an assumption
may contain the same active ingredients and that they, that if the one-tablet dose that has been prescribed
therefore, are at increased risk of problems with the provides partial but not complete relief of symptoms,
use of products they might assume to be safe because a two-tablet dose will be even more effective.
they do not require a prescription.
Although many individuals will have their pre- Drug abuse
scriptions dispensed in their local pharmacy, they The tendencies of some individuals to abuse or delib-
often purchase nonprescription drugs elsewhere, thus erately misuse drugs also may lead to an increased
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Fundamentals of pharmacy practice | 421

incidence of drug interactions. The antianxiety 5. Practicing physicians tend to doubt their observa-
agents, opioid analgesics, and amphetamines are tions concerning drug interactions unless the same
among the agents most often abused, and the inap- interaction has been reported previously.
propriate use of these drugs can result in a number of Although physicians are now well aware of
problems, including an increased potential for drug the occurrence of drug interactions, there are
interaction. situations in which a drug interaction may be
Many interactions that occur are undetected or occurring, but there are other factors that also
unreported. Koch-Weser observed that detection of could contribute to the altered response noted.
drug interactions by clinicians is inefficient and cited Therefore, physicians often accept a reasonable
six reasons for the existence of this situation.121 explanation, albeit incomplete, based on infor-
Although initially noted in 1972, many of these obser- mation with which they are familiar, rather than
vations are just as valid today. suspect a possibility that has not been reported
previously. Although many interactions that have
1. In most cases the clinical situation is too complex been reported via case reports have not been con-
to allow recognition of an unexpected event in firmed by other observations or additional study,
a patient’s course as related to his or her drug many single-case reports have served as the stimu-
therapy. lus for additional study that has resulted in warn-
2. With few exceptions, the intensity of action of ings about potentially dangerous interactions.
drugs in the therapeutic setting cannot be quanti- 6. Physicians frequently fail to report drug inter-
tated accurately. actions even when they have unequivocally
One reason for the many reports of interactions recognized them. Several factors, no doubt,
involving anticoagulants, antidiabetic agents, and contribute to this situation. The time it would take
antihypertensive agents is that there are specific to write up a case report to submit to a journal is
parameters, such as prothrombin time, blood glu- a deterrent to many physicians and pharmacists.
cose concentrations, and blood pressure that can Also, since drug interactions often represent an
be measured and can provide a quantitative indi- undesirable experience for the patient, health pro-
cation of drug activity. Therefore, any change fessionals often are reluctant to expose themselves
in these values that may be caused by introduc- to possible criticism, or even liability, regarding
ing another drug into therapy can be measured the therapy. However, it is important that health
with relative ease. In contrast, when one consid- professionals communicate information that will
ers drugs like the antipsychotic agents and anal- be useful to others or will help others to avoid the
gesics with which it is far more difficult to measure same problems.
degree of activity, it becomes increasingly difficult
to observe and measure the effect of other drugs
on their activity.
Reducing the risk of drug
3. Even when a deficient, excessive, or abnormal
interaction
response to one or both drugs is recognized
clearly during concomitant administration, it Although other mechanisms may be involved in the
is attributed usually to factors other than drug development of drug interactions, the ones cited are
interaction. the most important. As often stated, more than one
When an unexpected response to a drug develops, mechanism may be responsible for certain interac-
it often is attributed to something other than a tions; these mechanisms may work in concert or in
drug interaction, such as patient idiosyncrasy in opposition as determinants of the resulting effect. Still
the case of an excessive response, or tolerance in other drug interactions develop by mechanisms yet to
the case of a deficient response. be identified. However, an awareness of the factors
4. The index of suspicion of most clinicians con- predisposing to the development of drug interactions,
cerning drug interactions is quite low, and many as well as the mechanisms by which many of them
practicing physicians are hardly aware of the occur, will be of value in the identification and pre-
phenomenon. vention of potential problems.
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422 | An Introduction to Pharmacy

It is evident that significant limitations still exist in medications or dosage regimens that permit
trying to predict the results of combination therapy. less frequent administration may help avoid
In the following section, guidelines are provided to interactions that result from an alteration of
reduce the risk of the occurrence of drug interactions. absorption (e.g., when a drug is administered in
The reduction of the risk of drug interactions is a close proximity to meals).
challenge that embraces a number of considerations. • Educate the patient – Patients often know little
Although they could be applied to drug therapy in about their illnesses, let alone the benefits and
general, the following guidelines to reduce and man- problems that could result from drug therapy.
age drug interactions are offered to assist healthcare Individuals who are aware of, and understand,
professionals who have the responsibility of selecting this information can be expected to be in greater
and monitoring therapeutic regimens: compliance with the instructions for administering
medications and more attentive to the development
• Identify the patient risk factors – Factors such of symptoms that could be early indicators of drug-
as age, the nature of the patient’s medical prob- related problems. Patients should be encouraged to
lems (e.g., impaired renal function), dietary habits, ask questions about their therapy and to report any
smoking, and problems like alcoholism will influ- excessive or unexpected responses. There should
ence the effect of certain drugs and should be con- be no uncertainty on the part of patients as to how
sidered during the initial patient interview. to use their medications in the most effective and
• Take a thorough drug history – An accurate and safest way.
complete record of the prescription and nonpre- • Monitor therapy – The risk of drug-related prob-
scription medications a patient is taking, as well lems warrants close monitoring, not only for the
as products such as herbal products and dietary possible occurrence of drug interactions but also
supplements, must be obtained. Numerous inter- for adverse events occurring with individual agents
actions have resulted from a lack of awareness of and noncompliance. Any change in patient behav-
prescription products prescribed by another physi- ior should be suspected as being drug-related until
cian or nonprescription medications the patient that possibility is excluded.
did not consider important enough to mention. • Individualize therapy – Although the development
• Be knowledgeable about the actions of the drugs of a therapeutic regimen that meets the specific
being used – The knowledge of the properties needs of individual patients is inherent in many
and the primary and secondary pharmacological of the above guidelines, the importance of indi-
actions of each of the agents used or being consid- vidualization of therapy cannot be emphasized
ered for use is essential if the interaction potential too strongly. Wide variations in the response of
is to be assessed accurately. patients to the same dose of certain individual
• Consider therapeutic alternatives – In most cases, drugs are well recognized. It is difficult to predict
two drugs that are known to interact can be admin- the response of many therapeutic agents when they
istered concurrently as long as adequate precau- are given alone; the challenge and limitations in
tions are taken (e.g., closer monitoring of ther- anticipating the response with a multiple-drug reg-
apy or dosage adjustments to compensate for the imen are even greater. Therefore, priority should
altered response). However, in those situations in be assigned to the needs and clinical response of the
which another agent with similar therapeutic prop- individual patient rather than to the usual dosage
erties and a lesser risk of interacting is available, it recommendations and standard treatment and
should be used. monitoring guidelines.
• Avoid complex therapeutic regimens when
possible – The number of medications used should The pharmacist will be involved actively in the
be kept to a minimum. Therapeutic duplications observance of the guidelines described above. In addi-
in which agents are given that have overlapping tion, the need to not only maintain complete and
pharmacologic actions should be avoided unless current patient medication records but also to super-
clinically necessary. In addition, the use of vise and monitor drug therapy more closely places
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Fundamentals of pharmacy practice | 423

the pharmacist in a strategic position to detect and Undoubtedly, the most important role played
prevent drug interactions. By observing the preceding by a pharmacist is in the area of prevention.
guidelines and recommendations and by strengthen- This role, relative to poison-prevention packaging
ing communication with patients and other healthcare of prescription drugs, was mentioned previously.
professionals, the pharmacist has a valuable oppor- However, the role of the pharmacist is particularly
tunity to make a significant contribution toward the critical with regard to nonprescription or OTC items.
further enhancement of the efficacy and safety of drug With prescription medications there is involvement
therapy. of a physician who may provide instructions and
precautionary advice. However, with OTC products,
the pharmacist is often the only person who is in a
Poison control position to serve these functions.
The pharmacist can and should provide, explain,
It is estimated that there are between five and ten and amplify directions for proper use of potentially
million poison exposures annually in the United toxic materials, bearing in mind that the concern
States. Accidents cause more deaths in children over is for the safety of the patient and that of other
one year of age more often than the five leading household individuals. Thus, the dispensing of a toxic
fatal diseases combined. Also, suicide is among the medication provides an opportunity to warn the buyer
most common causes of death in preadolescents, about the hazards of leaving the material within reach
adolescents, and adults. Often these accidents and of unsuspecting children.
suicides involve poisons. Another important cause of In some instances, it is desirable to affix warning
morbidity and mortality is the intentional use of illicit labels on the products that a pharmacist dispenses
drugs and also various chemicals, especially among or to hand out patient information materials. The
the young. Even though the reporting undoubtedly dispensing of a drug also provides an opportunity
is incomplete, there are known to be more than to inquire and give advice about facilities for safe
40 000 deaths annually in the US attributable to storage. Because of this contact, the pharmacist can
poisoning.122 The majority of these are intentional play a personalized role in cautioning about prescrip-
self poisonings. In addition to the fatalities caused by tion and commercial products. The pharmacist can
poisoning, there are staggering numbers of nonfatal do much to reduce the aforementioned limitations of
cases requiring medical treatment. labeling. Although the public often may not read or
In most instances, unintentional poisonings are appreciate precautions on labels, the effectiveness of
preventable. This is especially true of unintentional the latter are increased significantly if a pharmacist
poisonings in young children by medications and takes time to explain them. The pharmacist also has
chemicals found in the home. Acute and chronic poi- a unique role to play in detecting product or label-
sonings are of great public-health significance. The ing defects and an obligation to call to the attention
solution to this problem requires the efforts of indi- of appropriate manufacturers or regulatory agencies
viduals in many various disciplines as well as of the potential labeling or product defects.
lay public. Among these instrumental persons are There has been a tendency in the past for the
pharmacists, who can play a key role in prevent- development of too many small and ineffectual poi-
ing or mitigating the consequences of unintentional son centers, the activities of which could be carried
poisonings, especially those caused by medications. out more effectively and efficiently if they were amal-
gamated with others in the same area. Local pharmacy
associations should support the trend toward central-
Role of the pharmacist
ization and regionalization of poison information and
There is much that a pharmacist can do to help pre- treatment facilities.
vent poisoning and to improve the treatment thereof. Finally, pharmacists can assist greatly in the edu-
Pharmacists direct and staff many regional poison cen- cational efforts of a community by distributing liter-
ters. They actively provide consultation to physicians ature and by providing space for displays related to
treating poisoned patients to assure quality care. poisoning prevention.
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424 | An Introduction to Pharmacy

Medication disposal and federal regulations, but also for maintaining a

healthy environment. The following sections describe
Introduction various applicable types of waste streams for phar-
maceuticals.
Proper disposal of medications is a challenging and
complex issue. Many variables should be consid- Hazardous waste
ered when determining the most appropriate method There are very specific laws for managing waste from
for medication disposal, including federal and state products that are defined as ‘‘hazardous.’’ Accord-
laws, environmental impact, type, volume, and tox- ing to the Resource Conservation and Recovery Act
icity of medication being disposed, setting (acute (RCRA) of 1976, waste is considered hazardous if
care institution, long-term care institution, commu- it exhibits certain characteristics (ignitability, corro-
nity pharmacy, clinic, personal supply, etc.), and risk sivity, reactivity, or toxicity) or if it is included on
for diversion. While the optimal method of medication specific ‘‘lists’’ of wastes that the EPA has deemed
disposal is incineration, there are several barriers to hazardous.123 The RCRA established requirements
optimal disposal such as cost, incinerator accessibility, on generators of hazardous wastes, including health-
and confusing or cumbersome laws and regulations. care facilities. These regulations are set forth in the
Multiple regulatory agencies are involved in United States Code of Federal Regulations (CFR) at
pharmaceutical waste management, including the 40 CFR Parts 240–282.125
Environmental Protection Agency (EPA), Depart-
ment of Transportation (DOT), Drug Enforcement Pharmaceuticals considered hazardous based on
Administration (DEA), Occupational Safety and characteristics:
Health Administration (OSHA), state pharmacy
boards, state/local environmental protection agen-
• Ignitability – Pharmaceuticals that are consid-
ered hazardous based on ignitability include, but
cies, and Local Publicly Owned Treatment Works
are not limited to, any aqueous drug formulation
(LPOTW).123 Additional federal, state, and local laws
containing >24% alcohol by volume,126 oxidizers
may also dictate medication disposal. The Joint Com-
or materials that readily supply oxygen to a reac-
mission accredits healthcare organizations, including
tion in the absence of air (example: silver nitrate
hospitals, home care, laboratory, ambulatory care,
applicators), and flammable aerosol propellants
and behavioral healthcare organizations. Joint
meeting the DOT definition of compressed gas
Commission standards EC.3.10 and EC.9.10 address
(example: Primatene aerosol).127
appropriate management of hazardous materials.
• Corrosivity – Corrosive agents are those with a
We will focus on (a) distinguishing types of phar-
pH < 2 or > 12.5. Occasionally ingredients used
maceutical waste, (b) federal laws and best practices
in pharmaceutical compounding may fall into this
regarding the management of hazardous pharmaceu-
corrosive category (examples: glacial acetic acid,
tical waste, regulated medical waste, and universal
sodium hydroxide).126
waste, (c) medication disposal in the community, and
• Reactivity – Nitroglycerin may fall into the reac-
(d) minimization of pharmaceutical waste. Pharma-
tive category; however, most medical formulations
ceutical waste management in healthcare facilities
of nitroglycerin are not reactive,5 and nitroglycerin
will be discussed first, followed by management of
regulations vary by state. 126
pharmaceutical waste in the community.
• Toxicity – Toxicity characteristics apply primar-
ily to heavy metals such as barium, selenium, and
Pharmaceutical waste management in thimerosal.126
healthcare facilities
In addition to the four characteristics described above,
Types of pharmaceutical waste wastes can also be ‘‘listed’’ if they are acutely haz-
Distinguishing the type of pharmaceutical waste and ardous (fatal to humans or animals at low doses) or
identifying the appropriate waste stream for disposal if they contain any of the toxic constituents listed in
is critical for not only ensuring compliance with state 40 CFR Part 261, Appendix VIII and are capable of
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Fundamentals of pharmacy practice | 425

posing a substantial present or potential hazard to be called biohazardous waste or infectious medical
human health or the environment.124 waste. Exact definitions of regulated medical waste
There are four lists of hazardous wastes:124 may vary slightly by state or institution. However,
a key component of these definitions is that the
• The F List (non-specific source waste) waste is contaminated with blood, body fluids, or
• The K List (source-specific waste) other potentially infectious material, posing a risk
• The P List (discarded commercial chemical for transmission of infection. Sharps (items capable
products that are acutely hazardous) of cutting or piercing the skin such as needles with
• The U List (discarded commercial chemical or without syringes, scalpels, etc.) are considered
products that are identified as toxic). regulated medical waste. It is important to note that
in pharmacy circles, ‘‘biohazardous’’ is a term that
Pharmaceuticals are included in the P and U Lists. is often erroneously used to describe chemotherapy
Examples of medications included in the P List are waste.123 Although chemotherapy is hazardous
warfarin, arsenic trioxide, epinephrine, phentermine, to living/dividing cells, chemotherapy waste is
nicotine, and physostigmine. Examples of pharma- not ‘‘biohazardous’’ unless it also contains body
ceuticals on the U List include mitomycin, chloral fluids or other potentially infectious material. This
hydrate, chlorambucil, cyclophosphamide, diethyl- confusion may be compounded by the availability
stilbestrol, lindane, phenol, and selenium sulfide. of auxiliary labels that have both ‘‘chemotherapy’’
All dangerous pharmaceuticals are not technically and ‘‘biohazardous’’ on them.123 There are situations
considered hazardous waste under RCRA. Since the where waste is both RMW and hazardous waste.
RCRA was written in 1975, many drugs have been Proper management of this dual waste would be
brought to the market that are equally or more toxic determined by both the drug being dispensed and the
than those specifically mentioned in RCRA. The phar- administration instrument used.123
maceuticals on these lists have not been updated
regularly. Although not technically regulated as such, Disposing of hazardous and regulated
it would be considered best practice to treat similar, medical waste
more recently approved agents as hazardous waste as ASHP recommends that healthcare facilities have a
well. According to the American Society of Health multidisciplinary waste management team responsi-
System Pharmacists (ASHP), pharmaceutical waste ble for maintaining compliance with RCRA and state
should be considered dangerous if it contains any of waste management regulations.126 Hazardous waste
the following: 126 must be incinerated at an EPA-approved facility to
dispose of RCRA defined hazardous waste.126 Non-
• P or U listed drugs hazardous pharmaceutical waste should be disposed
• Chemotherapy agents of in a medical waste or municipal incinerator that
• Drugs with LD50 s (lethal dose in 50% of test ani- is permitted to accept nonhazardous pharmaceutical
mals) of < 50 mg kg−1 waste.126 Although some states may allow nonhaz-
• Endocrine disruptors ardous waste to be disposed of in sewers, this method
• Immunosuppressants of disposal is not optimal for the environment. There
• Drugs meeting National Institute for Occupational are many waste management companies which spe-
Safety and Health (NIOSH) or OSHA criteria cialize in disposal of medical waste. Healthcare facil-
• Drugs with potential toxicity due to chromium, ities should partner with an appropriately approved
selenium, or cadmium (including multivita- waste management company to ensure compliance
min/mineral preparations). with all federal, state, and local laws and to ensure
environmentally appropriate disposal methods.

Regulated medical waste Universal waste

It is important to understand terminology regarding The universal waste rule is a modification of haz-
regulated medical waste (RMW). RMW may also ardous waste rules (RCRA),127 designed to reduce
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426 | An Introduction to Pharmacy

requirements and foster environmentally sound dis- our sewer and water systems, this method of disposal
posal of certain types of commonly generated haz- is increasingly discouraged.123 In the retail pharmacy
ardous wastes. Currently, the universal waste rule setting, expired or unwanted controlled substances
applies to items such as batteries, pesticides, mer- are managed via DEA-registered reverse distributers
cury containing products, and bulbs/lamps. The EPA (see below) and/or pursuant to DEA forms 41 Reg-
proposed the addition of hazardous pharmaceutical istrant’s Inventory of Drugs Surrendered129 or 222.
wastes to the federal universal waste rule.128 The In the long-term care facility setting, management of
proposed rule would not only add hazardous phar- unwanted/unused controlled substances is challeng-
maceutical waste to the universal waste rule, but ing, and policies and procedures at individual facilities
it also encourages generators to dispose of nonhaz- may vary. Most long-term care facilities are not regis-
ardous pharmaceutical waste as universal waste thus tered with the DEA and there is no provision currently
removing unregulated waste from wastewater treat- in the CSA that would allow a non-registered facil-
ment plants and municipal solid waste landfills.128 ity to return controlled substances to the dispensing
This proposed rule applies directly to healthcare facil- pharmacy.130
ities that generate pharmaceutical waste (pharmacies, The verbiage in the original CSA makes the dis-
hospitals, physician and dentist offices, outpatient posal of unwanted/unused controlled substances in
and residential care facilities, veterinary clinics, etc.). the long-term care and general community environ-
It also makes possible the collection of personal med- ments difficult. However, the Secure and Responsible
ications from the general public at various waste Drug Disposal Act131 that was signed into law on
management facilities.128 As of August 2011, the October 12, 2010 amends the CSA. This act autho-
proposed rule to add pharmaceuticals to the univer- rizes the Attorney General to issue new regulations to
sal waste program had not been finalized and ‘‘the allow for disposal of controlled substances by long-
Agency does not have a projected date for the finaliza- term healthcare facilities, and allow individuals in the
tion of the rulemaking . . . ’’.128 Concerns have been community, who have lawfully obtained prescription
expressed about safety and security, as well as notifi- controlled substances, to deliver them to an autho-
cation and tracking. The EPA is considering additional rized person for proper disposal. As of January 2012,
regulatory options that address these concerns.128 the Attorney General has not yet issued these new
regulations.
Controlled substance waste
Properly disposing of controlled substances is espe- Reverse distribution
cially challenging due to risk of drug diversion, Pharmaceutical reverse distribution is the process
varying state laws, differing regulations based on of returning recalled or expired pharmaceuticals for
type of healthcare facility, and additional regulations manufacturer’s credit. Potentially creditable medica-
imposed by the Controlled Substance Act (CSA). tions, in the original manufacturer’s packaging, are
Individual state laws differ, but frequently in the processed through reverse distributors. If the condi-
hospital setting when controlled substances must be tions of the product coincide with the return policies
‘‘wasted,’’ they need to be destroyed such that they of the manufacturer, the item is returned to the man-
are beyond recovery and witnessed and documented ufacturer, or its designated agent (which may be a
by two qualified healthcare professionals. This situ- reverse distributor), and credit is issued to the phar-
ation occurs commonly when a partial dose needs macy. Non-creditable medications include, but are
to be wasted; for example when a patient needs not limited to: samples, repackaged products, par-
6 mg of morphine. Morphine is available as 5 or tially used products, compounded pharmaceuticals,
8 mg syringes, thus an 8 mg syringe is partially used, patient owned medications, and products that are
and the remaining 2 mg is destroyed. Some states inherently waste-like (such as those that are broken,
mandate the method of destruction, others do not. spilled, used, or unidentifiable). Creditable medica-
Unfortunately, in some areas, this type of controlled tions are not considered waste and do not count
substance waste is accomplished via drain disposal. toward a healthcare facility’s waste generator sta-
Given the environmental impact of medications in tus. Once transferred to the reverse distributor, it
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Fundamentals of pharmacy practice | 427

is their responsibility to return the product to the its own set of concerns. Medications thrown away
manufacturer, or dispose of the medication in a with prescription labels still on them contain personal
manner that complies with federal and local regu- information which can promote identity theft.
lations, as well as Return Industry Association (RIA) Furthermore, disposing of medications in the trash
standards.126 can lead not only to accidental exposure by children,
pets, and wildlife but it can also be a source for phar-
maceutical drug diversion.131,134 The nonmedical
Disposal of medications in the use of prescription drugs continues to be a concern
community/private sector and throwing controlled substances out in the trash
Accumulation of unused or ‘‘leftover’’ medications or simply not disposing of them at all can lead to
in a community setting can occur for a variety of inappropriate access to prescription medications.
reasons, such as patient non-compliance, medica- As a result of these concerns, as well as the
tion expiration, or changes in drug therapy.132,133 confusion and uncertainty surrounding medication
A survey by Kuspis and Krenzelok published in 1996 disposal, various organizations have developed
found that only 2% of study participants took their programs or published guidelines on the proper
medications completely prior to reaching their expi- disposal of prescription drugs. In February 2007,
ration dates. Most of the survey participants who the White House Office of National Drug Control
had unwanted medications, threw them in the trash Policy (ONDCP), the Department of Health and
(54%) or used the toilet or sink (35.4%) for disposal, Human Services (HHS), and the EPA issued guidance
while others (7.2%) did not dispose of their medi- for consumer drug disposal. Around the same time,
cations at all.134 A more recent survey, published in the American Pharmacists’ Association (APhA),
2006 in the Journal of the American Board of Family the Pharmaceutical Research and Manufacturers of
Medicine, asked 301 outpatient pharmacy customers America (PhRMA) and the United States Fish and
about their unused or expired medication disposal Wildlife Service’s (USFWS) partnered and developed
practices. The authors found that >50% of those the SMARxT Disposal2122 program.134,135 This
surveyed stored their unwanted medications in their campaign was designed to educate consumers about
homes and another 50% said they flushed them down disposing of medications in a safe and environ-
the toilet. Only 20% reported ever receiving advice mentally protective manner.138 Both the ONDCP
from a healthcare provider on the proper disposal of guidelines and the SMARxT™ disposal program have
unwanted medications.132 the same goal – to increase public awareness of safe
There are concerns with these disposal practices. disposal practices when medications are no longer
Disposal by sink or toilet has resulted in increased needed. The following are main points made by both
levels of pharmaceuticals in our rivers, streams, and guidelines:
drinking water supplies.134 A US Geological Survey
that studied wastewater and surface, ground, and • Utilize medication collection programs whenever
drinking waters in Minnesota found organic contam- possible
inants in 90% of the samples tested, most of which • Do not flush away medications
were prescription and nonprescription drugs.126 • When disposal programs are not available, throw
Current water treatment systems do not remove away unwanted medications in the trash using
pharmaceuticals in drinking water and long-term appropriate safeguards.
exposure, even in trace amounts, could potentially be
dangerous.132 Such disposal practices could lead to Collection events
adverse outcomes such as water quality degradation, The best way for consumers to dispose of unwanted
endocrine disruption (potentially leading to problems medications is to utilize medication take-back
with physical, mental, or sexual development), programs or other hazardous waste collection events
antibiotic resistance, and negative public perception in their communities, whenever possible. These
regarding water cleanliness.126 On the other hand, programs give the public an opportunity to bring
disposing of unwanted medications in the trash has unused/unwanted medications to a central location
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428 | An Introduction to Pharmacy

for proper disposal. They are designed to ensure Flushing

that unused, expired, or unwanted medications Current guidelines have strong warnings against
are collected and destroyed in a safe, legal, and flushing. Most prescription medications should NOT
environmentally sound way and not stolen or used be flushed down the toilet or washed down the
by unauthorized individuals. They also provide an drain.134 – 136 A few, select medications, mostly high-
opportunity for unused drugs to be inventoried – to potency opioids and other controlled substances,
determine the types and amounts of pharmaceuticals may be especially harmful and/or deadly if taken by
wasted and identify reasons why they were not used. someone other than for whom the medication was
There are various types of collection programs prescribed, so the FDA139 recommends flushing these
available, ranging from small, one-day events to down the toilet when controlled substance take-back
continuous, on-going programs. One initiative, the programs are not available (see Table 10.14).140
National Prescription Drug Take Back Days, is con- The most complete and up-to-date list of expired,
ducted by the DEA along with state and local law unwanted, or unused medications recommended
enforcement agencies in all 50 states. The National for flushing may be found on the FDA website at
Prescription Drug Take-Back event that took place http://www.fda.gov.
on April 30, 2011 yielded over 376 593 pounds
(171 tonnes) of unwanted or expired medications.137 Trash disposal
As mentioned above, when the Secure and Respon- If a collection program is not available and the med-
sible Drug Disposal Act of 2010 is implemented, ication is not one that is recommended for flushing,
additional ‘‘authorized parties’’ will be allowed to both the federal and SMARxT™ disposal guidelines
collect and properly dispose of unwanted and expired suggest throwing unwanted and expired medications
medications throughout the community. Prior to pass- away in the household trash.136,139 However, con-
ing this law, controlled substances returned by con- sumers should first:
sumers at take-back programs are only allowed to
be collected and inventoried by law enforcement.134 • Take drugs out of their original containers and
Until the regulations are finalized, the DEA will con- crush or dissolve oral medications.136 Topical
tinue offering take-back opportunities.138 More about patches should be folded in half, adhesive side in,
these national take-back initiatives can be found and should remain intact.135
on the DEA’s Office of Diversion Control’s website • Mix the medications with an undesirable sub-
at http://www.deadiversion.usdoj.gov/drug_disposal/ stance, such as used coffee grounds, sawdust, or
takeback/index.html.137 kitty litter to make them less appealing to children
City, county, or state sponsored take-back and animals. This will also make it more difficult
programs are also available. One can often find infor- for individuals who intentionally go through the
mation regarding prescription take-back programs trash to recognize the drugs.136,139
by contacting local waste management agencies • Place the mixed contents in a sealable bag, empty
or utilizing the Drug Take-Back Network website canister, or other container to prevent the medi-
at http://www.takebacknetwork.com. Community cation from leaking or breaking out of a garbage
pharmacies may offer drug disposal programs as bag. These steps will further assure the drugs are
well. Some pharmacies take back unwanted or not diverted.136,139
expired medications at any time, while others • Throw the container away in household trash.140
hold periodic take-back events to collect expired,
unused, or unwanted medications. Dispose My Meds Additionally, when disposing of medication con-
(http://www.disposemymeds.com) is a website that tainers, it is advised that consumers first remove
provides information not only on medication safety any personal information by peeling off the label or
and its environmental effects, but also includes a removing all identifying information prior to throw-
Pharmacy Locator that allows consumers to find a ing the containers away in the garbage.136 This will,
pharmacy in their community that offers safe disposal once again, minimize the risk of illegal activities such
of unwanted medications. as personal identity theft and drug diversion.
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Fundamentals of pharmacy practice | 429

Table 10.14 List of medications recommended by the FDA for disposal by flushing when controlled
substance take-back programs are not available.142

Brand name Dosage form Active ingredient(s)

Abstral Sublingual tablets Fentanyl

Actiq* Oral transmucosal lozenge Fentanyl citrate

Avinza ER capsules Morphine sulfate

Daytrana Transdermal patch system Methylphenidate

Demerol* Tablets, Oral solution Meperidine HCl

Diastat AcuDial Rectal gel Diazepam

Dilaudid* Tablets, Oral liquid Hydromorphone HCl

Dolophine HCl* Tablets Methadone HCl

Duragesic* ER patch Fentanyl

Embeda ER capsules Morphine sulfate, Naltrexone HCl

Exalgo ER tablets Hydromorphone HCl

Fentora Buccal tablets Fentanyl citrate

Kadian ER capsules Morphine sulfate

Methadone HCl* Oral solution Methadone HCl

Methadose* Tablets Methadone HCl

Morphine sulfate* Tablets, Oral solution Morphine sulfate

MS Contin* ER tablets Morphine sulfate

Nucynta ER ER tablets Tapentadol

Onsolis Buccal soluble film Fentanyl citrate

Opana Tablets Oxymorphone HCl

Opana ER ER tablets Oxymorphone HCl

Oramorph SR SR tablets Morphine sulfate

Oxecta Tablets Oxycodone HCl

Oxycodone HCl Capsules, Oral solution Oxycodone HCl

(continued overleaf)
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430 | An Introduction to Pharmacy

Table 10.14 (continued)

Brand name Dosage form Active ingredient(s)

OxyContin* ER tablets Oxycodone HCl

Percocet* Tablets Acetaminophen, Oxycodone HCl

Percodan* Tablets Aspirin, Oxycodone HCl

Xyrem Oral solution Sodium oxybate

∗ These medications have generic versions available or are only available in generic formulations.

Minimization of pharmaceutical waste may not exceed the amount that would have been
collected with the usual, longer cycle. This short-cycle
Another way to address pharmaceutical waste man-
dispensing program is intended to decrease the
agement is by actively minimizing the amount of
amount of medications that are wasted or unused
waste generated. Healthcare providers can help min-
with traditional 30 to 90 day supplies by changing to
imize waste by controlling inventory levels, using
daily, biweekly, or weekly prescription fills. The Con-
just-in-time dispensing and compounding practices,
gressional Budget Office estimated that implementing
dispensing smaller quantities (especially on initial
short-cycle dispensing would result in Part D program
fills), reconsidering 3-month supplies or automatic
savings of $5.7 billion. However, others argue that
refills, using available tools to prevent adverse drug
without baseline data and credible evidence there
reactions and interactions, improving compliance, is no way to objectively determine whether or not
and minimizing prescription drug therapies when short-cycle dispensing will actually save money for
appropriate.141 the Medicare Part D program. In fact, the increase
in dispensing costs associated with shorter fills may
Short cycle prescribing erase the potential savings from reduced waste.144
To help minimize waste and increase savings, some CMS plans to collect data from Part D plan sponsors
managed care organizations are offering programs to determine how effective short-cycle dispensing is
that encourage dispensing of smaller quantities, when at reducing medication waste and saving money.
appropriate, especially at the beginning of therapy.142
They encourage prescribing and dispensing small, trial Drug recycling
amounts when patients are starting a new medica- Another initiative gaining popularity is prescription
tion regimen since new therapies are sometimes not drug recycling. Many states now allow unused
effective or patients experience an adverse effect. prescription drugs to be collected and reused or given
The Centers for Medicare and Medicaid Services away to those who are uninsured or poor. Although
(CMS) has revised Medicare to implement a Medicare individual states may have their own regulations
Part D long-term care ‘‘short-cycle’’ rule which went regarding drug reuse and recycling, some allow
into effect on January 1, 2013. As a component prescription drugs in single use or sealed packages
of the Patient Protection and Affordable Care Act to be returned from state programs, nursing homes,
(ACA), CMS proposed a ruling that would require and other medical facilities.145 A small number
long-term care facilities to dispense drugs in 14-day of states allow donations from individuals. The
increments. This rule applies to all brand name, solid National Conference of State Legislatures (NCSL)
oral dosage prescription drugs dispensed to long-term identifies and tracks state legislation on prescrip-
care residents. So any pharmacy that serves long-term tion drug recycling, repository, or redistribution
care facilities will have to comply with this rule.143 programs for unused medications.145 Their website
The rule also states that a resident’s total co-payments (http://www.ncsl.org/default.aspx?tabid=14425)
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Fundamentals of pharmacy practice | 431

provides the most up-to-date information about surgical supply houses. Every pharmacist, however,
the specific recycling laws for each state. Common should be familiar with two of the products mentioned
requirements of these programs include: above: surgical dressings and sutures. The selection of
the correct type of surgical dressing or suture is crucial
• Drugs must not be expired
to safeguarding the welfare of the patient undergoing
• A licensed pharmacist or pharmacy is involved in
surgery. Many items in these categories are handled
the verification/distribution process
routinely by pharmacists, and all of these items come
• Each patient receiving a medication must have a
within the purview of their professional responsibility.
valid prescription in her/her own name
• Controlled substances are typically excluded from
these programs. Health accessories

Conclusion Pharmacists are trusted and relied upon to provide

their expertise and knowledge to patients seeking
Healthcare professionals should play a significant role home medical equipment (HME) in a variety of set-
in minimizing pharmaceutical waste and educating tings. The transitioning role of pharmacists providing
consumers about appropriate disposal of medica- care as well as medication segues well with their ready
tions. Proper disposal of pharmaceutical waste and accessibility almost anywhere patients are located.
unwanted medications is a complicated issue, involv- Physicians and other health professionals recognize
ing many regulatory agencies and healthcare organi- the value pharmacists provide in fulfilling a patient’s
zations. New initiatives are being developed to reduce HME needs. In recent years there has been much
medical waste, minimize its impact on the environ- consolidation in HME delivery, driven by payors,
ment, and limit drug diversion. It is recommended mergers, and competition. However, there are still
that healthcare facilities partner with accredited waste many opportunities for pharmacists to provide HME
management companies to ensure compliance with to their patients. There are large numbers of people
complex federal, state, and local laws regarding dis- who do not have insurance or a third party source
posal of pharmaceuticals. In the community setting, of payment. These people are looking for a source of
it is currently recommended that medications be dis- supply for their needs and they will frequently look to
posed of via prescription take-back programs and not their pharmacy as their source for medical equipment
introduced into the sewage system, whenever possi- and their other healthcare needs. The specially trained
ble. Implementation of the Secure and Responsible pharmacist is becoming recognized more widely as an
Drug Disposal Act and the possibility of pharma- expert in this area by other health professionals and
ceutical waste being re-classified as Universal Waste this area of expertise can provide a professional and
may drastically change how pharmaceutical waste profitable adjunct to the pharmacy’s other services.
and expired and unwanted medications are disposed A comprehensive HME department may include
of in the future. a wide variety of surgical dressings and supplies;
and home medical equipment including wheelchairs,
Surgical supplies walkers, hospital beds, hydraulic patient lifters, urol-
ogy and incontinence supplies, ostomy appliances,
A professional service rendered by many pharmacists elastic supports, compression stockings, mastectomy
consists of supplying surgical instruments, sutures, breast forms, and orthopedic braces. In addition,
surgical dressings, and other equipment employed many pharmacies specialize in home healthcare
by the surgical personnel during and after a surgi- equipment such as traction devices, blood-glucose
cal operation. Some pharmacists who have obtained monitors, diabetic shoes, blood-pressure-monitoring
the necessary background of information carry a com- devices, suction machines, oxygen and respiratory-
plete line of such supplies and are even able to provide therapy equipment, nerve and muscle stimulators,
operating tables and other heavy equipment. phototherapy lights, apnea monitors, and rehabilita-
There are comparatively few such completely tion equipment. Fewer pharmacies are specializing
equipped pharmacies; the major outlet consists of in providing intravenous medications and supplies
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432 | An Introduction to Pharmacy

for enteral or parenteral nutrition due to exclusive the equipment can be used where it is needed. For
contracting and national conglomerates. The cost of instance, a wheelchair will not be utilized properly
establishing a sterile environment for the preparation if the patient’s home has doors or hallways too nar-
of intravenous medications can be steep. row for the wheelchair to fit through. An assessment,
Even more important than merely providing a whether on site or through verbal communication,
wide range of health accessories is the pharmacist’s needs to be performed to determine whether the envi-
role in selecting and fitting them, and in instructing ronment will allow the medical equipment to fulfill
the patient in their proper use and maintenance. the patient need. The pharmacist has the ability and
HME products and services, in many cases, require expertise to provide this service.
specialized training if the patient is to be properly Other steps may include consulting with the
served. Collaboration with and referral to, when patient, physician, and family; selecting the accessory
necessary, other healthcare professionals who are from stock or ordering it from the manufacturer or
more knowledgeable ensures that a patient’s needs distributor; and checking the accessory to ensure
are properly met. that it meets the appropriate specifications. Usually,
To provide these services the pharmacist may follow-up adjustments or modifications are necessary.
need to acquire new skills and expertise that can be Useful forms (e.g., certificates of medical necessity
obtained through a variety of sources, such as spe- (CMN) which is a written statement by a physician
cial courses given by health-accessory distributors and verifying that the necessary criteria for the use of
manufacturers, professional associations, and college the equipment or supplies is met, disability analysis,
or university-based programs. A thoroughly trained measurement, prescription and ordering forms) are
staff and informed provider community also will con- usually available from health-accessory manufactur-
tribute to your success. Medicare and some insurance ers, insurance companies, and government agencies.
payors also require certification through one of the In fact, some insurance companies and government
accreditation organizations, a list of which can be agencies may mandate the use of their customized
found on the CMS website. forms. Documentation of patient analysis, measure-
The initial step in selecting the appropriate health ments, and what was sold/dispensed is an essential
product is a thorough evaluation of the patient’s part of record keeping, especially with more stringent
needs and then matching these needs to the available Fraud, Waste and Abuse regulations established by
options. Multiple factors must be considered includ- the Center for Medicare and Medicaid Services.
ing age, disability related factors, lifestyle, patient
equipment measurements, diagnosis, patient ability Professional approach
for self-care, prognosis, and reimbursement sources. Pharmacists should not conclude hastily that they will
Note that the option may very well be referral to be successful in this field, regardless of their estimate
another source for care. of the local market, their inventory, and their display
Each of these factors should be considered when facilities. The pharmacist must be willing to devote
selecting the most appropriate health accessory for time and intelligent effort to the venture or he or she
the patient. It is often necessary to verify insurance will fail. Their attitude must be professional, and their
coverage, including whether particular equipment is approach to prospective referring physicians and the
mandated by a health maintenance organization and public must be made on that basis, not on mere avail-
which equipment will be considered for reimburse- ability or price. They must become knowledgeable in
ment by Medicare, Medicaid, or insurance compa- the areas of reimbursement and accreditation. Most
nies. Although a standard ‘‘prescription’’ may not important, they must have developed the expertise
be required, some form of a physician order and to recommend the right equipment and supplies and
possibly a prior authorization are required as veri- instruct their patrons in their proper use.
fication of medical necessity by most third parties. Pharmacists who seriously are considering devel-
Reimbursement will not be made without this order. oping this specialty will need to expand their reading
Along with supplying medical equipment the pharma- list of relevant professional journals and periodi-
cist should also take the necessary steps to ensure that cals. In addition to the major pharmacy journals,
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Fundamentals of pharmacy practice | 433

the following publications will broaden their knowl- in pharmacy practice provides limitless opportunities.
edge and perspective concerning home health equip- This section focuses on these entrepreneurial activities
ment: HomeCare Magazine, HomeCare News, HME and opportunities.
News, Medical Product Sales, Home Care Provider, The Oxford English Dictionary defines an
Home Health Products, Ostomy/Wound Manage- entrepreneur as ‘‘one who undertakes an enterprise;
ment, Home Healthline, and journals in specialty one who owns and manages a business; a person
fields such as physical therapy, occupational therapy, who takes the risk of profit or loss.’’147 According to
or respiratory therapy. the Cambridge Dictionary Online, an entrepreneur is
The National Community Pharmacists Associ- ‘‘someone who starts their own business, especially
ation (NCPA) created a special division of Home when this involves seeing a new opportunity.’’148
Health Care Pharmacy Services. This division can The Raynet Marketing Dictionary says ‘‘the owner
provide additional information to pharmacists on or manager of a business who by risk, initiative,
changes in government programs that affect phar- and innovation attempts to make a profit’’ is
macists providing home healthcare accessories. The an entrepreneur.149 Peter Drucker150 states that
NCPA publishes a newsletter, the Alternative Pharma- entrepreneurship and innovative business activities
cist Monthly. The NCPA, an accredited Accreditation are neither an art nor a science but should be seen in
Council for Pharmacy Education (ACPE) provider, the context of a practice and discipline. He states that
also provides educational programs concern- entrepreneurship is not mysterious, or some special
ing ostomy, incontinence, wound management, gift, talent, or inspiration, but purposeful tasks that
orthotics, and prosthetics. An advanced certificate can be organized as systematic work. Finally Collins
program in orthotics and prosthetics is offered by the and Moor,151 in their classic book The Organization
National Community Pharmacists Association, and a Makers, suggest that an entrepreneur is someone
number of other certification programs are available. ‘‘who created out of nothing an ongoing enterprise.’’
The surgical supply department of the modern These definitions and insights provide the underlying
community pharmacy is recognized by physician and theme for this section – the entrepreneurial phar-
layman alike as a proper extension of the pharma- macist is one who assumes risk, takes responsibility,
cist’s professional service. Physicians and allied health looks for opportunity, is creative, and assumes a
professionals quickly assess this new service as an leadership role in the inception and evolution of a
important contribution to the health-team concept. new pharmacy-related business concept.
‘‘Managing’’ the enterprise was not included in
The entrepreneurial and our entrepreneurial themes. This in not because we
intrapreneurial pharmacist believe that the activities and skills of a manager
are not important – they are. Managerial activities
Entrepreneur and entrepreneurial activities are well- are essential to the ongoing success of all business
understood terms. In this section, we broaden the ventures. However, as stated earlier, while not
interpretation of these terms and suggest that small all business owners are entrepreneurs, the same
business ownership alone is insufficient to describe can be said of managers – not all managers are
entrepreneurism fully. A community pharmacy owner entrepreneurs. Stewart and Ross,152 in their evalua-
is certainly an entrepreneur, and entrepreneurial activ- tion of the primary differences between entrepreneurs
ities occur in a community pharmacy. In addition, and managers, found a higher risk-taking propensity
entrepreneurial activities regularly occur within large among entrepreneurs than managers. Additionally,
and medium-sized corporations and organizations the type of entrepreneur influenced the magnitude of
– defined by some as intrapreneurship.146 As the the difference. Income-oriented entrepreneurs (i.e.,
profession of pharmacy moves from a primarily inde- business owners) had slightly elevated risk propensity
pendent ownership model of practice to a more scores when compared with managers, whereas
employee-based profession, the opportunities for cre- growth-oriented entrepreneurs had much higher
ative ventures within these corporate entities cannot risk propensity scores than individuals identified
be ignored, and a return to the entrepreneurial spirit as managers. Discussion in this section focuses
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434 | An Introduction to Pharmacy

on the pharmacist-entrepreneur. One aspect that proposed the following definitions to differentiate
differentiates the pharmacist-entrepreneur from the entrepreneurial ventures from small business ventures.
pharmacist-manager is his or her comfort with and
willingness to take calculated risks. • Small business venture: ‘‘Any business that is inde-
pendently owned and operated, not dominant in
its field and does not engage in new marketing or
Intrapreneurship innovative practices.’’
Does entrepreneurial activity happen only as a busi- • Entrepreneurial venture: ‘‘A business whose prin-
ness venture of a single or small group of individuals? cipal goals are profitability and growth, and the
Clearly, the answer is ‘‘no.’’ Pinchot and Pinchot153 business is characterized by innovative strategic
coined the term intrapreneurship to describe the practices.’’
entrepreneurial activities that occur within organi-
These definitions were based on earlier work by
zations. The Oxford English Dictionary defines the
Schumpeter156 and Vesper,157 who identified five
intrapreneur as ‘‘an employee given the freedom to
strategic behaviors that described entrepreneurial
work independently within a company with the objec-
ventures:
tive of introducing innovation to revitalize and diver-
sify its business.’’149 In this section we will use the • Introduction of new products or services
more familiar terms entrepreneur and entrepreneurial • Introduction of new methods of production
in our discussions, with the understanding that we are • Opening new markets
using the terms to refer to innovative opportunistic • Opening new sources of supply
risky business ventures both inside and outside formal • Industrial reorganization.
organizations (Fig. 10.23).
Specific pharmacy-based ventures can be used to
illustrate each of these strategic behaviors.
Entrepreneurial actions
Small business and entrepreneurship overlap, but are Introduction of new products or services
not the same. The key difference is the focus on Several pharmacy ventures fall into the category of
growth and market planning.154 Carland et al.155 introducing new products or services. Long-term care

Entrepreneur Intrapreneur

Risk shared with

Sole risk-taker organization

Leadership

Idea champion
Self/external funding Funded by
organization
Teamwork/bring
together resources

Innovation
Own boss
Works within an
organization

Figure 10.23 Characteristics of entrepreneurs and intrapreneurs.

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Fundamentals of pharmacy practice | 435

consulting is a good example. In 1965, passage of the was the creation of pharmacy benefit management
Medicare/Medicaid legislation provided guidance for firms. Today these firms influence virtually all medica-
the provision of pharmacy services in nursing homes. tions delivered to persons who have a pharmaceutical
Following the development of drug distribution sys- benefit.
tems for this unique setting, the role of the consultant Practice-based pharmacists have created success-
pharmacist soon evolved. This new practice model ful entrepreneurial ventures using each of these strate-
(service) is now part of the established standard of gic behaviors. If past success provides any insight
care in long-term care facilities throughout the United into the future, it would seem that there are great
States. opportunities ahead.

Introduction of new methods of production

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11
The scope of pharmacy practice

The practice of community pharmacy 441 Pharmacists in government 474

The practice of health systems pharmacy 446 Pharmacists and public health 475

Pharmacy technicians, medication preparation, Consultant pharmacy practice 475

and distribution systems 448
Nuclear pharmacy practice 475
Clinical pharmacy services 452
Home infusion pharmacy practice 482
Medication use policy 456
Specialty pharmacy 483
Leadership 460
Pharmacists in academia 485
Contracting and procurement 464
Nutrition in pharmacy practice 486
Human resources 467
Veterinary pharmacy 487
Information technology and automation 469
Extemporaneous prescription compounding 489
Education and training 472
References 517
Pharmacy practice in industry: potential roles for
pharmacists 474

The practice of community company-driven mail order pharmacy, consolidated

healthcare providers such as Health Maintenance
pharmacy
Organizations (HMOs), growth of community health
centers, with pharmacies dispensing products with
A practice in transition federally reduced product cost, and the availabil-
The image of what was once considered community ity of medications from neighboring countries and
pharmacy practice has been blurred both by the multi- from the Internet. The change in the reimbursement
ple types of practice in this setting and by the speed of system for medications has progressed on an equal
change now occurring. Traditional independent own- pace. The passage of the Medicare Modernization
ership and chain pharmacy continue to exist along Act in 2003 resulted in the creation of Medicare
with a growing presence of pharmacies in grocery Part D, an outpatient prescription drug benefit for
and mass merchandiser operations. Many factors have Medicare beneficiaries. This and the growing pen-
resulted in a rapid evolution of the distribution system etration of prescription insurance have significantly
for the ambulatory patient, such as the growth of vir- reduced the numbers of cash-paying patients. The
tual community pharmacies in the form of insurance community pharmacy environment is increasingly
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442 | An Introduction to Pharmacy

impacted by these changing forces, while at the consumer spending for prescription drugs was 56% in
same time it is attempting to fully implement the 1990, it decreased to 26% by 2001, and declined fur-
patient-oriented practice that has been envisioned ther to 21% by 2008. At the same time, private health
since the early 1990s. Continuing to maintain control insurance covered 26%, 50%, and 42% of prescrip-
of the responsible distribution of medications, while tion drug costs in 1990, 2001, and 2008, respectively.
increasingly providing direct patient care services in A steady increase in coverage has occurred in publicly
an environment of reduced reimbursement, are the funded programs such as Medicaid, Medicare, and
challenges that now face community practice as it other government programs. In 1990 these programs
strives toward the Joint Commission of Pharmacy accounted for 18% of expenditures, rising to 24% in
Practitioners Future Vision of Pharmacy Practice in 2001, 28% in 2005, and 37% in 2008.6 The accel-
2015. In meeting this challenge, pharmacists will be erated rise after 2005 is reflective of the Medicare
the healthcare professionals responsible for providing Part D benefit going into effect and its new function
patient care that ensures optimal medication therapy as the primary coverage for beneficiaries having both
outcomes.1 Medicaid and Medicare drug benefits. With this rise
in third party reimbursement for prescription drugs
has come continued pressure from insurance plans
Distribution and control of medications and their pharmacy benefit managers (PBMs) to con-
The pharmacist’s role in assuring the safe distribu- tain medication expense. Strategies such as increasing
tion of medications continues as a major area of beneficiary co-payments and establishing co-pay tiers
responsibility in the community setting, as elsewhere. to limit use of non-preferred or expensive drugs, use
Pharmacists, as the most readily available healthcare of formularies to direct therapies to preferred or con-
provider, are maintaining this role while becoming tracted drug entities and to exclude others, limiting the
more involved clinically. The retail setting was the quantity to be dispensed, and requiring pre-approval
place of employment for 65% of the nation’s 270 000 of medication selection and reimbursement prior to
pharmacists working in 2008.2 The need for phar- dispensing have all impacted the community phar-
macists in this setting remains high because the per- macist in practice. Beyond increasing the complexity
centage of Americans taking prescription medications of the pricing systems that must be maintained for
has increased over the past decade, along with the the many different plans accepted by a community
percentage taking multiple prescription medications.3 pharmacy, these schemes are also confusing for the
Over $234 billion, or approximately 10% of overall beneficiary, and considerable time is spent by phar-
national health expenditures, was spent on retail out- macists assisting the patient in both understanding
let sales of prescription drugs in 2008, nearly twice their benefit and working with their providers and
the amount spent in the year 2000.4 In 2010 the the PBM to get the patient the needed medication.
number of prescriptions totaled over 3.6 billion, of Cost reduction strategies for the reimbursement of
which approximately 48% were filled in traditional pharmacists for the distribution of the prescription
chain pharmacies, 20% in independent pharmacies, by insurance companies provides another challenge
25% in supermarket and mass merchandiser phar- because decreased professional fees must often be
macies combined, and 7% via mail order pharmacy. accepted by a pharmacist to avoid the loss of patients
That same year, generic prescriptions accounted for eligible to receive services from their practice.
71.2% of prescriptions, with 28.8% being brand These pressures greatly affect the profitability
name drugs. The average price of a prescription had of community pharmacy. Information from the
risen to nearly $80 in 2010, up from approximately 2010 National Community Pharmacists Association
$64 in 2005, $46 in 2000, and $30 in 1995.5 The (NCPA) Digest suggests that 21% of independent
increased use of prescription drugs and associated community pharmacies are operating at a loss, with
increase in cost come at a time of a number of another 23.4% having just a 0–2% net profit.7
changes in the marketplace for outpatient prescription In order to most efficiently process prescription
medications. Patients are paying a smaller percentage orders and attempt to maintain a high level of qual-
of prescription drug spending. While out-of-pocket ity at the lowest cost, community pharmacies are
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The scope of pharmacy practice | 443

increasingly utilizing technology. The processing of selected, assuring the correct medication is added to
electronic prescriptions and automated refill requests counting devices and robots, and performing final
are now becoming part of the daily routine in phar- verification on filled prescriptions. Software solutions
macies. Utilization of computer systems to facilitate with these systems assist in work flow management,
prescription processing is nearly universal because quality assurance, inventory management, and auto-
processing of insurance with real time adjudication mated ordering. Technology innovation has resulted
of claims is the standard of practice. These same in many changes in how the basic dispensing functions
systems also assist the pharmacist in screening for are completed in a community pharmacy, and, conse-
drug–disease and drug–drug interactions and thera- quently, have produced new management challenges
peutic duplication. They also help with monitoring of in the day to day practice of pharmacy.9,10
adherence to therapy. Importantly, the utility of these Additional challenges to the practice of commu-
database solutions is limited in cases in which frag- nity pharmacy grow from other strategies to control
mentation of care prevents compilation of a complete costs associated with prescription medication. Alter-
and accurate record of a person’s medication history, native distribution strategies such as centralized filling
including non-prescription medications and comple- of prescription orders with delivery to distribution site
mentary and alternative medications. The future avail- pharmacies can change the relationship between the
ability of accessible personal health records should pharmacist and patient. These systems also require
allow for improved functionality in this regard. This
a different approach to pharmacy management to
is especially true as patients utilize a variety of medi-
assure efficiency. Mail order delivery of prescription
cation sources to minimize out-of-pocket expenses.
services has been a challenge to community phar-
In addition to computer systems to process pre-
macy as established pharmacist–patient relationships
scription orders, pharmacists are increasingly making
are broken, and access to the provision of services
use of other technologies to increase efficiency. Many
for involved patients is limited when plan sponsors
pharmacies use interactive voice response (IVR) sys-
and PBMs promote this system as a way to reduce
tems to allow patients to request refills on medications
prescription costs. While generally assumed to be
using their telephones. This functionality is also avail-
a most cost-effective way of delivering prescription
able using the Internet and with applications on smart
drugs, the design of mail order plans and incentives
phones. A variety of mechanical devices have taken
used to promote their use can increase the cost to
the place of the counting tray in regard to getting
the plan sponsor.11 These system-oriented changes in
the correct number of capsules or tablets into a con-
practice can further fragment the medication-related
tainer for the patient. Stand-alone counting machines
have evolved into dedicated counting devices for care a patient receives, and make the provision of
individual medications. Dispensing system interfaces pharmacist-provided care, which takes into consider-
with banks of these devices was an important step ation all of the patients medications, more difficult.
toward the development of robotics, which are prac- Patients can also complicate the ability of a single
tical for the community pharmacy. Many community pharmacy to have a complete record of their medi-
pharmacies now have one of the several available cations. This can occur when patients shop for the
automated counting or robotic dispensing devices that lowest prices for their medications. This could occur
count the solid dosage forms and place the counted at other local pharmacies or over the Internet. Increas-
medication into a labeled container. These devices ing the risks to the patient from this latter activity go
can decrease prescription filling time; however, this beyond provider knowledge of medications taken by
improvement does not necessarily gain efficiency or the patient. Studies completed by the US Food and
assure increased care will be provided. Knowledge Drug Administration (FDA) and National Association
on how to best meld technology with human activi- of Boards of Pharmacy (NABP) find that many of the
ties in these new environments is still developing.8,9 prescriptions filled from Internet pharmacies are adul-
Other technology, such as bar code scanning, allows terated and do not contain the labeled ingredients.12
the pharmacist to better ensure accuracy in dispens- Patients also obtain prescription medications from
ing by checking ordered medication against product neighboring countries. In some of these cases, quality
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444 | An Introduction to Pharmacy

also becomes an issue.13 A relatively recent develop- are positioned to help patients safely integrate CAM
ment to reduce prescription cost to the patient is the therapy with traditional medications to assist in
offering of $4.00 generic medications by a number patient self-care efforts.
of retailers. These patient-initiated methods need to Another expanded community pharmacy service
be considered by the pharmacist as they are working beyond the prescription counter is durable medical
with each individual. Other issues, such as the high equipment (DME). The Medicare Modernization Act
rate of both initial and ongoing non-adherence with of 2003, which established Durable Medical Equip-
prescribed medication, also reduces the pharmacist’s ment, Prosthetics, Orthotics, and Supplies (DMEPOS)
ability to know what a patient is really taking without Quality Standards, requires suppliers of these prod-
a detailed medication history. ucts to become accredited in order to bill Medicare.15
Some pharmacies may be exempt from this accredita-
tion, such as those with DME sales billed to Medicare
Areas of specialty practice of less than 5% of the total pharmacy sales. Accred-
The Practice of Community Pharmacy has expanded itation must be from a CMS-approved, independent
from the conventional role of prescription dispens- national Accreditation Organization, and accredita-
ing to include many other health related services, tion can cost more than $3000 for a three-year period.
such as compounding medications, integrating com- As of 2010 all states allow pharmacists to
plementary and alternative medications, supplying immunize; however, each state differs in their
durable medical equipment, and administering immu- laws and regulations for pharmacist immunization
nizations. administration.16 Many local, state, and national
Although compounding medication is not new to programs are available to pharmacists to obtain
the practice of pharmacy, it has gained popularity training on vaccine administration. Accessibility
for the ability to individualize patient medications to the community pharmacy allows pharmacist-
and produce pharmaceuticals that are not commer- administered immunizations to make a positive
cially available. Hospice medications, bio-identical impact on public health and improved vaccination
hormones, pediatric preparations, veterinary medica- rates.
tions, and gluten-free, preservative-free, or dye-free
preparations are just a few of the examples of com- Current issues in community pharmacy
monly compounded pharmaceuticals. Thousands of practice
community pharmacies offer compounded medica-
tions; however, the volume of compounded prescrip- Provision and reimbursement for patient care
tions varies from practice to practice. Some pharma- Community pharmacy continues to evolve in its
cies may base their primary business on compounded ability to provide medication-related patient care
medications alone. Pharmacies that specialize in com- services. Since the description of pharmacist respon-
pounding may choose to become certified by the sibilities in providing pharmaceutical care over 20
Pharmacy Compounding Accreditation Board. years ago17 and the inclusion of those principles in
Complementary and alternative medication professional organization statements,18,19 community
(CAM), which also has roots in early pharmacy pharmacists have endeavored to incorporate these
practice, is becoming more widely used in the precepts into the routine practice of pharmacy. To this
United States as an option to prevent and treat end, early investigations found that community phar-
health conditions. According to the 2007 National macists providing patient-centered care, as opposed
Health Interview Survey, 38.3% of Americans used to drug-centered care, could identify and address drug
some form of CAM.14 This category of treatment therapy problems beyond those associated with pre-
encompasses a wide range of therapies, including scription writing error or drug interaction. When
herbals and other natural products, acupuncture, pharmacists providing this care collected information
meditation, chiropractic care, or massage. Many necessary to evaluate patients’ drug therapy, problems
herbals and natural products have become a mainstay such as the need for additional therapy, availability
in the community pharmacy and these pharmacists of more appropriate drugs, adverse drug reactions,
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The scope of pharmacy practice | 445

and unnecessary drug therapy were identified at a be necessary at a time when others look to third
higher rate.20,21 Processes used by community phar- parties for reimbursement.34
macists in providing pharmaceutical care to patients
address many of the issues associated with the qual- Role of pharmacy technicians
ity of the medication use process and common types The use of technicians in community pharmacy has
of medication errors.22,23 The provision of pharma- increased considerably as pharmacists try to maximize
ceutical care by pharmacists is consistent with the efficiency in prescription processing while maintaining
methods recommended by the Institute of Medicine high quality standards. The training and incorpora-
report, To Err is Human, to identify and address drug tion of technicians into the workflow in a community
therapy problems (medication-related errors).24 Sub- pharmacy has transitioned from an informal process
sequent studies have found that pharmacists working to one which includes accredited training programs35
in the community setting can positively affect both and regulated practice.36 All but six states and the
the clinical, economic, and humanistic outcomes of District of Columbia regulate technician practice. Cer-
drug therapy by providing patient centered care.25 – 32 tification of technicians is required in sixteen states.36
The term used to describe pharmacist provided As of June 2011, over 400 000 pharmacy techni-
patient care is also changing. Names such as Compre- cians were certified by the two national certification
hensive Medication Review, Comprehensive Medica- exams.37,38 The role of technicians and limitations on
tion Therapy Management, and Pharmacist Care may their practice varies from state to state.36 Community
pharmacists hoping to maintain profitability at the
be used synonymously. Pharmaceutical care was gen-
same time they are providing more patient care ser-
erally accepted for years, but with the implementation
vices are increasingly utilizing technicians. They can
of Medicare Part D, and the inclusion of medication
reduce the amount of time spent by pharmacists in the
therapy management (MTM) as a part of that benefit,
dispensing process and allow increased effort to be
MTM is the current term used most often. Although
focused on providing patient care activities. How the
MTM was mandated to be provided by the PBMs,
use of technicians ultimately balances with practice
which administered the benefit, it was not necessarily
change of pharmacists, increased use of technology,
referring to care provided by a pharmacist to opti-
and evolution of pharmacy law remains to be seen.
mize an individual patient’s drug therapy. Its intent
was to assure that measures were in place to limit Residency training for pharmacists
the cost and assure quality of the benefit delivered
As more pharmacists provide patient care to patients,
by an individual PBM, focused on high utilizers of
the necessary training for pharmacists beyond com-
care. The number of Medicare Part D plans utilizing
pletion of a doctor of pharmacy degree program
the community pharmacist to provide MTM is vari- has been up for debate. Some national professional
able, as are the criteria for beneficiaries to be eligible organizations envision a future which includes res-
for the benefit from a Part D plan or an insurance idency training for all pharmacists providing direct
plan.33 The addition of the MTM benefit did give patient care.39,40 Important in this discussion are the
rise to a set of codes within the Current Procedural number and types of residency programs available
Terminology (CPT) codes published by the American to achieve this vision. While the number of hospital
Medical Association. These standardized codes are pharmacy Post Graduate Year One (PGY1) Resi-
used for pharmacist billing of MTM services provided dencies approached 2000 in 2011, the number of
to patients under Medicare Part D. positions in PGY1 Community Pharmacy Residencies
Having billing codes for use with Medicare or was only 110.41 This number is clearly insufficient
other insurers does not ensure these services will to train a substantial proportion of the pharmacists
be paid for by third parties. Delivering a consistent that choose community pharmacy as a career. As
set of care services to patients, and doing so with the number of patient care-focused community phar-
an agreed upon value, is necessary to solidify the macies increases, so will the need for these sites to
community pharmacists’ standing in the healthcare increase their role in residency development to expand
system. Clarifying this first in the private sector may advanced training opportunities.
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446 | An Introduction to Pharmacy

Community pharmacy accreditation The eventual outcome for these ideas and how they
Beyond State Board of Pharmacy licensure of commu- will look in practice remains to be seen.
nity pharmacies, a movement to establish Community The 2010 Affordable Care Act moved this pro-
Pharmacy Accreditation is in its early stages. The pro- cess forward for Medicare beneficiaries through the
posed voluntary program will have standards that creation of Accountable Care Organizations (ACOs).
will be focused on patient care activities and contin- Innovative ideas to bring together groups of providers
uous quality improvement.42 This effort is in concert and service suppliers with the goal of delivering seam-
with other healthcare quality assurance activities and less quality care to Medicare beneficiaries in a more
is being proposed in a way to ensure that pharmacy, cost effective way will be tested.46 The place for
rather than an outside organization, leads this quality the community pharmacist as a provider within an
initiative.43 ACO is still being envisioned as this manuscript is
being drafted; however, it offers yet another new
opportunity for community pharmacy practice.47
Pharmacist credentialing
The practice of community pharmacy has changed
Certification of individual pharmacists with creden-
dramatically over the past decade. The pace of this
tials beyond licensure is performed by the Board change seems to increase as new care delivery philoso-
of Pharmacy Specialties (BPS). Qualified pharmacists phies and the organization of the healthcare system
are able sit for a Board exam in several practice continue to evolve to address the issues of quality and
areas and subsequently recertify through exam or cost. While a defined path for community pharmacy
continuing education. Historically, some community does not at this time exist, opportunity for utilizing
pharmacists became Board Certified Pharmacother- the expertise of community pharmacists to ensure
apy Specialists. This credential did not pertain to the access to quality care related to medications remains.
community setting well, and in 2011 an examina-
tion for Board Certified Ambulatory Care Pharmacist
came into fruition. Whether or not this becomes the The practice of health systems
credential sought out by patient care-focused commu-
pharmacy
nity pharmacists remains to be seen.
The transformation of hospitals into health systems
The patient centered medical home and occurred over the past 20 years because of advance-
accountable care organizations ment in complex medical therapies and technologies,
The concept of the patient centered medical home as well as external pressures from ever changing
(PCMH) has developed as a model to address identi- revenue streams and restriction of resources. The
fied needs in the delivery of healthcare. The process traditional hospital of the past bears resemblance
of definition and setting standards is still in pro- to the complex health systems of today and the
cess but includes components such as a focus on the term ‘‘hospital’’ is still appropriately used. The term
patients getting access to the components of care they ‘‘health system’’ refers to a range of services that
need, a coordination of care with planning and track- include hospitals, hospital-based clinics, infusion cen-
ing of care, assisting in self-care as appropriate, and ters, and hospital based outpatient departments. For
measurement of performance data to improve care.44 the purposes of this section the two terms will be
Pharmacist involvement in the care of patients can used interchangeably. Similar to health systems, the
assist in improving the outcomes of care in a number practice of pharmacy within the hospital setting has
of areas envisioned in the PCMH model. Given the been transformed due to the increasing complexity of
track record of pharmacists working with physicians medication therapy and financial pressures to ensure
in ambulatory care environments and increasingly optimum clinical outcomes with cost effective treat-
in community pharmacy environments, a case can ment, while ensuring the safe use of medications
be made for roles for the community pharmacist in within the system. The skills and leadership that the
PCMHs.45 Issues remain for how best to link, utilize, pharmacist brings to table makes the practice of phar-
integrate and reimburse pharmacists in this model. macy in the health system very unique.
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The scope of pharmacy practice | 447

The health system private For Profit organizations owned by individu-

als, partnerships or corporations, private Nonprofit
The health system is an organized, integrated network
organizations operated by a church or other nonprofit
of relationships with different disciplines, facilities
group, and government (federal, state, and local) enti-
and healthcare providers, designed to improve or
ties. Combined, these entities account for over 37
restore the health of a community. According to the
million admissions and over $700 billion in expenses
World Health Organization (WHO), a health system
annually.49
consists of all organizations, people and actions whose
The AHA registers hospitals into four types:
primary intent is to promote, restore or maintain
health.48 The development of health systems began
with the forerunners of early hospitals in Ancient 1. General – providing services for a variety of medi-
Egyptian and Greek temples acting as centers for cal needs and patient types
healing, in that they provided refuge and treatment 2. Specialty – providing services for patients with a
for the sick, and also provided centers for teaching specified medical condition such as cardiac, oncol-
the healing arts. The first hospital on the American ogy, or orthopedic maladies or for specific patient
continent was built by the Spaniards (led by Cortez) in populations such as pediatrics or geriatrics
1524, the Hospital of the Immaculate Conception in 3. Rehabilitation and Chronic Disease – providing
Mexico City. In the American colonies, a hospital was care to individuals who require restorative or
built in 1663 on Manhattan Island for sick soldiers. adjustive services
The first incorporated hospital in the United States 4. Psychiatric – providing services to patients who
was the Pennsylvania Hospital, established in 1751. have a psychiatric related disease.
Early hospitals had a close relationship with for-
mal religious sects and aligned with Christian doc-
trine. They were supported as charitable organiza- Some health systems can further be distinguished
tions, primarily for the care of the poor. As medical by their function beyond patient care. That function
treatment and education developed, the public sector can be education, research, or public health. The
became more and more dependent on the services health system also functions within the community
provided by hospitals. Funding sources changed from as a focal point of emergency care and treatment
charitable contributions to government support and for large numbers of victims in the event of nat-
third party insurance companies. The medical care of ural disasters, catastrophic accidents, and terrorist
the patient and their spiritual needs began to separate, attacks.
in large part due to the secularization of university The patient care function at health systems is
based education, as well as the impact of the Social generally delivered through a structured organiza-
Security Act (Medicare) in 1965. However, religious tion of departments including acute care (i.e., emer-
influences can still be seen today in American health gency services, trauma, and surgical services), spe-
systems. Indeed, there are health systems that are still cialty units (i.e., cardiology, oncology, labor and
operated by formal religious organizations and help delivery, neurology, intensive care units) and outpa-
provide care to the indigent populations who do not tient departments (i.e., rehabilitation, physical ther-
qualify for government support or do not have access apy, cardiopulmonary, dialysis, behavioral health,
to health plans. and dental). Non-clinical departments also contribute
The transformation of the hospital into an inte- to the patient care function and mission of the organi-
grated health system generally involved the merger of zation by the services they provide: medical records,
different individual hospitals and the diversification of information services, facility maintenance, billing,
clinical services such as clinics, home health, ambu- quality improvement, marketing, risk management,
latory surgical centers, long-term care and wellness and security. Clinical support departments provide
facilities. Today, according to the American Hospital direct and indirect patient care: laboratory services,
Association (AHA), there are over 5700 registered pathology, radiology, respiratory therapy, and phar-
hospitals in the United States.49 Hospitals comprise macy.
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448 | An Introduction to Pharmacy

Health system pharmacy Pharmacy technicians, medication

The transformation of pharmacy practice in hospitals preparation, and distribution
is no less dramatic as the organization in which it systems
resides, from the first hospital pharmacist, Jonathan
Roberts, at the Pennsylvania Hospital in 1752 to the The role of pharmacy has historically been as sup-
advanced clinical pharmacy practices in our mod- plier of the tripartite medication use system with
ern health systems. Today pharmacists and pharmacy physicians controlling the ordering and nurses the
technicians work with various departments to assure administration. Over time these standard divisions of
the safe, efficient, and cost appropriate distribution labor have often blurred and shifted. For example, in
and medication use systems. They practice as a team many health systems, especially very small hospitals
with physicians, nurses, and other healthcare pro- with less than 50 beds without 24 h pharmacy ser-
fessionals to care for the patient. Health system vices, it is still the nurse’s responsibility to prepare
pharmacy has significantly grown in the latter quarter an intravenous dose of medication before it can be
of the twentieth century. The increasing complex- administered.50 Nonetheless, it is the prerogative of
ity of medication therapy continues to fuel the need the pharmacist and the pharmacy technician to ensure
for health system pharmacists with the skills and that appropriately selected medications are correctly
expertise that meet the pharmaceutical care needs of prepared and made available for the patient. Many
hospitals. years ago the pharmacist was the one who actually
This transformation of pharmacy practice was prepared all medications for distribution. Today that
accelerated by strong pharmacy leadership and is primarily the role of the pharmacy technician.
support from national pharmacy professional associ-
ations, such as the American Society of Health System
Pharmacists (ASHP). Starting with the landmark
Pharmacy technician
‘‘Hilton Head Conference’’ in 1985 which cemented The advancement of the pharmacist practice model
the need to rapidly advance clinical practice to into the clinical domain has been assisted to a great
the most recent Pharmacy Practice Model Initiative extent by the skilled pharmacy technician. Pharmacy
(PPMI) in Dallas, Texas in late 2010 which will technicians provide the technical support for a health
continue to drive the transformation of health system system’s medication preparation and distribution sys-
pharmacy practice for the next 10 to 15 years. tems. This support allows the pharmacist to expand
This continued transformation will be supported their focus to enhancing patient outcomes through
by expansion of pharmacy education and training appropriate medication management. Because indi-
requirements, the enhanced technical skills of the vidual state boards of pharmacy regulate and often
pharmacy technician, as well as the advancement of specify the functions that technicians can perform
pharmacy automation. under the supervision of a pharmacist, their roles
Challenges and opportunities to improve con- vary among states. In addition, the state board may
tinue to shape health system pharmacy practice. also specify the number of technicians relative to
It has evolved over the years in many ways. This the number of pharmacists that be utilized by the
section will describe the historic, current state, and pharmacy. This state to state variation has also led
some of the innovations that make health system to differences in training, competency standards and
pharmacy practice unique, highlighting the following certification requirements.
subject matter: pharmacy technicians and medication The article Opportunities and challenges related
preparation, clinical practice, medication use pol- to pharmacy technicians in supporting optimal phar-
icy, leadership, contracting and procurement, human macy practice models in health systems examined the
resources, information technology, automation, and wide variation in training and certification require-
education. ments across the United States. In 1995 the Pharmacy
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The scope of pharmacy practice | 449

Technician Certification Board (PTCB) launched the 2. The original medication order is scanned and the
first national voluntary certification examination; image is electronically sent to pharmacy to be
however, there are still some states that have yet printed or reviewed on monitor
to require it. Although ASHP accredited technician 3. The physician writes the medication order on a
training programs exist in colleges and technical separate prescription blank, commonly for home
schools, most pharmacy technicians received training, use
either formally or informally, on the job. The role 4. Physician inputs the order directly into a computer
of the pharmacy technician in most health systems (Computerized Provider Order Entry or CPOE).
is drug purchasing, preparation (compounding), and
distribution with the pharmacist being responsible Once the order is received by the pharmacist, it is
for direct oversight. This article states that, over the reviewed and if appropriate the medication is made
years, there have been numerous calls from many available to the patient. This can be accomplished
organizations to establish pharmacy technician com- using different distribution systems:
petency standards and formalized accredited training
programs leading to official certification. It further • floor stock system
argues that if the health system pharmacy practice • patient prescription system
model is to be elevated to the level that makes it • unit-dose system.
possible to meet the pharmaceutical needs of patients,
this must be achieved now so that the transition can In the early days of hospital pharmacy the floor
be made safely. There are many opportunities beyond stock system was the primary means that the phar-
the preparation and distribution of medications that macist used to distribute medications for patient use.
involve the pharmacy technician, including obtaining The pharmacist’s role in those days was little more
medication histories, administering medications, than a medication purchaser and stocker, with lit-
conducting benchmark surveys, manage vaccine tle involvement in the clinical review of medication
databases, screening electronic medical records orders. When a physician order was written the nurse
for potential pharmacist interventions, managing would retrieve the medication from a supply room on
medication assistance programs, and many others.51 the ward which was stocked by the pharmacist in bulk
containers. The nurse would prepare the dose, either
oral or IV, from the bulk containers and administer
Floor stock, patient prescription,
the dose. The pharmacist would rarely see the physi-
and unit-dose systems
cian order.52 In some cases the floor stock system is
Medications are administered to hospitalized patients still in use today in most hospitals for drugs that are
only upon the order of a physician (or designated used in emergencies or for immediate patient com-
allied health professional). Thus, a prescription order fort. However, the use of bulk containers to supply
originates in the patient’s medical record, where directly to the patient is no longer considered safe
physicians write all the orders (prescriptions) for the or hygienic and is therefore limited.50 Some hospital
patient. Because the patient’s medical record, unless pharmacies still supply floor stock multi-dose insulin
electronically stored, remains at the patient care area, vials to the nursing units to be used by the nurse to
it is essential that some means be used to transmit the draw up patient-specific doses for multiple patients.
prescription order from the patient area to the phar- Other forms of floor stock include emergency crash
macy. These orders are transmitted to the pharmacy cart trays or other similar ‘‘kits’’ that are used in
usually in one of four ways: emergent situations. If medication is floor stocked,
it is now considered safer if it is packaged as ‘‘unit
1. The medical record has a duplicate copy so the dose’’, which will be discussed later in this section.
pharmacy can obtain a carbon copy of the physi- Also to add more control, safety and accountability,
cian’s original medication order automated dispensing machines (ADMs) are used.
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450 | An Introduction to Pharmacy

The floor stock system evolved over time into the dose. An option that some health system pharma-
patient prescription system, in order to enhance safety cies choose to utilize is outsourcing the repackaging
and to promote inventory control. The patient pre- or compounding of unit-dose medications to third
scription system involves the pharmacist to a greater party pharmacies or compounding centers.
extent in the order review. In this system the nurse
transmits the order to the pharmacy and the phar-
Compounding
macist prepares several days of doses in a container,
labeled much like an outpatient prescription. The Pharmaceutical compounding, once the heart of the
nurse is still required to take the correct quantity of pharmacy profession, is still a necessity in today’s
doses from the container and administer them to the health system pharmacy practice. There are still many
patient; however, it is considered safer than the bulk pharmaceuticals that are either not available from
floor stock system because the medications are pro- commercial sources or not in the appropriate dosage
vided for a specific patient which would help reduce form. This is especially true for specialized patient
drug selection errors. This method may still be in use populations such as pediatrics.53 Health system phar-
today at some of the very small hospitals and nurs- macy compounding includes nonsterile and sterile
ing homes that do not have 24 hour and weekend products and represents one of the highest risks for
pharmacy coverage and do not have the resources to patient harm. The potential for human error is signif-
purchase ADMs. It is also the method used for patient icant and can occur through miscalculations, missed
specific bulk containers or multi-dose such as lotions, steps, product contamination or incorrect selection
aerosolized inhalers, eye or ear solutions, and some of a base drug or diluent, which can lead to patient
injections. harm or death. Often these tragic, preventable deaths
In the 1980s, the patient prescription system was become headline news stories.54 – 56 The risk escalates
largely replaced by the unit-dose system. This was because often compounding involves the preparation
done to promote patient safety and to avoid drug of pharmaceuticals for multiple patients and even if
errors. As a result, the safest, most accepted method the health system pharmacy elects to outsource a por-
of dispensing medications to the hospitalized patients tion of its compounding service to a third party, the
is the unit-dose system. This has become the standard potential for multiple patient harm and death exists.57
of practice in most hospitals today and is favored Although there are differences in the approach
by national regulatory agencies. In this system the and execution for compounding nonsterile or sterile
pharmacy prepares each dose of medication ready for products, fundamental elements that should be in
administration and dispenses in either a centralized place in every health system pharmacy include:
medication cart-fill exchange (with the carts contain-
ing individual patient trays with a 24 hour supply) or 1. Comprehensive training and competency program
decentralized through an ADM system. For example, for all personnel responsible for compounding.
tablets and capsules are labeled and dispensed as a 2. Standard Operating Procedures (SOPs) - a
single dose for each patient, liquids are measured detailed step by step roadmap for each different
into oral syringes, lyophilized injections diluted, mea- compounding category (i.e., chemotherapy
sured accurately and transferred aseptically into sterile infusions, neonatal oral liquids, ointments, total
syringes, parenteral medication admixtures added to parenteral nutrition (TPN), intermittent infusions,
intravenous solutions prior to use, and oral powders etc.).
and other unusual dosage forms measured and mixed 3. Compounding formulation cards or recipes espe-
appropriately. Most of these procedures involve phar- cially for multiple ingredient admixtures.
maceutical techniques called ‘‘compounding,’’ which 4. Quality control and assurance steps–double
are a pharmacist’s responsibility. Many of the drugs checks, weight and color verifications, bar-code
available today come from the manufacturer already verification of base components.
in unit-dose form, especially oral solid medications; 5. Compounding log – documenting source contain-
however, some oral liquids, topical and intravenous ers, lot numbers, expiration dates, preparation
drugs are packaged by the manufacturer as unit dates, beyond use dates, internal control number,
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The scope of pharmacy practice | 451

the initials of compounding personnel, and quality The USP Chapter<797> standards are enforce-
control documentation. able by federal law through the FDA; however, most
6. Compounding reference material – published ref- state boards of pharmacy have adopted these stan-
erence that supports the stability and viability of dards or similar standards into their state pharmacy
the compound or admixture. rules and regulations. This also makes it subject to
7. Appropriate, functioning, and calibrated com- survey from accrediting organizations like the Joint
pounding equipment. Commission.
8. Disciplined environment – compounding person-
nel and their colleagues must have a sincere appre-
Hazardous waste disposal
ciation for the seriousness of the work they are
performing. It must have the focus of their atten- One of the results of the medication preparation,
tion, without distractions. Pharmacy managers distribution and administration process is left over
must maintain this environment by immediate unusable drug waste. This is generated either through
coaching when at-risk behaviors or variation from remaining drug product after preparation, expired
SOP are witnessed. drugs that were not used, or drug residue from
packages or containers after the medication has been
Nonsterile compounds include products such as administered to the patient. In the past these remnants
ointments, creams, oral liquids, and to a much lesser were disposed of as regular landfill waste, incinerated
extent tablets, capsules and suppositories. The United in the hospital or simply flushed down the drain. It
States Pharmacopeia (USP) Chapter <795> provides has been determined that some of the drugs used in
a source for practice procedures and standards for the health system are considered too hazardous to the
nonsterile extemporaneous compounding. environment. The Resource Conservation and Recov-
Sterile compounds or admixtures include products ery Act, enacted in 1976, defined and attempted to
such as IV injections, intermittent antibiotic infu- minimize environmentally hazardous waste. This law
sions, chemotherapy infusions, pain ball pumps, TPN, was largely ignored in hospitals until 2002, when
cardioplegic solutions, large volume parenterals, eye Environmental Protection Agencies (EPAs) of a few
drops, and so on. Compounded sterile admixtures states started enforcing the act by levying very large
represent the greatest risk to patient safety because fines against hospitals that were found to be out
there is a greater chance of significant overdoses of of compliance. Enforcement has increased in other
toxic drugs and bacterial contamination. Therefore, states and health system accrediting agencies, such
after growing concerns and attempts to establish self- as the Joint Commission, are now including compli-
regulated professional guidelines, the USP created the ance in their surveys. This has created the need for
first enforceable national sterile compounding stan- each health system to develop a pharmaceutical waste
dards in 2004 called USP Chapter <797> which was stream management system.
later revised in 2007. This chapter establishes stan- Compliance with the law is both complex and
dards in environmental requirements and controls, expensive. It requires the health system to deter-
personnel training and garbing, quality assurance, mine if it is a small or large quantity generator of
storage requirements, beyond use date (BUD) limita- hazardous waste. This is based on the weight of
tions, and SOPs for five risk categories: acutely hazardous material, called P-List chemicals,
wasted within a calendar month. The next step is
1. Immediate use – for emergent situations to obtain an EPA identification number, then estab-
2. Low risk level – for simple, closed system transfers lish separate waste streams for three categories of
3. Low risk level with less than 12 h BUD waste:59
4. Medium risk level – admixtures with multiple
components or small volumes, batch prepara- 1. Commercial Chemical Hazardous Waste
tions, or complex manipulations a. P Listed – Acutely Hazardous (examples: war-
5. High risk level – admixture originating from non- farin, epinephrine)
sterile ingredients or open system transfers.58 b. U Listed – Toxic (Chemotherapy)
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452 | An Introduction to Pharmacy

2. Characteristic Hazardous Waste Clinical pharmacy services

a. Toxic
b. Ignitable The practice of health system pharmacy has changed
c. Corrosive dramatically over the past 20 years. Years ago, the
d. Reactive practice centered on preparation, compounding, and
3. Non-Hazardous Waste distribution of medications. Slowly, the practice of
‘‘clinical pharmacy’’ emerged in the 1980s. The term
In order to comply, some hospitals have set up ‘‘clinical services’’ refers to the practice of providing
multiple color coded waste receptacles on nursing medications to patients in the most safe, effective, and
units and used the hospital’s pharmacy information rational manner possible, while individualizing care
system to attach special codes on medications that will to the recipient. Clinical services were, at that time,
appear on medication administration records (MARs) conducted by a select few pharmacists who typically
or pharmacy labels directing the nurse to which recep- had advanced their education with a Doctor of Phar-
tacle the wasted drug belongs. The hazardous waste is macy degree (beyond the Bachelor of Science Degree)
then taken to a federally permitted hazardous waste and occasionally postgraduate residency training. In
incinerator and placed in a lined hazardous waste the mid-1990s there was a conversion of colleges of
landfill. pharmacy to the Doctor of Pharmacy degree alone,
eliminating the Bachelor of Science degree completely
in 2004. In 1985, the American Society of Health-
Ambulatory care services System Pharmacists (ASHP) conducted the Hilton
Head Conference, bringing together leaders in health
As ambulatory care activities continue to increase system pharmacy to set a future direction for the
within the institutional setting, the health system profession.60 The result of the conference was a
pharmacist becomes more and more involved in stronger emergence of the practice of pharmacy as
providing services to these patients, either as retail a ‘‘clinical’’ profession. It defined the fundamental
oriented pharmacy services or clinical pharmacy ser- purpose of the pharmacy profession as ‘‘serving as a
vices. The patients are often seen in clinic settings, force in society for the safe and appropriate use of
by home care services, by hospice services, infusion drugs.’’60 Soon after, ASHP developed a standard for
centers, etc. Pharmacists practicing in ambulatory residency programs specializing in the clinical prac-
care settings have expanded many of the service con- tice of pharmacy. Postgraduate residency programs
cepts initiated in the hospital and the community have been steadily growing ever since. The 1993, the
pharmacy settings. They include special patient infor- ASHP San Antonio Conference further established
mation brochures, patient dosing calendars, special Pharmaceutical Care as the primary role of the phar-
packaging, patient education for home care, review macist in serving patients.61 In 2010, ASHP held
of prescribing practices and recommendations for the Practice Model Initiative Summit, defining key
improvement, development of therapeutic protocols, roles of pharmacists and technicians in ideal future
etc. In addition, pharmacists in some clinics have col- practices.62 For pharmacists who wish to attain addi-
laborative practice agreements with physicians that tional recognition for their knowledge in specialty
allow the pharmacist to monitor selected patients areas, the Board of Pharmaceutical Specialties (BPS)
and prescribe or adjust specific medication therapy in has developed a certification process to recognize
accordance with the agreement or protocol (e.g., anti- areas of specialty such as nuclear pharmacy, nutrition
coagulation, hypertension, asthma, diabetes). These support, pharmacotherapy, oncology, psychiatry, and
collaborative practice agreements can be established ambulatory care. The BPS continues to evaluate other
in most states. In some states, depending on the specialty areas for inclusion in certification.63 Certi-
state law, pharmacists are granted provider status for fied Geriatric Pharmacist (CGP) is another recognized
providing medication management therapy services opportunity for specialty recognition and is offered by
which allows them to bill and be directly reimbursed the Commission for Certification in Geriatric Phar-
by third party payers for those services. macy.
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The scope of pharmacy practice | 453

Today, the modern practice of pharmacy often 1. Therapeutic Drug Monitoring – This term
integrates the traditional distribution functions with generally refers to the practice of obtaining
the clinical services of the pharmacist. Health sys- blood/serum concentration of medications, in
tems have either installed (or are planning to install) order to maintain the drug dose in the ‘‘thera-
fully electronic medical records, which blends the peutic range.’’ Often the pharmacist will apply
prescribing, dispensing, billing, administration, and various calculations to assure that the drug
documentation functions into one computer applica- reaches a ‘‘steady state’’ concentration that is
tion. Health system practitioners now have one system therapeutic, but not toxic.
to access a patient’s diagnosis, past medical history, 2. Drug Information – Medication therapies in
laboratory values, and medication list. Computer- health systems are growing increasingly complex
ized provider order entry (CPOE) is commonplace. and are frequently changing. The pharmacist is a
Orders that are entered into the computer system valuable asset to the physician for providing drug
by physicians must be verified or ‘‘released’’ by the dosing and monitoring information. In addi-
pharmacist to appear the medication administration tion, the pharmacist assists nurses in scheduling
record (MAR). The MAR is used by nurses to sched- medications appropriately, as well as providing
ule medication administration times and to document medication administration guidance.
medication administration. While verifying physician 3. Patient Care Rounds – The act of ‘‘rounding’’
is becoming common, even in community
orders, pharmacists are expected to review the follow-
hospitals. As teamwork and communica-
ing pertinent information: age, gender, weight, height,
tion are emphasized, there is a greater need
diagnosis, current medications, allergies, laboratory
for the healthcare team to come together to
information, and pregnancy or lactation status. Age,
discuss the multiple aspects of a patient’s
gender, weight, and height are used in equations to
care. Pharmacists are an integral part of the
estimate the kidney function of the patient. If the kid-
rounding team, and evaluate drug therapy
ney function is diminished, the pharmacist may need
and dosing during the rounds. Pharma-
to adjust medication doses, for those medications
cists will then advise dose changes that
that are eliminated through the kidney. A diagno-
may need to be made in the patient’s drug
sis or medication indication is obtained to verify the
therapy.
appropriate selection of the medication for that con-
4. Adverse Drug Events – Despite medication
dition. The current medication list is reviewed for any
safety efforts, medications can still cause adverse
potential drug–drug interactions that may occur with
outcomes in hospitalized patients. The phar-
the newly prescribed drug. The pharmacist will also macist has a key role in the prevention, detec-
evaluate the medications for food–drug interactions. tion, and mitigation of adverse drug events. The
Laboratory information is reviewed to determine the pharmacist can help prevent adverse events by
function of the kidneys and the liver. Any organ dys- ensuring that the patient is receiving an appropri-
function may affect the elimination of the medication, ate medication for their condition, and that the
thereby causing the potential for medication accumu- medication is given in the right dose, route, fre-
lation and toxicity. This is particularly important for quency, and for the appropriate duration. Phar-
medications that have a ‘‘narrow therapeutic index,’’ macists also prevent adverse events by ensuring
that is, when the therapeutic dose or blood level is proper administration of medications. Pharma-
very close to the dose or blood level that can cause cists can help detect adverse events by inves-
toxicity. Product selection and sterile injection prepa- tigating any unusual circumstances, unusual
ration remain important practices in health system prescriptions, or the administration of antidotes
pharmacy. or reversal agents. Finally, pharmacists can help
Other common clinical activities of the health mitigate adverse events by providing ready access
system pharmacists, either by consultation or by scope to any antidotes or reversal agents, and by partic-
of practice policies, include the following:64 ipating in an analysis of events after the fact.
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454 | An Introduction to Pharmacy

5. Code Blue – Pharmacists participate in ‘‘Code 10. Anti-Infective Stewardship – Pharmacists are
Blue’’ or resuscitation events when patients expe- an integral part of anti-infective stewardship
rience either a cardiac arrest or respiratory dis- teams. The Infectious Disease Society of America
tress. The pharmacist’s role is to prepare medi- (IDSA) recommendations call for the thoughtful
cations that may be needed during a code. Many and prudent use of antimicrobial agents to avoid
medications used in code situations require com- over exposure to patients, bacterial resistance,
plex calculations to determine the appropriate and secondary infections. The anti-infective
dose for the patient. The pharmacist can assist stewardship team advocated by IDSA includes
with these calculations to assure a therapeutic a pharmacist, infectious disease physicians, and
dose is used. infection control practitioners. The stewardship
6. Medication Dosing – The health system may team reviews antibiotic, antiviral, and antifungal
allow pharmacists to automatically adjust med- medication use in the health system daily. They
ication doses for any organ dysfunction that the will compare anti-infective use to the condition
patient is experiencing. Other dose modifications of the patient, site of infection, and culture and
may be made for age or weight. In addition, the sensitivity results. The team then will make
pharmacist may be able to convert a patient from therapy recommendations that meet the needs
an injection to an oral dosage form, if the patient of the patients, while avoiding over-exposure to
is able to ingest the oral dosage form. unnecessary anti-infective agents. Anti-Infective
7. Formulary – Pharmacists are expected to pro- Stewardship programs have been shown to be
mote adherence to the institution’s formulary list effective in reducing patient exposure to anti-
of medications. infective agents.65 Using proven anti-microbial
8. Anticoagulation – Current regulatory safety therapies is also a Joint Commission National
standards require that health systems have in Patient Safety Goal.
place protocols and processes for handling high- 11. Outcomes Management – Medicare, along
risk drugs, including anticoagulant medications. with some private insurers, is increasingly
These agents must be held within tight thera- basing payment to health systems on their
peutic control to avoid either bleeding (with ability to provide standard, proven therapies
an overdose) or clotting (with an underdose). for certain patient conditions. These therapies
These protocols are generally developed and car- are considered ‘‘core’’ to certain conditions. For
ried out by pharmacists for medications such as example, each and every patient who experiences
heparin and warfarin. The pharmacists moni- a myocardial infarction should receive low-dose
tor laboratory values daily to make sure that the aspirin, unless contraindicated, for prevention
anticoagulant therapy is at a therapeutic level of further ischemia. These therapies are referred
and change doses accordingly. to a ‘‘core measures’’ and are being measured as
9. Nutrition – When patients cannot receive oral a condition of participation in provision of care
or enteral nutrition, parenteral (IV) nutrition for Medicare patients. Pharmacists participate
is used. The sterile preparation of these prod- in compliance with core measures by assuring
ucts is conducted by pharmacists. There may core therapies are received by eligible patients.
be many chemical incompatibilities with nutri- The Joint Commission sets National Patient
tional products and the pharmacist may need to Safety Goals for health systems as a requirement
modify the nutritional formula to prevent any for accreditation. Pharmacists participate in the
product inactivation. In addition, the pharma- achievement of National Patient Safety Goals
cist calculates the nutritional formula according related to medications. Examples of this include
to the amount of protein, carbohydrate, and fat anticoagulation, medication abbreviations, drug
that is appropriate for the patient’s body weight interactions, and medication reconciliation.
and condition. The pharmacist calculates elec- 12. Managing Transitions of Care – Managing the
trolyte, vitamin, and trace element needs for the process of obtaining an accurate medication his-
nutritional formula. tory of a patient upon admission to the health
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The scope of pharmacy practice | 455

system and making sure that any needed and known. Just as pharmacists evaluate organ func-
intended medications are continued in the health tion for their impact on elimination of medica-
system is called medication reconciliation. The tions from the body today, in the near future they
term ‘‘reconciliation’’ is defined as ‘‘the process will begin to evaluate the genetic code of patients
of making consistent or compatible.’’ Medica- in order to better predict a drug response. This
tions prescribed in the health system should be prediction will be used to optimize the dose, and
consistent and compatible with the medications therefore the patient response to medications.
patients were taking at home, as well as with Some health systems are currently evaluating
their current condition and any new medica- genetic markers for drug elimination or toxicity
tions prescribed. Patient transitions from home as a routine.
to health system, within the health system, and 15. Medication Therapy Management Services
from health system back to home are considered – Medication therapy management services
high-risk processes. Addressing this high-risk (MTMS) are services that optimize therapeutic
process is a requirement of a Joint Commission outcomes for individual patients, usually in
National Patient Safety Goal. The list of medi- a clinic setting. MTMSs include medication
cations must be accurate and appropriate for the therapy reviews, pharmacotherapy consults,
anticoagulation management, immuniza-
patient condition, upon each transition of care.
tions, and health and wellness programs. The
A common reason for early re-admission to the
medication therapy review is defined as a ‘‘face-
hospital is inaccurate use of medications, caus-
to-face patient assessment and intervention
ing a deterioration of the patient condition or a
as appropriate, by a pharmacist. MTMS is
medication adverse event.66
provided to optimize the response to medications
13. Narcotic Stewardship – A growing area of
or to manage treatment-related medication
concern with the FDA, the Drug Enforcement
interactions or complications. MTMS includes
Agency (DEA), state pharmacy boards, and the
the following documented elements: review
public is the misuse of narcotic medications.
of the pertinent patient history, medication
Pain management, hospice care, and end-of-life
profile (prescription and non-prescription),
management with narcotic medications is a
and recommendations for improving health
practice area that is emerging for pharmacists.
outcomes and treatment compliance.’’67 It is a
Medication therapy is a primary mode of treat- systematic process of collecting patient-specific
ment for these conditions. In addition, opioid information, assessing medication therapies to
medications have a narrow therapeutic index. identify medication-related problems, develop-
The role of the pharmacist in the health system ing a list of medication-related problems, and
is to determine therapy for chronic or acute creating a plan to resolve them.
pain upon admission to the health system, to 16. Documentation – Documentation in the patient
manage acute pain that may surface during their record is one of the means by which healthcare
admission (usually with injectable medications), professionals communicate with one another
and to stabilize therapy and convert therapy and document care received by a patient. Phar-
back to oral medications when the patient leaves macists are expected to document in the patient
the institution. Risk Evaluation and Mitigation record information such as physician consulta-
Strategies (REMS) programs are commonly put tions of the pharmacist, drug information ques-
into place by the FDA for opioid medications. tion results, relevant drug serum concentrations
The pharmacist has a role in REMS strategy and their interpretation, and patient education.
implementation to make sure the medications
are provided in a safe manner. The practice of pharmacy has changed signif-
14. Pharmacogenomics – The relationship between icantly in response to organizational standards,
genomes and the efficacy, elimination, and tox- patient safety, growth of technology and informatics,
icities of medications is becoming more well and increasingly complex medication regimens.
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456 | An Introduction to Pharmacy

The American College of Clinical Pharmacy defines The committee should meet on a regular schedule,
clinical pharmacists as ‘‘someone who takes care of that is, monthly or bi-monthly depending on the
patients in any setting’’ and clinical pharmacy as level of medication activity at the hospital. Optimally
‘‘that area of pharmacy concerned with the science the membership includes a cross-sectional represen-
and practice of rational medication use.’’68 As such, tation of key stakeholders of the medication use
all pharmacists are involved in clinical pharmacy system, including pharmacists, medical staff (pre-
services. scribers from different medical disciplines), nurses,
and other healthcare professionals. Administrators,
quality improvement personnel, and risk managers
Medication use policy should also be present because of their supportive
role in medication use. It is also common that mem-
The practice of health system pharmacy includes col- bership include a clinical dietitian due to the use of
laborating with other healthcare professionals in the TPN therapy and food–drug interactions. The clini-
development of sound medication use policies. The cal dietary department will often take advantage of
pharmacist lends their expertise and leadership ensur- the opportunity to interface with the physicians to
ing that medications used within the health system fulfill their requirement of medical staff oversight of
are thoughtfully considered prior to being procured, the health system’s clinical dietary manual.
stored, prescribed and administered. Also, these steps A successful P&T program relies on active physi-
are done safely and in the most cost effective man- cian membership because the P&T Committee rep-
ner while achieving the desired clinical outcome. The resents the medical staff for medication use issues.
ASHP Guidelines on the Pharmacy and Therapeutics In most health systems the actions and decisions
Committee and the Formulary System69 is an excellent made serve as advice and recommendations to both
resource in developing sound medication use policies, health system administration and the medical execu-
including the formulary system, the role and function tive committee, where those decisions are ratified and,
of a Pharmacy and Therapeutics (P&T) Committee, if structured in the medical staff by-laws, are binding
as well as other medication use and improvement to the entire medical staff. In small hospitals it is not
strategies. unusual for physicians to be represented by only one
or two members on P&T.
Part of the responsibility of establishing and main-
Formulary and formulary system taining the formulary system is deciding which med-
The ASHP guidelines discuss the historical develop- ications will be added to the formulary, evaluation
ment of the formulary from a basic list of medications of medication use and outcomes within the system,
that the military used on soldiers in the 1940s and, monitoring and creating interventions that prevent
based in large part on published evidence of value, medication errors and adverse drug reactions, devel-
grew into a comprehensive tool to ensure safe, appro- opment or evaluation of clinical practice guidelines
priate, and cost effective use of drugs in the health as they relate to medication use, development of
system.69 The formulary of today represents the med- policies and procedures for the procurement, stor-
ications available for use by the health system, which age, prescribing, preparation, distribution, adminis-
have been critically assessed by the practitioners tration and monitoring of medications and educa-
and pharmacists, as well as medication use policies, tion of health professionals on the optimal use of
decision support tools, and system guidelines. The for- medications.70
mulary system is the mechanism in which a formulary
is established and maintained. Medication selection and review
The evaluation of medications for formulary inclusion
Pharmacy and therapeutics committee should be an evidence-based, unbiased process using
The role of the P&T Committee is to provide over- relevant scientific literature and a thorough analysis of
sight of medication management and manage the risks and benefits to the patient. Information should
formulary system, including investigational drugs. be presented to the P&T committee in a formal,
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The scope of pharmacy practice | 457

standardized document, i.e. formulary monograph. relevant information about a drug that is already on
ASHP guidelines suggest that the formulary document the formulary, or as a therapeutic class review. Ther-
include these elements: apeutic class reviews should be performed regularly
with the goal of reviewing the entire formulary annu-
• Brand and generic names and synonyms ally. These reviews should include internal use data
• FDA approval information, including date and of existing formulary items, non-formulary drug use,
FDA rating new scientific evidence and relevant medication error
• Pharmacology and mechanism of action data.
• FDA-approved indications The formulary system should not, in all cases,
• Potential non-FDA-approved (off-label) uses prevent the use of agents that have not been formally
• Dosage forms and storage approved by the P&T. There should be a policy that
• Recommended dosing regimens defines a process in which a non-formulary product
• Pharmacokinetic considerations may be used when medical necessity exists. P&T com-
• Use in special populations (e.g., children, elderly, mittees should consider an expedited review process;
patients with renal or liver failure) in this way education and safety gaps can be identified
• Pregnancy category and use during breast-feeding and addressed quickly.
• Comparisons of the drug’s efficacy, safety, conve-
nience, and costs with those of therapeutic alterna- Strategies for managing medication use
tives (with evidence tables when feasible) Once established as formulary the P&T Commit-
• If information on comparable efficacy is minimal tee’s responsibilities are not concluded. The P&T
or lacking, data on absolute efficacy (i.e., efficacy and pharmacy has an ongoing obligation to ensure
versus placebo) that medications are used safely as well as eco-
• Clinical trial analysis and critique nomically. Several proven strategies are available for
• Medication safety assessment and recommen- managing medication use in the health system. These
dations (adverse drug reactions; drug–drug and include generic substitution, therapeutic interchange,
drug–food interactions; specific therapy monitor- IV to PO switch programs, renal dosing programs,
ing requirements; unusual administration, storage, pre-printed orders, clinical practice guidelines, and
or stability issues; and potential for medication medication use evaluations.
errors, such as look-alike or sound-alike issues),
and 1. Generic Substitution – One of the earliest strate-
• Financial analysis, including pharmacoeconomic gies used in hospitals to help manage cost. There
assessments.69 are high quality generic products available that
have been determined by the FDA as bioequiva-
As part of the medication safety assessment the lent and have been given an AB rating. Substitut-
FDA’s Risk Evaluation and Mitigation Strategies ing less expensive generic products for branded
(REMS) or MedGuide requirements should be has benefits for both the health system and the
included in the document, if they are appropriate for patient.
the facility and services provided. Other information 2. Therapeutic Interchange – The P&T Committee
sources that are helpful and should be considered can create a policy that allows the pharmacist to
for the review and decision include local health plan interchange one drug that has been established to
formulary status, internal data including physician be therapeutically equivalent to the drug ordered.
prescribing and outcomes, and the experience of local Therapeutically equivalent drugs possess different
recognized experts. The monograph should conclude chemical structures but have similar therapeutic
with a recommendation to accept into formulary, profiles. Dosing must be adjusted accordingly.
reject formulary status, or accept with restrictions as 3. IV to PO Switch Programs – Many drugs possess
to its use. similar bioavailability whether they are admin-
Drug reviews by the P&T committee can occur istered through the intravenous or oral routes.
when a new drug enters the market, there is new The IV route is necessary if the patient is unable
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458 | An Introduction to Pharmacy

to or ordered not to take medications by mouth. There are many resources to obtain clinical prac-
There are significant cost and safety implications tice guidelines. One source for clinical practice
to switching appropriate drugs from IV to PO. guidelines is the national guideline clearinghouse
Generally oral medications cost much less than sponsored by the Agency for Healthcare Research
their IV counterparts and the IV route subjects the and Quality (http://www.guideline.gov).69 Clin-
patient to inherent risks, i.e., medication errors ical practice guidelines serve as a useful tool in
and sepsis. developing pre-printed orders and establishing
4. Renal Dosing Programs – Policies allowing the criteria for MUEs.
pharmacist to automatically adjust doses of med- 7. Medication Use Evaluations – The MUE process
ications that are metabolized and/or eliminated is a quality improvement tool for medication use.
through renal mechanisms in patients who have The objective is to use data to improve the use
compromised renal function provide for safer of medications in the health system for the pur-
therapy with fewer side effects and includes an poses of improving clinical outcomes, reduce the
added financial benefit. The program should spec- potential for medication errors or adverse drug
ify the appropriate drugs and the specific dosing reactions or improve the financial performance
adjustment that can be made. Under the P&T pro- of the therapy under study. It begins by establish-
tocol, when the pharmacist receives an order for ing pre-determined utilization or outcome criteria
that drug they check the patient’s renal function based on the best available scientific literature
and adjust the dose according to policy. or clinical practice guidelines. Observations are
If approved by the medical staff, via the P&T conducted either retrospectively or concurrently,
Committee, adjustments like this one and the variance from the criteria is noted, data collected,
ones mentioned above generally do not require and interventions are made based on the results.
a new physician’s order. However, they should be In retrospective MUE studies, the data is collected
recorded in the patient’s medical record as adjust- and reviewed generally from patient charts or the
ments made per P&T approved protocol. Notifi- electronic medical record and the intervention
cation should also include the patient’s nurse so occurs some time after the event. The benefit of
that they are aware of the change. concurrent studies is the immediacy of improve-
5. Pre-printed Orders – A useful strategy to help ment efforts, in that the pharmacist can screen the
manage the appropriate use of medications. They medication at the time of order entry or verifica-
can contain orders for medications, labs, nurs- tion and the intervention can occur prior to the
ing treatments, monitoring parameters, and other start of therapy. MUE activity is generally per-
therapies all pre-printed on a physician order formed around problem prone, high risk or high
form. This program has multiple benefits includ- cost medication use but can also be used to mon-
ing clear legible orders, dosing hints, guided ther- itor the medication use policy decisions made by
apy choices (based on established clinical practice the P&T Committee.
guidelines), and convenience for the physician.
Pre-printed orders also help the transition to com-
Medication safety
puterized physician order entry. They should be
reviewed by P&T on a regular basis for any neces- An important duty of the P&T Committee is address-
sary modifications. ing medication safety concerns for the health system.
6. Clinical Practice Guidelines – These are based on Opportunities to address this duty include:
established outcomes-oriented clinical evidence. It
is designed to educate the care team on the most 1. When a new drug is being submitted for formu-
efficacious method for treating specific condi- lary consideration, a thorough assessment of the
tions. National clinical practice guidelines have drug’s risks should be included in the monograph
been developed by expert panels of clinicians for a document containing potential toxicities, prepa-
variety of diseases and are available for the health ration issues, look alike/sound alike problems,
system to use as a resource for building their own. and administration issues. The P&T Committee
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The scope of pharmacy practice | 459

should provide recommendations for mitigating are responsible for creating, following FDA require-
that risk. ments, for targeted drugs. The FDA specifies the use
2. If the organization is undergoing a project that of MedGuides under two different laws.
impacts medication use (e.g., smart pump imple-
mentation), there should be a proactive assess- • RiskMap Drug (21 CFR 208) – Considered part of
ment of the risks involved. This assessment should labeling requirement.
be in the form of a failure mode and effects anal- • REMS Drug (Food and Drug Administration Act
ysis (FEMA) which weighs the criticality of each (FDAA) of 2007 – Considered required patient
risk element by analyzing the potential serious- education.
ness of an error, the frequency that the error might
occur, and the chances of the error being caught MedGuides are required to be given to patients
(visibility). when specific targeted medications are dispensed from
3. Adverse drug event data should be routinely the outpatient pharmacy for the patient to take at
reviewed. This review should incorporate reports home or if the medication is to be self-administered by
of ‘‘good catches’’ or events that were caught the patient in the outpatient setting, namely the clinic.
prior to reaching the patient or have the potential REMS are programs (strategies) developed by the
for causing error. Pharmacist interventions serve manufacturer, and required by the FDA, to manage a
a very useful purpose here providing ‘‘good known or potential serious risk associated with a par-
catch’’ data for the ordering component of the ticular drug or biological product. The law requires
medication use system. manufacturers to submit proposed REMS prior to
4. Targeted quality improvement projects that product approval and, if warranted, the FDA can
involve medication use. These can be identified require post approval REMS for established products.
through trending adverse drug event reports. For Examples of strategies include:
example: improving ADM mis-fills.
5. Medication use policies that are created by the • Medication guides
P&T Committee should take into account poten- • Communication plans for healthcare professionals
tial risks or adverse consequences of that policy. • Elements to assure safe use (ETASU)
6. The P&T Committee should champion evidence • Special training or certification for prescribing or
based systems that prevent medication errors (e.g., dispensing
smart IV pumps). • Limited dispensing (specified pharmacy)
7. Continually learn about medication safety events • Special monitoring
or best practices that mitigate risks through • Use of patient registries
the review of safety literature. Examples of • Implementation system – mechanism(s) to assure
sources include: Institute of Safe Medication components of the ETASU are followed.
Practices (http://www.ismp.org), Medwatch
(http://www.fda.gov/medwatch), FDA Patient From the health system perspective MedGuides
Safety News (http://www.accessdata.fda.gov/ pertain primarily to the outpatient setting; however,
scripts/cdrh/cfdocs/psn/), and the US Phar- inpatients and inpatient pharmacies can be impacted
macopeia Patient Safety Tools and Resources by REMS. Certain drugs are only made available
(http://www.usp.org/hqi/patientSafety/resources/). through a selected pharmacy provider which can cause
delays due to ordering and shipping. This can cause
some difficulty in providing the continuum of care to
FDA MedGuides and REMS the patient.
In an attempt to improve the safety of medication use
in the United States, the federal government created Medication safety officer
the requirement of MedGuides and Risk Evaluation The Medication Safety Officer (MSO) or similar title
and Mitigation Strategies (REMS). MedGuides are is a fast growing specialty area of practice in the
printed medication information that manufacturers health system for one who is focused on the safe
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460 | An Introduction to Pharmacy

use of medications across the organization. Although The position of MSO is a recent development
suited for the expertise of a pharmacist, in some in health systems due to the increased interest in
cases the role might be filled by a registered nurse or patient safety over the past 10 years. There were not
even a physician. If a pharmacist, it is important to many opportunities for formalized training. Generally
remain an unbiased resource for nursing, physicians these individuals developed themselves through read-
and administration. Some MSOs report to the director ing, attending conferences, being mentored by safety
of pharmacy, others to hospital administrators or leaders, participating on medication safety panels, etc.
quality/risk managers. Today there are more formalized medication safety
Although the MSO is involved in quality-related training programs including accredited residency and
improvement strategies and programs for the safe use fellowship programs. A new professional association
of medications, the job description can vary from called the American Society of Medication Safety
system to system depending on reporting structures. Officers (ASMSO) has been created to assist in pro-
Some of the responsibilities could include: fessional development and to help establish resource
networks.

• Providing support to the P&T Committee on issues

related to safe medication use Leadership
• Leading the health system’s medication safety com-
mittee or team The health system or hospital is an organization of
• Identifying and leading the implementation of best people, each one of whom has their own individual
medication practices mind filled with their own individual thoughts, goals,
• Development of standard operating procedures expectations, ideas, personal problems, and person-
and training tools alities. The people also have responsibilities to the
• Conducting educational programs regarding medi- organization that make it possible achieve the out-
cation safety comes necessary to keep doing what the organization
• Encouraging medication event reporting and pro- is designed to do, in this case, improve the health
viding report analysis and trending of the community it serves. That way it can obtain
• Identifying and/or leading quality improvement enough financial reward so that it can continue to do
projects involving medication safety what it is designed to do, whether that responsibility
• Serving as an internal safety consultant by is to clean a recently vacated room so that it can be
rounding in all areas where medications are used, ready for the next patient or be the CEO of the entire
assesses current state and makes recommendations organization. Each is important to the success of the
for improvement organization and leadership makes it happen, and
• Participating in the health system root cause anal- good leadership makes it happen well even through
ysis (RCA) program when a significant medication challenging times.
misadventure occurs, determining where all the Many definitions exist for the term leadership.
risks exist and developing medication safety plans One source defines leadership as ‘‘(1) establishing
to address them for the entire health system a clear vision, (2) sharing that vision with oth-
• Reviewing external information resources such as ers so that they will follow willingly, (3) providing
journal articles, alerts, and safety bulletins. Creat- the information, knowledge, and methods to real-
ing a medication safety library and sharing perti- ize that vision, and (4) coordinating and balancing
nent information with pharmacy, nursing, physi- the conflicting interests of all members or stake-
cians, and administrators holders. A leader comes to the forefront in case of
• Keeping medication safety issues in front of asso- crisis, and is able to think and act in creative ways
ciates with newsletters, alerts, notices, and so on in difficult situations.’’71 John Maxwell’s definition is
• Working with senior leadership to ensure that briefer: ‘‘leadership is influence – nothing more, noth-
there is a strategic priority placed on medication ing less.’’72 The ability to influence others is clearly the
and patient safety. key to leadership, and the ability to create and share
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The scope of pharmacy practice | 461

a vision that others will want to follow by providing providing resources, that is, patient throughput con-
them with rationale for change and demonstrating a sultants, whereas a solitary housekeeper can inspire
caring attitude to their welfare are tools for creating other housekeepers through their actions and com-
influence. Leaders are able to adapt to change and mitment to excellence by turning an empty patient
inspire others to commit to follow. room around quickly, because they know that is their
Managers may be leaders, but there is a clear contribution to moving the organization closer to its
distinction between leading and managing people. goal of improved throughput.
A manager makes sure things get done, SOPs are
followed, and variances are corrected. They make
sure the work schedule is complete and posted, that Health system leadership
quality controls are in place and functioning correctly. The health system has an organized leadership struc-
Managers bring value to the organization by being ture. The ultimate accountability belongs to a gov-
good at getting people to do what they are supposed erning board, usually called the Board of Directors
to do and maintaining the status quo in day to day or Board of Regents, who delegates responsibilities to
operations. Leaders observe trends, identify needs, the CEO or president including: fulfilling the mission,
create direction, communicate passion, and inspire strategic planning, selection of competent personnel
others to follow. Covey73 makes the distinction clear including the medical staff, control of health system
in his analogy of two types of lumberjacks. A manager funds, and supervision of the physical plant. The gov-
lumberjack is great at making sure saw blades are kept erning board generally has several committees that
sharp, workers are felling trees at the appropriate assist in fulfilling its role, such as:
rate to make quota, and OSHA requirements are
adhered to, while the leader lumberjack climbs the
• the executive committee
tallest tree, surveys the landscape and yells down • committee dealing with personnel appointments,
to the manager ‘‘Hey, we’re in the wrong forest, especially the medical staff
we need to be 25 miles north of here!’’ Leaders • finance committee
focus on getting people to commit to the right goal, • public relations committee.
while managers concentrate on getting people to move
toward a goal.74
The CEO hires subordinates to assist him or
Leadership is not always about titles and posi-
her in carrying out their responsibilities. Depend-
tions. In all organizations there are those leaders who ing on size and complexity of the health system,
are in the formal position to lead, from the CEO to there could be more than one layer of administrators.
the director of pharmacy. These are individuals in These administrators, in turn, hire a leader for each
position of authority, and have a greater potential to department, including a nursing service, blood bank,
influence others because they have greater access to physical medicine, business office, housekeeping, and
information, resources, and contact with other lead- pharmacy. These leaders are responsible for strategic
ers. White75 calls these individuals ‘‘big L’’ leaders. planning, hiring, control of funds (i.e., budget) and
Then there are those who are not in an official role as operations of their individual departments.
a leader, who do not possess the title or authority, yet The medical staff have a different leadership struc-
they clearly can influence those around them. In some ture due to the independent status of some of the
cases they can be very powerful leaders. White75 calls physicians. Generally there is a medical executive
these ‘‘little L’’ leaders. One of the skills of a suc- board which is supported by various medical staff
cessful ‘‘big L’’ leader is to recognize, influence and committees that take care of the requirements of
tap into those ‘‘little L’’ leaders to help drive ini- the medical staff: credentialing, peer review, medical
tiatives. The CEO of a health system can create a education, quality, P&T, and so on. There are also
passion within the organization to improve services department level leaders that are generally broken
and throughput, establish goals and priorities, and down into therapeutic categories, namely cardiology,
support his subordinates in reaching those goals by transplant, and oncology.
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462 | An Introduction to Pharmacy

Pharmacy leadership health system, giving them direct access to the chief
executive officer or chief operating officer, provide
The head of the pharmacy department is the pharmacy
input to system decisions and the ability to impact
director. If they are head of several hospital pharma-
strategic planning. Thus the CPO has access to more
cies in a system their title may be system director,
information and resources and a greater opportunity
executive or senior director. The director’s responsi-
to influence more people, making it possible to drive
bilities include leading overall pharmacy operations larger, more far reaching medication use improvement
and clinical services, human resource management initiatives.
(selecting, developing, and coaching pharmacy staff),
initiating quality improvement programs, creating
and revising pharmacy policy and procedures, finan- Strategic planning and goals
cial management (budgeting, billing, and revenue),
The pharmacy leader recognizes opportunities for
and maintaining regulatory compliance. Depending
improving the practice of pharmacy at their organi-
on the size and complexity they may be assisted by
zation, understands the shifting health care environ-
managers, supervisors, clinical leaders, and so on.
ment, the challenges faced by the health systems, and
Historically the pharmacy director was limited innovations in pharmacy technology. They use this
only with the operations within the four walls of information to create a vision for pharmacy services
the pharmacy department. The pharmacy was seen that stretches beyond boundaries of current practice.
as a revenue department back when fee-for-service Thomas Edison once said ‘‘a vision without execution
reimbursement was the norm. This is no longer the is hallucination.’’
case and the pharmacy director can no longer remain Strategic planning and goal setting are necessary
inside the pharmacy. The challenges of today’s lim- elements to turn daydreams into reality. The health
ited resources, economic downturns, dwindling reim- system executive team uses strategic planning and
bursement, pay-for-performance programs, focus on goal setting to establish the map and the milestones of
quality and medication safety, and increasingly regu- the organization’s vision. It sets priorities and direc-
latory mandates demand that the head of pharmacy tion for others to follow, sometimes linking them
take an active role as a health system leader. to accountability measures and pay incentives. In
Medications now take up a large portion of the some organizations some form of formal planning
overall health system expense. In some larger health is required of each department head following an
systems this could be $30 million or more.76 Billing for established template. If this does not exist the phar-
medications has also become increasingly difficult and macy leader must establish his or her own method of
complicated with regulatory requirements for Medi- strategic planning and goal setting.78
caid and Medicare programs. Corporate compliance Before establishing a strategic plan the pharmacy
laws place legal accountability for the financial prac- leader will begin with a vision of what pharmacy
tices on the health system and its leadership, including services will need to look like in the future in order
the pharmacy director. This increase in responsibility to meet the needs of the patient and the health sys-
and accountability on the head of pharmacy services tem. He or she will use available information about
is out of balance with the title ‘‘pharmacy director.’’ the future direction of pharmacy practice, i.e. the
Health systems have identified key areas that are Pharmacy Practice Model Initiative (PPMI) and exter-
strategic to the success of the organization and have nal trends and changing laws in health care, such as
placed leaders in ‘‘chief’’ roles. For example, there reimbursement tied to quality outcomes, the estab-
are chief financial officers, chief medical officers, chief lishment of accountable care organizations (ACOs),
nursing officers, chief information officers, and chief and patient centered medical homes.
compliance officers. Recognizing the impact and scope ACOs were established by the Patient Protection
of medication use in the health system, the role of and Affordable Care Act (PPACA) of 2010. It is a
chief pharmacy officer has developed over the past 10 model for delivering health care services. To qual-
years.77 This position allows the pharmacy leader to ify for special reimbursement, doctors and hospitals
have a seat at the executive leadership table of the must establish a network that would provide the
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The scope of pharmacy practice | 463

entire healthcare needs of a Medicare population of to address it. There are several formalized perfor-
patients for 3 years. If the health system desires to mance improvement models available and health sys-
form an ACO the pharmacy has an opportunity to tems usually adopt a particular methodology, estab-
contribute by providing pharmacy services along the lish resources and reporting structures, and require
entire continuum of care. A similar model, patient leaders to use them. Some of performance improve-
centered medical home, is a physician-coordinated ment methodologies include: Six Sigma, Lean, and
team of care providers who work together to provide PDCA.
all of the healthcare needs of the patient. The pharma- Six Sigma is a method used to improve quality by
cist is uniquely qualified to participate on this team. identifying and removing defects in a particular pro-
For example, they could manage medication therapy cess and eliminating variability. There are a specific
in chronic conditions, helping to optimize outcomes steps and statistical tools used to achieve improve-
and reduce utilization costs.79 ments and these generally require intense training and
Recognizing the importance of creating a shared resources to implement and maintain in a health sys-
vision with the pharmacy staff, the pharmacy leader tem. Six Sigma refers to the statistical value in the
involves not only pharmacy leadership, but also the manufacturing industry where the output of a process
‘‘little L’’ leaders in his or her staff to develop a yields three defects in a million products. Some Six
strategic plan for the pharmacy department that incor- Sigma improvement strategies have been blended into
porates both long term and short term goals. In order the Lean method for performance improvement. In
to influence and gain the support of health system Lean, the idea is to identify a particular value stream
administrators, it is important for the pharmacy leader or process and remove wasted steps in the workflow,
to tie pharmacy’s goals into the goals of the health creating less variation and optimum output. Lean also
system. For example, it may be a health system goal to requires specialized training and significant commit-
reduce the number of hospital re-admissions from the ment from the organization to implement; however,
emergency department by a certain percentage. The the gains from these methodologies can be significant.
pharmacy leader can demonstrate the effectiveness of PDCA is an established performance improve-
placing a pharmacist in the emergency department and ment management process in use in many health
reducing re-admission rated by educating patients on systems. PDCA stands for Plan, Do, Check, Act. The
targeted medications and providing follow-up com- planning step usually involves identifying stakehold-
pliance phone calls. In this way the pharmacy can ers, creating an improvement team, understanding
contribute to achieving a health system goal as well the current process and quality gaps, developing an
as achieve a goal of improving pharmacy services. improvement intervention and appropriate measures
of success, then implementing the intervention (Do).
Check involves collecting the data and determining
Performance improvement if successful or where further improvements can be
made. Act is the action of taking that information
It should be the goal of each pharmacy leader to estab- and applying it to the process. PDCA can be done
lish a program that continually reviews the current over and over again, as in a cycle, making incremen-
medication use system and identifies areas that are in tal improvements as refinements are made. It is often
need of improvement. This can be identified through called the rapid cycle improvement program.
direct observation and measurements, customer feed-
back, employee feedback, medication event reports
or data retrieved through information systems. These
Regulatory and accreditation
could be internal pharmacy only issues, such as phar-
macy STAT order turnaround time or involve other Because healthcare has become recognized by the pub-
disciplines such as medical staff or nursing, such as lic as a right and because the government is a major
the anticoagulation management program. funding source for heath systems, it stands to reason
Once a gap in performance is identified the phar- that health systems would be highly regulated includ-
macy leader should employ an improvement program ing health system pharmacy practice. These include
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464 | An Introduction to Pharmacy

governmental agencies and accrediting bodies. Some standards, that are regularly revised and enhanced.
of the governmental agencies include: They have also created the National Patient Safety
Goals (NPSGs) that address specific patient safety
• Food and Drug Administration (FDA) – safety, concerns. TJC performs unannounced surveys about
efficacy, labeling of medications every 3 years and accreditation is for 3 years.
• Drug Enforcement Administration (DEA) – con- The American Osteopathic Association’s (AOA)
trolled substance laws Healthcare Facilities Accreditation Program (HFAP)
• Occupational Safety and Health Administration accredits primarily osteopathic healthcare facilities,
(OSHA) – hazardous materials but is not limited to just those hospitals. HFAP also
• National Institute for Occupational Safety and have compliance standards and the accreditation cycle
Health (NIOSH) is for 3 years.
• Centers for Disease Control and Prevention (CDC) Det Norske Veritas Healthcare’s National Inte-
– infection control issues grated Accreditation for Healthcare Organizations
• Office of Inspector General (OIG) – protection (NIAHO) integrates CMS Condition of Participation
of integrity of government programs; conducts with International Organization for Standardization
audits, investigations, inspections, and other func- (ISO) 9001 Standards. NIAHO works closely with
tions the health system to develop and implement a Quality
• Environmental Protection Agency – pharmacy Management System. The accreditation cycle is for 3
waste stream management years.80
• Office for Civil Rights (OCR) – Portions of the
Health Insurance Portability and Accountability
Act of 1996 (HIPAA) Contracting and procurement
• State Boards of Pharmacy – licensure requirements
Group purchasing organizations
for individuals and pharmacies. Enforces the rules
and regulations of the state’s pharmacy practice An integral function of the pharmacy department is
act.80 the contracting for medication purchases and pro-
curement of medications. Most hospitals join Group
In order to participate in the federal Medicare Purchasing Organizations (GPOs) or buying groups
programs and receive federal funds, health systems to take advantage of volume based discounts.81 In a
must be certified by Centers for Medicare and Medi- network of hospitals, a uniform contract can be nego-
caid Services (CMS) and adhere to the Conditions of tiated for all members of the network. The GPO may
Participation (CoP), which are standards established also negotiate performance-based contracts with indi-
by CMS to ensure quality and protect the health and vidual drug companies. In a performance-based con-
safety of Medicare and Medicaid recipients. Health tract, the hospital or network is rewarded for buying
systems can be inspected by a state health agency for a higher percentage from a drug company, as com-
compliance to CoP or they voluntarily receive accred- pared to that company’s competitor. For example,
itation through an accrediting body that has received two drug companies may produce similar medications
deeming authority by CMS. Deemed status indicates for a health condition. Typically, the two competing
that the healthcare organization has met relevant medications will be in the same drug class and have
Medicare requirements. There are three organizations similar chemical structures (such as angiotensin recep-
with deeming authority: The Joint Commission (TJC), tor blockers (ARBs) as an example). Because the two
Healthcare Facilities Accreditation Program (HFAP), drugs have similar chemical structures and clinical
and Det Norske Veritas Healthcare’s (DNV) National indications, the hospital can designate them as similar
Integrated Accreditation for Healthcare Organiza- enough to be interchangeable. Efficacy and outcomes
tions (NIAHOSM ).80 data must support this interchangeability. As such, the
The Joint Commission is the primary accred- companies may offer the hospital a discount incentive
iting body for hospitals and health systems. TJC to move the utilization towards their product, thereby
establishes a set of performance expectations, called creating a favorable market share. ‘‘Market share’’ is
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The scope of pharmacy practice | 465

80% of the institution’s expenditures. Typically, the

Table 11.1 An example of an ARB market share
80/20 report consists of such agents as chemotherapy,
incentive program
blood products, biologic agents, and antibiotics.
Utilization tier Market share percentage Price discount Annual or semi-annual inventories should be
taken as a check on the theoretical inventory record
Tier 1 discount 50 3% maintained by pharmacy.81 For high-cost medications
or medications of abuse, a more frequent inventory
Tier 2 discount 75 5%
should be done to discover any shrinkage that is
Tier 3 discount 90 7% occurring. Medications such as narcotics, steroids,
blood enhancing products or erectile dysfunction
products are targets for theft and re-sale. Special
the amount of utilization of a medication divided by precautions and more frequent inventories of these
the utilization of that medication plus other ‘‘like’’ agents should be done.
medications (as defined by the contract) An example The pharmacy will, in general, take advantage
of an ARB market share incentive program is depicted of generic medication availability. Certain high-risk
in Table 11.1. medications with unreliable or variable bioavailability
In this example, the higher the market share of this may require purchase of a brand-name medication.
medication compared to its competitor, the higher the The wholesaler will assist in determining a preferred
discount. product list in the purchasing system, so that buyers
know which medication products should specifically
Wholesaler be purchased. Some products may need to be pur-
chased directly from the manufacturer. Other prod-
Although contracting services are provided by the
ucts may be available only through a limited distribu-
GPO, the warehousing and delivery of medications
tion by the manufacturer. Biopharmaceutics are medi-
to the hospital site is accomplished by a wholesaler.
cations developed using existing DNA from human or
Most hospital pharmacies obtain all of their con-
other biologic source. Examples of biopharmaceutics
tract pharmaceuticals through a single wholesaler.
includes blood factors, hormones, growth factors,
This system is known as the prime-vendor system
interferons, interleukins, and monoclonal antibod-
and allows the hospital to work primarily through
ies. Because the manufacture of biopharmaceutics
one company.81 In this manner, multiple purchase
is a complex process, generic biopharmaceutics, or
orders are eliminated and ordering is further facil-
‘‘follow-on biologics’’ usually do not exist. Com-
itated through computer systems. Although using a
panies attempt to replicate biopharmaceutics; these
prime-vendor system is desirable, it is also useful to
generic-like products are not identical to the original
develop a relationship with a secondary wholesaler,
in the event that the prime vendor cannot meet the products, and are termed ‘‘biosimilars.’’82 For very
hospital’s needs. Most hospitals order electronically high-cost medications, usually biologics for chronic
on a daily basis. Typically, the pharmacy department conditions, patients may receive assistance with pur-
will have personnel dedicated to this activity, usually chase through a Pharmaceutical Manufacturer Patient
a pharmacy buyer. Deliveries are usually received the Assistance Program, to have all or part of the purchase
same day. The goal of daily ordering is to maintain priced paid.
a just-in-time inventory at the hospital site, reduc- Using the utilization reports available from the
ing product expiration and waste. An ideal inventory wholesaler, the pharmacy department will target cer-
‘‘turn’’ rate is 10 to 20 times annually. The prime tain drugs or drug classes where there is an oppor-
vendor will usually provide useful utilization reports tunity for cost savings. Cost savings programs may
to the hospital that can be used for trending and cost be related to operation changes, clinical or utilization
savings analysis. A snapshot of high cost utilization is changes or contract changes. Operational changes
obtained through an 80/20 report. Which depicts the in the pharmacy can lead to product cost savings.
20% of medications used that typically account for Re-packaging products at a reduced price, splitting
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466 | An Introduction to Pharmacy

tablets, batching sterile product preparation, and re- of administration. Physician communication needs
using returned product are all ways to save costs from to take place to inform physicians of the shortage
an operational perspective. Using therapeutic inter- and the appropriate replacement therapy. Prescribing
change programs, changing injections to oral medi- processes, including the electronic medical record are
cations when possible, using pharmacist monitored impacted. Drug selection and standard order sets need
dosing programs, and changing physician prescribing to be changed in the electronic medical record. Phar-
practices are all ways of achieving drug cost savings macy distribution processes may need to be changed
through changes in clinical utilization of medications. as a result of a drug shortage. The preparation may
Finally, generic medications, performance-based con- include changes in dilution, solution, labeling, expi-
tracts, and consistent buying practices are all ways of ration, and stability. Nursing administration process
achieving drug cost savings through the contracting may be affected by a drug shortage. A nurse may
process.81 not be familiar with the new product that is pro-
vided by the pharmacy, and what its indication is.
Dilution and infusion or injection requirements may
Drug shortages be different for the replacement drug. Communica-
Drug shortages are emerging as a significant burden tion of these requirements on the labeling is essential.
for health system pharmacies.50 There are many rea- Finally, monitoring of the drug effects may change as
sons for this. Keeping ‘‘just-in-time’’ inventories leads a result of drug shortages. Although one agent may
to minimal product on hand. When one product expe- need dose adjustments for renal failure, another may
riences a shortage, there may not be enough on hand not. Laboratory monitoring for therapeutic effect and
to meet the patient needs. The majority of raw mate- for adverse effects may be different with the new drug.
rials for drug manufacture comes from outside the All of these aspects must be taken into consideration
United States. If political unrest or a natural disaster when responding to a drug shortage.83
befalls the country of the raw material origin, it has the As a result of the emergence of drug shortages,
potential to lead to a drug shortage. Industry mergers obtaining medications from outside sources or from
can lead to product shortages. A drug manufacturer compounding pharmacies has become more com-
may decide to discontinue production of a medica- mon. The Director of Pharmacy and buyers need
tion, putting the entire burden of demand on another to make sure that the outside sources are reliable
company. The FDA cannot require a company to and reputable. Use of compounding pharmacies that
produce a drug and the company may decide the do not employ good manufacturing processes has
product line is no longer profitable. Manufacturing led to patient deaths. Quality assurance is a top
difficulties or regulatory citations are major reasons priority when evaluating a compounding pharmacy.
for drug shortages. If a manufacturing plant is not When obtaining medications from outside sources,
meeting regulatory production standards, the plant the Director or buyer should require a ‘‘pedigree’’
may need to close while repairs or process changes or chain of ownership document from any sources
are put into place. This is the most common rea- with which they are unfamiliar.84 Inadequate storage
son for current medication shortages. Drug shortages conditions and inappropriate expiry can be prob-
have the potential to cause therapy delays or can- lems with pharmaceuticals obtained from unfamiliar
cellations, procedure delays or cancellations, adverse sources.
drug events, and rising costs of medications. Health The contracting and procurement functions of a
systems are particularly affected by drug shortages of pharmacy are paramount to the provision of care in
injectable medications. health systems. Buying contracted products, receiv-
Drug shortages impact on almost every process ing these products, maintaining inventory controls,
in the hospital. The hospital will need to deter- ensuring product integrity, and controlling costs are
mine an appropriate replacement for the unavailable all a part of the contract and procurement process.
drug. The replacement drug should be selected based Drug shortages lead to alteration in processes and
on common FDA-approved indications, drug class, deserve careful attention to avoid therapy delays and
chemical structure, side effect potential, and route cancellations, or adverse patient events.
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The scope of pharmacy practice | 467

Human resources Recruitment

In the early 2000s a severe pharmacist shortage cre-
Human resources (HR) management in health sys-
ated a significant demand for pharmacists and also
tem pharmacy includes a broad range of functions.
resulted in significant increases in pharmacist salaries.
The successful operation of a hospital pharmacy
In response, many states and private schools started
department requires strength in numerous critical HR
new schools of pharmacy. From 2000 to 2009, the
functions such as the recruitment, hiring, and contin-
number of pharmacy schools increased from 78 to
uous training of staff. The practice of pharmacy in
92.89 During this same period, numbers of graduates
hospital environments has become very complex. This
increased by 50% (7176 to 10 764 graduates). By
complexity only continues to increase. Issues such as
February, 2011 there were 104 accredited schools of
increased patient acuity, increased involvement of
pharmacy. By the late 2000s a change in the national
pharmacists in clinical decision making, the manufac-
economy, driven by faulty mortgage loans, resulted
turing, prescribing, distribution, administration, and
in a slowdown in the demand for pharmacists and
monitoring of very complex drug therapies such as
technicians in most urban areas.
immune modulators, have all changed the scope of
Recruitment of pharmacy staff largely depends on
pharmacy practice as well as the skills needed to sup-
the unique needs of the position, as well as the sup-
port pharmacy services. Pharmacy technicians have
ply and demand of the types of skills that potential
also advanced along with the development of the
employees possess for the position. Also affecting the
pharmacist’s practice. Higher functioning roles for
recruitment of staff are location of the practice site,
pharmacy technicians (e.g., tech-check-tech85,86 ) and
size of the hospital pharmacy, acuity of the patients,
the further development and integration of pharmacy
and relative importance of the needed position. Inter-
technology have also driven the types of individuals
nal development of staff and promotion is one option
needed for hire by hospitals.
for filling open positions. If staff promotion is not
an option, pharmacies may utilize a broad range of
recruiting tools including:
Regulatory impact on pharmacy roles
National pharmacy standards and most state laws • Advertisements in professional journals, newspa-
require that a pharmacist provide oversight of all pers, state professional society newsletters, and
aspects of drug management.87 Pharmacists are electronic bulletin boards,
licensed by State Boards of Pharmacy to practice • Personnel placement services provided by national
pharmacy. Traditional tasks requiring a pharmacist’s or state professional societies
license include functions such as the review and • Oral and written recommendations from col-
approval of prescriptions or orders written by leagues. Some organizations offer a ‘‘finder’s fee’’
licensed independent practitioners (e.g., physician, for hires that result from an employee referral
nurse practitioner, physician assistant), as well as the • Personal discussion or correspondence with poten-
final check on drug products prior to dispensation tial candidates
and administration. • Recruitment visits to colleges of pharmacy or to
States vary widely on how pharmacy technicians facilities that conduct technician-training pro-
are recognized. Some states require licensure, others grams
require registration, certification or proof of the com- • Professional recruiting firms, which typically
pletion of a pharmacy technician training program. charge the organization a percentage of the
Other states do not require any licensure, certification, position’s annual salary. In addition, recruitment
or registration. A few states minimally acknowledge advertising companies offer access to a list of job
the role of the pharmacy technician. Technicians per- seekers for a fee
form many traditional distributive or operational task • Familiarizing students with the organization by
such as pouring, counting, labeling, profiling, adjudi- offering summer jobs or participating in college of
cating claims, stocking, and so on.88 pharmacy experiential rotations
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468 | An Introduction to Pharmacy

• Tuition assistance programs for students in service given the numbers of staff available. Staffing in
exchange for future work commitments this manner produces a much more reliable pharmacy
• A ‘‘prospect list’’ of individuals applying for previ- service and minimizes errors. Cross-training staff to
ous job openings, which can often be supplied by work in more than one area also extends the ability of
the human resources department a pharmacy department to maintain a constant level of
• Internet-job-site postings service regardless of absences, planned or unplanned
• Community job fairs and local or state welfare-to- (e.g., vacation, sickness, FMLA). Some states mandate
work programs that a licensed pharmacist review medication orders
• Organization-sponsored events such as continu- prior to dispensation or be available to answer drug
ing education sessions, award presentations, or information questions. In isolated areas, where phar-
community outreach programs.90 macist resources are limited, this may be performed
remotely by a pharmacist working on behalf of a tele-
Many organizations will recruit technicians from pharmacy service. Staffing agencies are another option
technician training programs which range from 6 to considered when pharmacist and technician staffing
24 months. Other organizations may offer on-the- needs exceed the ability of a hospital pharmacy to
job instruction to help train individuals lacking prior supply them.
technical experience. Some technical schools offer Non-traditional work schedules have become
an Associate of Science (AS) degree. The American more prevalent in the hospital pharmacy workforce,
Society of Health System Pharmacists has recom- especially for pharmacists. This has become an
mended that employers hire pharmacy technicians important factor in the retention of highly qualified
that have completed an ASHP-accredited pharmacy pharmacists in an era of pharmacist shortages and in
technician training program and are certified by the the creation of less desirable shifts (e.g., night shift).
Pharmacy Technician Certification Board (PTCB).87 The need for staffing flexibility has been compounded
If technicians are not certified they should receive this by an aging pharmacist workforce. More than
certification within 24 months of employment. one-third of practicing pharmacists are 60 years of
age or older. In addition, the number of women
practicing pharmacy also continues to increase, also
Work schedules having an impact on adjustable schedules. In 2009,
Pharmacies in larger hospitals remain open 24 hours 46.4% of the pharmacist workforce was female vs.
a day and 365 days a year. As a result, scheduling 31.3% in 1990. In addition, a larger number of
becomes much more complex in these organizations. women work part time than do men (29.8% versus
Smaller hospital pharmacies may be open for limited 18.4%, 2009).91 Creative schedules have included:
hours throughout the week or may have no pharma- seven days on seven days off (10 hours per night),
cist or technician at all. Depending on the size of the four 10-hour shifts, offering part-time work at the
organization, a broad range of staff with varying skills discretion of the employee, job sharing in which one
may be needed. These skills may include, but are not full time position is covered by two or perhaps three
limited to, dispensing, clinical drug knowledge, sterile pharmacists.92
product preparation, billing, information systems and
technology, medication safety, operational effective-
Performance planning
ness, medication use process, formulary management,
and compliance, to name a few. Performance planning is another important aspect
Services offered by a hospital pharmacy are usu- of pharmacy human resources management. The best
ally arrived at through agreements between the phar- performance planning systems are provided in a struc-
macy, hospital administration, nursing, and medical tured way such that the strengths and weaknesses
staffs. These services are based as much on the needs of of an individual are identified. These strengths and
patient care in the hospital as it is based on the supply weaknesses are usually reviewed in both the behav-
of staff. When scheduling staff, much effort is placed ioral and job function domains. As an outcome,
on providing consistent and highly reliable levels of goals and objectives are developed with the intent
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The scope of pharmacy practice | 469

to challenge the individual in a positive way to grow Pharmacy related automation is represented by a
professionally. Professional growth is a lifelong pur- wide variety of systems. They include: robots (cart-
suit in pharmacy. Many state boards of pharmacy fill, IV and syringe compounding, retail prescrip-
require pharmacists to obtain continuing education tion vial fill, and delivery), automated dispensing
(CE) hours as a mechanism to ensure that contin- machines (ADMs), carousels, drug repackaging/bar-
ued learning occurs. Similarly, the PTCB also requires coding machines, and IV infusion smart pumps, to
annual CE hours for pharmacy technicians. Another name a few.
form of continued learning is continuing professional Numerous information systems in hospitals and
development (CPD). The principles of CPD can be health systems include drug data. These systems range
summarized as follows:93 from pharmacy practice specific information systems
such as the inpatient and outpatient pharmacy infor-
• CPD is a systematic, ongoing, cyclical process of mation systems, to systems that affect the workflow
self-directed learning of other practitioners and the care of patients (e.g.,
• CPD includes everything that practitioners learn electronic medication administration record (eMAR),
that enables them to be more effective as profes- computerized provider order entry (CPOE), and elec-
sionals tronic health records (EHRs)). In addition, drug
• CPD includes the entire scope of the practitioner’s library databases are also found within smart infu-
practice and may include activities both within and sion pumps, drug utilization benchmarking databases,
outside the usual work setting ADMs, and drug repackaging/bar-coding machines.
• CPD can strengthen the partnership between the Pharmacy drug data are equally important within
practitioner and his or her organization, so as to financial systems such as the charge data master
meet the development needs of both (CDM) for hospital financial billing.
• Practitioners are responsible for their own profes-
sional development. The organization can have a
role in helping practitioners meet the developmen-
Pharmacy informatics
tal needs related to job performance. Pharmacy informatics has been defined as ‘‘the use
and integration of data, information, knowledge,
technology, and automation in the medication
Information technology and use process for the purpose of improving health
automation outcomes.’’47 With the significant growth in phar-
macy information systems, automation, and other
Information technology and automation significantly related technologies, pharmacy informatics has
impact the delivery of hospital pharmacy services. become a specialty field of practice much like what
Almost all pharmacy services are supported in some has happened for pharmacy practice in clinical areas
way by these systems. The impact of technology on of specialization. Pharmacy informaticists come
pharmacy services has also resulted in the need for from a wide variety of backgrounds and include
pharmacists to develop skills and in many cases spe- professionals ranging from non-clinical information
cialize in this practice area in order to optimally technology programmers and project managers, to
support these systems. pharmacy technicians and pharmacists. Although
Pharmacy distributive services are usually high there are a few training and residency programs,
volume, include tasks that should be consistently most individuals in this field have ‘‘knowledge of
repeated with precision, and whose output will result computer systems, medication-use processes, safety
in the administration of a medication to a patient. Due issues, clinical management of medications, drug
to the number of opportunities for medication errors distribution, and administration, and have developed
and drug diversion in the medication use process, extensive expertise in using technology to support
many companies have developed automated systems these activities.’’47 Pharmacy informaticists develop
to ensure the accurate dispensation and administra- programming requirements, oversee medication
tion of medications as well as prevent diversion. databases and clinical decision-support systems,
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470 | An Introduction to Pharmacy

resolve system issues, assess and design information to the pharmacy. This has avoided the countless
technology so as to avoid errors, and utilize clinical hours of delay during which paper orders would
data to improve patient outcomes.94 remain in a chart prior to being found and sent to
Pharmacy information systems have greatly pharmacy. Likewise, medication order legibility has
evolved over the decades. However, in general improved, virtually eliminating errors associated with
pharmacy information systems should perform the poor handwriting because CPOE has the ability to
following activities: standardize the medication ordering process and com-
municate textual information. Whereas CPOE has
• Inpatient and outpatient order entry, management, been useful in the hospital environment, the process
and dispensing of sending electronic prescriptions to outpatient/retail
• Inventory and purchasing management pharmacies (e-Prescribing) has also improved com-
• Reporting (utilization, workload, financial) munication in the ambulatory environment.
• Clinical monitoring
• Manufacturing and compounding
Electronic health record (EHR)
• Intervention management
• Medication administration An EHR is an ‘‘electronic record of health-related
• Connectivity to other systems (pharmacy automa- information on an individual that can be created,
tion, CPOE, EHR, financial, etc.) gathered, managed, and consulted by authorized clin-
• Pricing, charging, and billing.95 icians and staff across more than one health care
organization.’’97 The data contained within the EHR
Pharmacy information systems have been and are inclusive of medication (prescribing, dispensing,
continue to be the leading clinical medication systems administration, monitoring). EHRs are seen as impor-
for performing such tasks as identifying drug–drug tant tools in improving the quality of care provided
interactions, avoiding drug–food interactions, to patients.98 However, in one study, only 18% of
drug–disease state monitoring, and detecting over- physicians reported having an EHR.99
dosing or under-dosing of medications, to name a few. To promote the rapid adoption of EHRs, Congress
passed in 2009 the Health and Information Technol-
ogy for Economic and Clinical Health (HITECH) Act.
Computerized provider order entry The bill ‘‘allocates approximately $44,000 for each
(CPOE) practicing clinician and between $2 million and $10
As a profession, pharmacists have adopted technology million for each hospital that qualifies as a ‘meaning-
at a much faster rate than other clinical professions. ful’ user of EHRs.’’100 The Act requires information
Physician adoption of information systems such as systems to demonstrate electronic prescribing, the
CPOE have taken much longer. During the late 1990s ability to share health data between providers and
and early 2000s, adoption of CPOE became more hospitals, and quality reporting.
prevalent as data began to show that CPOE utilization
possibly prevented mediation errors. This momentum
Electronic medication administration
was spurred with the publication of the 1999 Institute
record (eMAR)
of Medicine (IOM) report To Err is Human.96 The
report indicated that between 44,000 and 98,000 With the development of pharmacy information sys-
Americans potentially die each year due to hospital tems, pharmacies were able to preserve and update
based medical errors and recommended CPOE as one patient medication profiles electronically instead of
possible solution. maintaining handwritten medication lists. The ability
The advent of CPOE has been important for the to maintain such lists of medications within the phar-
advancement of pharmacy practice, improvement of macy information system also led to the practice of
pharmacy services, and the prevention of medication pharmacy printing the ‘‘profiled’’ medication lists for
errors. CPOE has resulted in time savings through the use as MARs. Through clinical system integration
efficient communication of medication orders directly and real-time electronic communication, MARs are
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The scope of pharmacy practice | 471

now being provided in a completely electronic format to improve the accuracy and therefore safety during
(eMAR). This has allowed caregivers such as nurses to the act of medication administration. The concept
immediately view ordered medications on a computer. is similar to that utilized by numerous other indus-
The eMAR can also be used to communicate location tries (grocery stores, delivery companies, aviation,
of products, provide administration information, and etc.) to ensure highly accountable, safe services. In
document medication administration. 2009, a survey conducted by the American Society of
Health-System Pharmacists concluded that 27.9% of
Automated dispensing machines (ADMs) hospitals were utilizing BCMA.64
‘‘BCMA assures that the ‘five rights’ are
ADMs have been rising in prominence for several confirmed – right patient, right medication, right
decades. They are decentralized and located in vari- dose, right time, and right route.’’101 In one study, the
ous areas such as hospital patient care units, surgical
researchers found a 41.4% reduction in medication
suites, procedural areas, emergency departments,
errors through the utilization of BCMA. The authors
and clinics. ADMs are similar to automated teller
also found a 50.8% reduction of potential adverse
machines (ATMs). However, instead of money,
drug events (excluding timing errors) as well as
ADMs ensure controlled access to medications by
a reduction of transcribing errors from 6.1% on
requiring users to provide personal identification in
non-BCMA units to 0.0% on patient care units that
order to access the contents. Most of these systems
used the technology.102 However, just the presence of
utilize bio-identification or fingerprint technology for
bar coded medications will not prevent errors. Users
controlling medication access.
must also follow the proper procedures for the use
ADMs can charge and credit patients for medi-
of the BCMA system. Workarounds have included
cations removed on their behalf or returned if not
scanning the medication outside of the patient’s
administered. Some ADMs are used for the floor-
room, scanning a patient bar code not attached to
stocking of medications. In this scenario, while access
the patient, and confirming administration before
to medications is still controlled, any medication may
administration occurred.103
be removed for any patient. This particular option
One major challenge for hospital pharmacies is
is more commonly utilized in procedural, emergency
the fact that not all unit–dose medications provided
or outpatient environments. The use of ‘‘profiled’’
by manufacturers are barcode ready. In organizations
medications is considered to be a much safer method-
committed to BCMA, this requires pharmacies to find
ology for medication management within ADMs. This
vendors who may repackage unit-of-use items into
option is more commonly used in hospital patient care
bar-coded packaging. Alternatively, hospital pharma-
units and only allows the removal of medications that
cies may purchase bar code packaging equipment
have been reviewed and approved by a pharmacist.
to overwrap already unit-dosed items or to prepare
Products of high abuse potential such as controlled
unit–dose packaged medications from bulk contain-
substances may also be tightly controlled by requiring
ers. Bar-coding equipment is also available to place
users to provide an accurate count of the medica-
bar-coded flags or stickers on vials, ampules, and
tion prior to removal. ADMs support medication
syringes. Pharmacies that maintain these types of sys-
inventory management including placing orders for
tems must also develop rigorous systems of quality
wholesaler replenishment based on the inventory on
assurance to prevent the introduction of mislabeled
hand. In cases where medications are needed urgently,
products.104
certain medications where permitted can be accessed
via an ‘‘override’’ function. This option is discouraged
because it bypasses pharmacist review. Other technologies
The use of IV Robotics for the preparation of
Bar code medication administration
sterile products is an emerging area of pharmacy
(BCMA)
technology.105 This technology is offered by a limited
BCMA is the application of bar-coding technology number of vendors and provides pharmacies with an
to the medication administration process in order alternative to manually prepared IV medications. IV
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472 | An Introduction to Pharmacy

robotics support the preparation of sterile products the use of these systems. One study demonstrated
within an enclosed sterile ISO class 5 environment. that CPOE facilitated 22 types of medication error
These robots can fill both syringes and IV bags and risks.109 Another 62-hospital study utilized a simu-
utilizes a ‘‘combination of bar codes, images, and lation tool to assess the safety of decision support
weight checks to ensure that the appropriate medica- and determined that 53% of the medication orders
tion is used and dispensed based on patient-specific processed by clinical information systems would have
needs.’’106 resulted in fatalities.110 As a result, many hospitals
Also growing in strength of use is the application have implemented systems for conducting readiness
of smart infusion pumps. Although infusion pumps assessments and have limited initial implementation
have been around for years, the application of clin- of technologies and information systems to ‘‘pilot’’
ical data at the point of care in the form of drug areas in order to minimize the impact of new systems
libraries is a more recent development. These libraries until all potential sources of error have been limited,
provide clinical support in the form of soft and hard isolated or resolved.
stops to guide the safe administration of intravenous
medications. Many of these systems also support bar
code technology that allows the pump to access the Education and training
patient’s medication profile. This ensures that the cor-
rect medication and dose are being administered at Health system pharmacists are commonly involved in
the right rate and allows for auto programming of the education of doctor of pharmacy students, health
the pump to ensure that pump programming errors professionals, patients, and pharmacy residents.
are avoided. Errors have been seen with these sys-
tems when the drug library has been bypassed, alerts
are overridden or independent double checks are not
Hospital practice experience
followed.106 The Accreditation Council for Pharmacy Education
Hospital pharmacies have begun using carousel (ACPE) for doctor of pharmacy programs requires
dispensing technologies (CDT). This technology uti- two types of experiential training for pharmacy stu-
lizes the concept of a rotating carousel with shelves dents. The first type is called an introductory phar-
for drug storage. The user of the system remains sta- macy practice experience (IPPE). The IPPEs should
tionary while the requested medication is brought to begin early in the curriculum, be interfaced with
the user. These systems have been shown to improve didactic course work that provides an introduction to
operational efficiency, reduce error rates associated the profession, and continue in a progressive manner
with dispensing requests, decrease inventory carrying leading to entry into the advanced pharmacy practice
costs, and minimize space required for drug storage. experiences.111 These introductory experiences must
These systems are also capable of self-replenishment be at least 300 hours total and occur over the first 3
by placing orders directly with wholesalers based on years of the professional curriculum. IPPEs occur in
decremented inventory. CDT is utilized for dispens- either institutional or community settings, and may
ing STAT doses, first doses, ADM replenishment, and allow the pharmacy student to assume direct patient
filling clinic orders. Most of these systems utilize bar- care activities. IPPEs are conducted by qualified phar-
code and pick-to-light technologies in which product macist preceptors who are licensed in the United
selection can be highlighted and verified to support States. As such, it is common for the health system
accuracy.107,108 pharmacists to be involved in providing IPPEs. Activ-
One tenet of technology and automation in health- ities typical for an IPPE in the health system include
care is that these tools and systems would support observation of surgical procedures, shadowing a phar-
the delivery of care in a safe and effective man- macist on duty, conducting projects, attending staff
ner. Many of those improvements (e.g., legibility, meetings, joining physician rounds, and participation
timeliness, accuracy of dispensation) have been seen. in the dispensing pharmacy. Some unique aspects
However, there is an increasing body of work that is of health system pharmacy that do not necessarily
also reflective of errors that may be facilitated through exist in the community setting include the presence of
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The scope of pharmacy practice | 473

an electronic medical record, automated dispensing became more complex and the profession learned how
machines, physician rounds, sterile products prepara- medications were absorbed, distributed, metabolized,
tion, and bar-code medication administration. and excreted differently in various patient popula-
The Advanced Practice Pharmacy Experiences or tions. The application of clinical knowledge became
APPEs, occur during the last professional year after all more common in the pharmacy profession. The Amer-
didactic courses are completed.111 The APPEs must ican Society of Health-System Pharmacists developed
be at least 1440 hours (36 weeks) in length. Advanced an accreditation standard for residency training in
practice experiences meet specific goals and objectives clinical pharmacy practice. Since then, the number of
and meet competencies in community pharmacy, hos- postgraduate students seeking residency positions has
pital or health system pharmacy, ambulatory care, grown steadily. There are a number of reasons for this
and inpatient/acute care general medicine. Health sys- growth in residency programs and applicants. Medi-
tem participation in the provision of APPEs ranges cation therapies have grown more complex over the
from 63 to 100% of hospitals, with an average of years, as the population ages. People are living longer
78% of health systems providing this type of student with chronic diseases. The number of colleges of phar-
experience.112 Of these sites, an average of 78% also macy has grown, increasing the pool of applicants for
provide experiential education to physicians, nurses, residency positions. This growth has also increased the
and other allied health professionals. Pharmacists in competition for residency positions. Finally, national
these settings typically will provide medication edu- organizations have advocated for residency training
cation to other health professionals, as well. as a prerequisite for health system pharmacy practice.
Modern pharmacy practice models focus on Residency programs have been recognized by some
patient safety, continuity of care, and patient organizations as essential to future growth and inno-
education.15 A pharmacist therefore may provide vation in practice.116 Residents allow organizations
education to patients regarding proper use of their an extra set of hands to ‘‘try out’’ new ideas and
medications. Medication related education, along new ways of doing things. A resident’s natural curios-
with medication therapy management can improve ity as a new practitioner will motivate pharmacists
patient outcomes and reduce costs of care.113 to maintain medication knowledge and competency
Elements of patient education regarding medications in the profession. Residents can serve as pharmacist
include proper drug, dose, frequency, indication ‘‘extenders,’’ providing pharmacy services in areas
for use, potential side effects, and how to handle that had not been served prior to the residency pro-
missed doses. In addition, the pharmacist can provide gram. Finally, residents can assist with the education
special instructions for techniques used to deliver of pharmacy students, nurses, physicians, and other
medications that are inhaled, absorbed through the health professionals.
skin or injected. In addition to providing education, Well over half of health system pharmacists are
providing a patient discharge plan that includes involved in the training and education of health pro-
follow-up by a pharmacist for high risk patients can fessionals. In US hospitals, this number approaches
reduce hospital readmissions.114 80%.112 Health system pharmacists are involved
in the education of pharmacy students, physicians,
nurses, other health professionals, patients, and phar-
Residency programs macy residents.
Pharmacy residency training has undergone an evolu-
tion over the past 80 years. The first health system res-
Conclusion
idencies, called ‘‘hospital pharmacy internships’’ were
established in 1927. Early residencies focused on oper- The practice of health system pharmacy continues
ational aspects of pharmacy, as well as leadership.115 to evolve as the medication therapies become more
As drug manufacturers continued to refine the devel- complex. Regulatory requirements remain prevalent
opment and packaging of medications, the profession in the health system environment. The use of tech-
could focus less on product preparation and more on nology and technicians will bring the pharmacist’s
clinical aspects of patient care. Medication therapies expertise closer to the patient, in order to facilitate
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474 | An Introduction to Pharmacy

optimal use of medications. The automation of some and control functions; in clinical research, analysis,
of the distribution processes has allowed pharmacy marketing and other business functions; and other
technicians a greater role in managing the medica- supportive functions such as regulatory affairs, legal
tion use process. Although the pharmacist is still affairs, and patents. Pharmacists with additional edu-
accountable for overall supervision of the prescrip- cation are able to utilize their total education in indus-
tion process, their roles are growing at a faster rate try positions. For example, many pharmacists have
in areas such as clinical pharmacy, drug policy, med- biology, chemistry, engineering, or business degrees
ication safety, performance improvement, transitions prior to receiving their pharmacy degree. Other phar-
of care, and informatics. Most health systems are macists pursue advanced degrees such as PhD, MPH,
involved in training future pharmacists and future MS, JD, MBA, or other specialized training after
leaders of the profession. receiving the PharmD. Advanced education in project
management, industrial science, and other disciplines
provides further personal development and special-
Pharmacy practice in industry: ized skills used in industry. Pharmaceutical practice
potential roles for pharmacists in industry provides opportunities for fulfilling careers
for all of these individuals.
Modern pharmaceutical education endows pharma-
cists with a broad background of scientific, technical,
and clinical knowledge associated with state-of-the- Pharmacists in government
art medications. Pharmacists have a comprehensive
understanding of drugs, dosage forms, delivery Current challenges on access, safety, quality, and
systems, therapeutics, administration, clinical effects, cost in healthcare coupled with increasing healthcare
healthcare settings, patient needs, outcomes, and workforce shortage as well as the recent enactment
associated expertise. While most pharmacists utilize of the Affordable Care Act on March 23, 2010
this background in some form of community offer significant opportunities for pharmacists and
practice,117,118 their expertise is particularly suited pharmacist-delivered patient care services. New and
for the work within the pharmaceutical and related exciting possibilities for advanced pharmacy prac-
industries. Pharmacists have numerous opportunities tice and careers are offered in government sectors,
to utilize all aspects of their diverse education in with the federal sector offering the broadest range of
professional practice in industry, and to do so in a sig- opportunities.
nificant, meaningful, and personally rewarding way. The trend toward systems of managed care admin-
The healthcare industry encompasses a wide vari- istration has set into motion several initiatives that
ety of specific companies of varying size and capa- have reformed the provision of healthcare in the
bilities. Pharmaceutical and related companies may United States. Although commitments and action
be large multinational corporations or may be small steps at the end of the last century sought to reduce
virtual enterprises. The scope of products manufac- the overall size of the federal establishment, it became
tured and distributed by these companies is broad and clear at the beginning of this century that certain parts
diverse. Companies may manufacture small molecule of that establishment designed to protect against ter-
and biotechnology products, medical devices, diag- rorism needed expansion. The effect of changes in the
nostic reagents, dietary supplements, cosmetics, and federal sector will be spread over several years. It can
other products. Collectively these products contain be anticipated that federal-sector health systems will
great numbers of individual drugs, reagents, and other be extremely dynamic through the turn of the century
ingredients in a variety of traditional and evolving and beyond.
delivery systems. Pharmacists and the profession of pharmacy are at
Pharmacists are involved in the manufacturing, the crossroads of healthcare with many opportunities
testing, and support of these products in many ways available for the creation of new forms of practice.
during the product life cycle. They may work in Nowhere is this truer than in the federal sector, which
technical areas such as chemistry, manufacturing, offers numerous opportunities for innovation through
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The scope of pharmacy practice | 475

novel clinical service delivery models, research, and in Environmental, community, behavioral, and occupa-
policy and regulatory mechanisms. It used to be true tional health are other important subfields.
that pharmacists practicing within the several federal The focus of public health intervention is to
services were not the highest paid practitioners in the improve health and quality of life through the pre-
profession. However, changes due to federal legisla- vention and treatment of disease and other physical
tion providing for a sign-on bonus, special pay, loan and mental health conditions, through surveillance of
repayment, and board certified pay for pharmacist cases and the promotion of healthy behaviors. The
officers have made practicing pharmacy in federal ser- programs, services, and institutions involved empha-
vices competitive with the private sector. Pharmacist size the prevention of disease and the health needs
officers and federal civil service pharmacists also enjoy of the population as a whole. Public health activities
a benefits package that is generally more supportive change with changing technology and social values,
of personal and family needs than is in the private but the goals remain the same: to reduce the amount of
sector in terms of leave and medical benefits. In addi- disease, premature death, and disease-produced dis-
tion, pharmacists desiring to practice advanced forms comfort and disability in the population. Public health
of clinical activities usually find greater fulfillment in is thus a social institution, a discipline, and a practice.
federal practice than in most of the private sector as The Institute of Medicine defines the mission of pub-
there are greater capacity with a variety of practice lic health as ‘‘fulfilling society’s interest in assuring
settings and unique inter-professional practice envi- conditions in which people can be healthy.’’121
ronments in the federal sector. Federal uniformed
service also offers the unique opportunity to pursue
a career in which one’s seniority and retirement pro- Consultant pharmacy practice
gram remain intact throughout one’s career moves.
Those pharmacists oriented toward patient care and Consultant pharmacists come from a variety of phar-
public health find a particularly rewarding form of macy practice backgrounds. Rooted in the com-
practice in federal service. Finally, even if pharmacists munity pharmacy tradition, consultant pharmacists
do not choose a full-time federal career, there are are expert clinicians in geriatric pharmacotherapy,
ample opportunities for part-time and intermittent adept practitioners of pharmacy systems manage-
federal service throughout the nation. ment, enterprising business leaders, and integral mem-
bers of the geriatric interdisciplinary team. Consultant
pharmacists possess a unique position and an impor-
Pharmacists and public health tant history in the development of pharmacy prac-
tice in America. To understand consultant pharmacy
Public health is a societal effort to protect, promote, requires an appreciation of the sweeping legislation
and restore the public’s health.119 It is a combina- enacted by Lyndon Johnson in the 1960s. Intrinsi-
tion of sciences, skills, and beliefs that are directed to cally linked to the enactment of Title XVIII and Title
the prevention of diseases, maintenance of a healthy XIX of the Social Security Act, consultant pharmacy
life, and improvement of the health of all the people was created out of a basic unmet need – to improve
through collective or social actions. It is concerned medication management in nursing homes.
with threats to health based on population health
analysis. The population in question can be as small
as a handful of people or as large as all the inhabi- Nuclear pharmacy practice
tants of several continents (e.g., during a pandemic).
The dimensions of health can encompass ‘‘a state of Nuclear pharmacy, also referred to as radiopharmacy,
complete physical, mental and social well-being, and is the specialty practice of pharmacy that focuses
not merely the absence of disease or infirmity,’’ as on the safe and efficacious use of radioactive drugs.
defined by the WHO; http://www.who.int.120 Public Radioactive drugs, referred to as radiopharmaceu-
health incorporates the interdisciplinary approaches ticals, constitute a special class of drugs according
of epidemiology, biostatistics and health services. to the Food, Drug, and Cosmetic Act (FD&C Act).
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476 | An Introduction to Pharmacy

The FDA, in Title 21 of the Code of Federal Regu- departments, radiopharmaceuticals are prepared by
lations (CFR), defines a radioactive drug as a drug Nuclear Medicine Technologists, working under the
that exhibits spontaneous disintegration of unstable supervision of an authorized user Nuclear Medicine
nuclei with the emission of nuclear particles or pho- physician or nuclear pharmacist), or in a local
tons and includes any nonradioactive reagent kit or commercial nuclear pharmacy that then delivers
nuclide generator intended for use in the prepara- the finished products to surrounding hospitals and
tion of any such substance. Similarly, the British and clinics.
European Pharmacopoeias define a radiopharmaceu- Radiopharmaceuticals can be categorized as
tical as any medicinal product which, when ready either diagnostic or therapeutic. Diagnostic radio-
for use, contains one or more radionuclides (radioac- pharmaceuticals are intended for use in the diagnosis
tive isotopes) included for a medicinal purpose. From and/or monitoring of various disease states. Relatively
these definitions, it is apparent that a radiophar- small radiation doses are delivered in diagnostic
maceutical consists of both a drug component and nuclear medicine procedures, similar in magnitude
a radioactive component. The drug component is to radiation doses from diagnostic X-ray procedures
responsible for localization in specific organs or tis- roughly corresponding to the same organ system
sues. The radioactive component is responsible for (see Table 11.2). Examples of diagnostic radiophar-
the emission of gamma rays for external detection maceuticals include Tc-99m medronate (MDP) (in
in diagnostic imaging and/or particulate radiation for
practice, most radiopharmaceuticals are referred to
radionuclide therapy. Radioactive in vitro diagnos-
by common names, such as abbreviated chemical
tic kits for radioimmunoassays and brachytherapy
names, rather than by nonproprietary drug names
sources for radiotherapy implants are classified by the
established by the United States Adopted Names
FDA as devices, in contradistinction to radiopharma-
Council (USAN)) for bone imaging procedures,Tc-
ceuticals, which are classified as drugs.
99m macroaggregated albumin (MAA) for lung
A distinctive feature of radiopharmaceuticals, in
imaging procedures, and I-123 sodium iodide for
contrast to traditional drugs, is their lack of pharma-
thyroid imaging procedures (see Table 11.3). Thera-
cological effects. Radiopharmaceuticals are employed
peutic radiopharmaceuticals, conversely, are intended
as tracers of physiological functions. Their small
for use in the treatment of various disease states.
amounts of mass produce negligible effects on bio-
Relatively large radiation doses are purposefully
logical processes, while their radioactivity allows
delivered to cause localized radiation damage, similar
noninvasive external monitoring or targeted thera-
in magnitude to radiation doses from teletherapy
peutic irradiation. The ratio of radioactivity to mass
is termed ‘‘specific activity.’’ Accordingly, radiophar- (external beam irradiation). A common example of
maceuticals typically have a high specific activity (i.e., a therapeutic radiopharmaceutical is I-131 sodium
abundant radioactivity per small amount of mass). iodide for treatment of hyperthyroidism or thyroid
Some radiopharmaceuticals are simply salts cancer (see Table 11.4).
of radioisotopes of elements (e.g., I-131 sodium Radiopharmaceuticals are employed in the dis-
iodide, Tl-201 thallous chloride, Sr-89 strontium cipline termed ‘‘nuclear medicine.’’ Nuclear medicine
chloride), but most radiopharmaceuticals consist may be a separate unit or found as a part of radiology.
of radioactive atoms attached to, or incorporated In some situations, limited groups of radiopharma-
into, other drug molecules that serve to carry the ceuticals may also be employed in specialty practices,
radioactive atoms to the intended tissues or organs. such as radiation oncology, cardiology, or endocrinol-
Some radiopharmaceuticals are manufactured and ogy. In a diagnostic nuclear medicine procedure, the
commercially marketed by pharmaceutical companies radiopharmaceutical is administered to the patient
in their final, ready-to-use dosage forms. Due to their most often by IV injection, although sometimes by
short half-lives, however, most radiopharmaceuticals oral, inhalation, or other routes. The localization, dis-
require preparation of the final product either on-site, position, and/or clearance of the radiopharmaceutical
such as in a hospital’s nuclear pharmacy or nuclear is then determined by detection of the gamma radi-
medicine department (in some nuclear medicine ation emitted from the radionuclide. Conventional
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The scope of pharmacy practice | 477

Table 11.2 Radiation doses for selected nuclear medicine and X-ray imaging procedures*

Effective dose Effective dose

Nuclear medicine procedure (mrem) X-ray procedure (mrem)

Bone scan 422 Spine series 347

Gastric emptying scan 35 Barium meal 300

Infection scan 665 CT abdomen/pelvis 1400

Liver scan 278 CT liver 790

Perfusion brain scan 688 Head CT 210

Perfusion lung scan 163 CT chest 930

PET scan, FDG 703 CT chest/abdomen/pelvis 1800

Renal scan 518 Intravenous pyelogram 250

Thyroid scan, I-123 326 CT neck 480

∗ Data from RADAR (Radiation Dose Assessment Resource), http://www.doseinfo-radar.com/RADARHome.html.

nuclear medicine imaging employs a ‘‘gamma cam- show a ‘‘cold’’ area (i.e., an area with less radioac-
era,’’ which detects gamma radiation in two dimen- tivity than the surrounding normal liver; Fig. 11.1).
sions and produces ‘‘planar’’ images. Single Photon The opposite effect is noted in the case of a radio-
Emission Computed Tomography (SPECT) refers to pharmaceutical designed to localize in areas of the
the special case when a gamma camera rotates around bone metastases. Excessive amounts of the radioac-
the patient and detects individual gamma rays through tivity will occur in the area of the metastatic lesion, in
a series of angles. These data are then processed by comparison to the surrounding normal bone. This is
a computer to create images of three-dimensional termed a ‘‘hot’’ spot on the image (Fig. 11.2).
The radionuclides used for radiopharmaceuticals
slices. Positron Emission Tomography (PET) refers to
employed in diagnostic nuclear medicine studies have
the detection of annihilation photons, subsequent to
short half-lives. Half-life is defined as the time it takes
emission of positrons by certain radionuclides. PET
for one-half of the radioactive atoms to undergo
scanners are constructed as solid rings of detectors
radioactive decay with emission of their characteris-
that employ coincidence detection of the annihila-
tic radiation. For example, technetium Tc-99m has a
tion photon pairs. These data are then processed by a
physical half-life of 6.0 hours (Fig. 11.3). The shorter
computer to create images of three-dimensional slices.
the half-life, the lower is the total number of atoms
Normal versus abnormal images vary, depending necessary for the production of a given unit of activity
on the procedure. For example, a normal image with a and, hence, the higher the specific activity, compared
radiopharmaceutical designed to be phagocytized by with a longer half-life radionuclide. Simply stated,
the liver will appear as a rather uniform uptake and the atoms for a short-half-life radionuclide do not
distribution of the radiopharmaceutical throughout exist very long before emitting their radiation. This
the liver. A space-occupying lesion, such as a tumor, allows a patient to receive an extremely small mass of
lacks phagocytic cells, so it does not concentrate the radionuclide, which provides a high degree of safety
radiopharmaceutical. Thus, the image of the liver will for the patient, while allowing the nuclear medicine
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478 | An Introduction to Pharmacy

Table 11.3 Diagnostic radiopharmaceutical products* commercially available in the United States in 2011
and their common uses

Albumin, iodinated I 125 (I-125 RISA) injection Determination of plasma volume

Albumin, iodinated I 131 (I-131 RISA) injection Determination of plasma volume

Ammonia N-13 injection Myocardial perfusion imaging

Fludeoxyglucose F-18 (F-18 FDG) injection Brain, heart, and tumor imaging

Gallium citrate Ga-67 injection Tumor and infection imaging

Indium In-111 capromab pendetide injection† Imaging of prostate cancer

Indium In-111 chloride sterile solution Radiolabeling of peptides and antibodies

Indium In-111 ibritumomab tiuxetan injection† Non-Hodgkin’s lymphoma imaging

Indium In-111 oxyquinoline (In-111 oxine) sterile solution Radiolabeling of leukocytes

Indium In-111 pentetate (In-111 DTPA) injection Imaging of cerebrospinal fluid flow

Indium In-111 pentetreotide injection† Imaging of somatostatin receptors on tumors

Iodine I-131 tositumomab injection Non-Hodgkin’s lymphoma imaging

Iobenguane I-123 (I-123 MIBG) injection Imaging of neuroendocrine tumors

Ioflupane I-123 injection Imaging of dopamine transporters in brain

Iothalamate sodium I-125 injection Determination of glomerular filtration rate

Rubidium chloride Rb-82 injection Myocardial perfusion imaging

Sodium chromate Cr-51 injection Determination of red cell volume

Sodium fluoride F-18 injection Bone imaging

Sodium iodide I-123 capsule Thyroid imaging

Sodium iodide I-131 capsule Thyroid uptake measurement, thyroid imaging

Sodium iodide I-131 oral solution Thyroid imaging

Sodium pertechnetate Tc-99m injection (Tc-99m TcO4 - ) Thyroid, salivary gland, blood pool imaging

Technetium Tc-99m albumin aggregated injection (Tc-99m MAA)† Lung perfusion imaging

Technetium Tc-99m bicisate injection (Tc-99m ECD)† Cerebral perfusion imaging

Technetium Tc-99m disofenin injection (Tc-99m DISIDA)† Hepatobiliary imaging

Technetium Tc-99m exametazime injection (Tc-99m HMPAO)† Cerebral perfusion imaging

Technetium Tc-99m mebrofenin injection (Tc-99m BRIDA)† Hepatobiliary imagng

(continued overleaf)
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The scope of pharmacy practice | 479

Table 11.3 (continued)

Technetium Tc-99m medronate injection (Tc-99m MDP)† Bone imaging

Technetium Tc-99m mertiatide injection (Tc-99m MAG3)† Kidney imaging

Technetium Tc-99m oxidronate injection (Tc-99m HDP)† Bone imaging

Technetium Tc-99m pentetate injection (Tc-99m DTPA)† Kidney, lung ventilaiton imaging

Technetium Tc-99m pyrophosphate (Tc-99m PYP)† Bone, myocardial infarct, blood pool imaging

Technetium Tc-99m labeled red blood cells injection (Tc-99m RBCs)† Blood pool imaging

Technetium Tc-99m sestamibi injection (Tc-99m MIBI)† Myocardial perfusion, breast tumor imaging

Technetium Tc-99m succimer injection (Tc-99m DMSA)† Kidney imaging

Technetium Tc-99m sulfur colloid injection† Liver/spleen and gastric emptying imaging

Technetium Tc-99m tetrofosmin injection† Myocardial perfusion imaging

Thallous chloride Tl-201 injection Myocardial perfusion imaging

Urea C-14 capsule Breath test for H. pylori infection

Xenon Xe-133 gas Lung ventilation imaging

∗ Proper name (common name).

† Approved product exists in kit form.

Table 11.4 Therapeutic radiopharmaceutical products* commercially available in the United States in
2011 and their common uses

Iodine I-125 3-iodo-4-hydroxybenzenesulfonate (HBS)* Intracavitary brachytherapy of brain tumors

Iodine I-131 tositumomab injection Treatment of non-Hodgkin’s lymphoma

Samarium Sm-153 lexidronam pentasodium injection (Sm-153 EDTMP) Palliation of painful bone metastases

Sodium iodide I-131 capsule Treatment of hyperthyroidism, thyroid cancer

Sodium iodide I-131 oral solution Treatment of hyperthyroidism, thyroid cancer

Strontium chloride Sr-89 injection Palliation of painful bone metastases

Yttrium Y-90 chloride sterile solution Radiolabeling of ibritumomab tiuxetan

Yttrium Y-90 ibritumomab tiuxetan† Treatment of non-Hodgkin’s lymphoma

Yttrium Y-90 microspheres§ Intravascular brachytherapy of liver tumors

∗ Proper name (common name)

† Approved product exists in kit form.
§ Radioactive device, rather than a radioactive drug.
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480 | An Introduction to Pharmacy

Figure 11.1 A hemangioma is exhibited as a cold spot (arrow) relative to surrounding normal liver uptake on a Tc-99m sulfur
colloid liver scan.

procedure to be conducted satisfactorily. A rapid rate of the radionuclide to the compound) and other com-
of decay and, thus, frequent radiation emission is fur- ponents necessary to accomplish the labeling process
ther desirable for the efficient performance of these and allow administration of the final product. The
procedures, since the gamma camera must ‘‘see’’ a cer- radionuclide generator most often employed is the
tain number of gamma rays to obtain sufficient data technetium generator. The radionuclide technetium
to create the desired image.This half-life, based on Tc-99m is produced by the decay of molybdenum
radioactive decay, is also referred to as ‘‘physical half- Mo-99. Molybdenum-99 has a half-life of 6 hours
life.’’ Because radiopharmaceuticals administered to and allows the generation of Tc-99m over a period
patients undergo biologic elimination, there is also a of 1 to 2 weeks. The Tc-99m is separated from the
drug excretion half-life referred to as ‘‘biologic half- Mo-99 by passing a sterile saline solution through an
life.’’ Hence, a radiopharmaceutical administered to ion-exchange column containing the Mo-99 and the
a patient undergoes both radioactive decay and bio- Tc-99m that has been generated. The Mo-99 remains
logic elimination, so its overall ‘‘effective half-life’’ is on the column, whereas the Tc-99m, in the chemical
equal to [(physical half-life) × (biologic half-life)] ÷ form of sodium pertechnetate, elutes from the column
[(physical half-life) + (biologic half-life)]. and is collected in a sterile vial. Aliquots of this eluate
Because the radionuclides commonly employed are then used to prepare radiopharmaceuticals with
in radiopharmaceuticals have short half-lives, most the reagent kits.
radiopharmaceuticals must be prepared on the day Quality-control issues are important in this pro-
of use. This is accomplished most frequently with cess. The possibility of the presence of Mo-99 in the
the aid of a nonradioactive reagent kit and radioac- eluate must be determined, because this radionuclide
tivity obtained from a radionuclide generator. The has a longer half-life, emits a more damaging form
reagent kit is usually a multi-dose vial that contains of radiation (beta), and is in the wrong chemical
the compound (ligand) to be labeled (i.e., attachment form. The purity of the desired compound must also
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The scope of pharmacy practice | 481

be determined following preparation of the radio-

pharmaceutical with the sodium pertechnetate and a
reagent kit. This is usually accomplished using paper
or thin-layer chromatography procedures. A specified
percentage of the radioactivity must be incorporated
in the specified compound (i.e., the radiopharma-
ceutical). If a significant fraction of the radioactivity
remains as sodium pertechnetate, the radiopharma-
ceutical product will not distribute in the body as
expected and might cause confusion or even an
improper diagnosis.
A few radiopharmaceuticals are employed in the
treatment of disease, most often certain cancers. Like
diagnostic radiopharmaceuticals, these compounds
are designed to localize in the diseased tissue. How-
ever, these radiopharmaceuticals emit particulate
radiation, typically beta particles, that deposit their
energy in a localized area with the intent to destroy
cells in the diseased tissue.
Perhaps the best known approach to therapy with
a radiopharmaceutical involves the use of radioactive
iodine, I-131, administered as sodium iodide to the
patient. The I-131 is taken up by the thyroid gland
and incorporated into thyroid hormones. Whereas
small, diagnostic dosages of I-131 produce negligi-
ble biological damage, the beta radiation emitted by
large, therapeutic dosages of I-131 destroys thyroid
tissue. Depending on the disease state, hyperthy-
roidism or thyroid cancer, the amount of radioactive
iodide given to the patient varies considerably. The
usual dosage ranges for treatment of hyperthyroidism
(partial destruction) and thyroid carcinoma (total
destruction) are 140 to 370 MBq (4 to 10 mCi) and
3700 to 5550 MBq (100 to 150 mCi), respectively. In
contrast, less than 1 MBq (a few microcuries) of I-131
is given for diagnostic purposes. This is an important
consideration when counseling a patient regarding the
use of radioactive iodine for diagnostic procedures.
One of the more recent developments in onco-
logic nuclear medicine is the use of monoclonal
antibodies labeled with a gamma-emitting radionu-
clide for diagnostic imaging and with a beta-emitting
Figure 11.2 Multiple metastases to the bone from primary
radionuclide for subsequent therapy. For example,
breast cancer are exhibited as ‘‘hot’’ spots (arrows) relative to
ibritumomab, the parent murine monoclonal anti-
surrounding normal bone uptake on a Tc-99m medronate
bone scan. Kidneys and urinary bladder are also seen (open body of the widely used chimeric antibody rituximab,
arrows), due to normal excretion into the urine. selectively binds to the CD20 antigen found on the
surface of B-lymphocytes and lymphatic tumor cells.
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482 | An Introduction to Pharmacy

100
90
80

Percent remaining
70
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Hours

Figure 11.3 Radioactive decay of Tc-99m demonstrating its half-life of 6 hours.

When radiolabeled with gamma-emitting In-111, ibri- Home infusion pharmacy practice
tumomab tiuxetan is used for imaging in patients with
non-Hodgkin’s lymphoma; when radiolabeled with The provision of home care has existed since the late
beta-emitting Y-90, ibritumomab tiuxetan is used for 1800s, when societal concerns regarding immigration,
subsequent radioimmunotherapy of non-Hodgkin’s industrialization, and infectious diseases generated the
lymphoma in these same patients. need for visiting nurses. Early home care services pri-
As described, radiopharmaceuticals constitute a marily consisted of midwife and nursing assistance
unique and specialized category of drugs. Similarly, for births, and the care of influenza and tuberculosis
individuals who handle radiopharmaceuticals need to patients. This early form of home care paved the way
possess a unique and specialized body of knowledge for the development of alternate site healthcare. The
and skills. Specifically, nuclear pharmacy practition- term home care generally refers to community-based
ers must have specialized training in several areas, nursing and hospice services provided to patients in
including nuclear physics, radiation detection instru- their homes. The term includes a wide variety of ser-
mentation, radiochemistry, and radiation protection. vices provided outside the confines of the hospital,
An experiential component of this training in a as outlined in Table 11.5. The National Association
practice setting is essential as well. The level of knowl- for Home Care and Hospice (NAHC) estimates that
edge and experience necessary, as well as services 12 million Americans receive home care from over
provided, vary with the practice site. The major- 33,000 providers.122,123 In 2009, $103.2 billion was
ity of nuclear pharmacists practice in a commercial spent on home healthcare and durable medical equip-
nuclear pharmacy. Most practitioners in this set- ment, accounting for 4% of the total US national
ting have a first professional degree, whereas nuclear healthcare expenditure.124
pharmacists in an institutional site have commonly Since the early 1990s, home healthcare has
obtained an advanced degree (e.g., MS). The basic become the fastest growing segment of healthcare.
functions are similar; however, the pharmacist in In 1999, the US Supreme Court rendered a decision
the larger hospital may be more involved with clin- in Olmstead v. L.C., affirming the Americans with
ical service, investigational products, and teaching. Disabilities Act of 1990, which ‘‘increased pressure
The pharmacist in a commercial nuclear pharmacy on federal and state programs to deliver advanced
inherently spends considerable time preparing and health care services to patients at home.’’125
dispensing radiopharmaceuticals, since one pharmacy The dramatic increase in the alternate site health-
services a dozen or more different hospitals and care market has largely occurred due the nation-
clinics. wide effort to control healthcare costs. During the
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The scope of pharmacy practice | 483

Standard for Home Care Pharmacies,127 a home care

Table 11.5 Types of home care services
pharmacy is one that provides primarily, if not exclu-
• Homemaker Services (e.g., cleaning, cooking for the homebound) sively, home infusion products and related monitoring
• Personal Care Services (e.g., bathing, dressing) services.
• Durable Medical Equipment (e.g., walkers, oxygen, hospital beds)
Currently, approximately 1000 pharmacy orga-
• Home Respiratory Care (e.g., respiratory therapy, nebulizers)
nizations nationwide provide infusion therapy ser-
• Medical Devices and Supplies (e.g., glucometers and glucose test
strips) vices. These pharmacies include local, regional, and
• Skilled Nursing Services national pharmacy organizations that are indepen-
• Physical Therapy dently owned, publicly traded, or affiliated with
• Occupational Therapy
hospitals, health systems, home health agencies, retail
• Speech/Language Pathology
pharmacies, retail pharmacy chains, or durable med-
• Medical Social Work
• Hospice Care ical equipment suppliers.126 Home nursing services
• Pharmacy Services (e.g., infusion therapies, inhalation therapies, may be provided by the infusion pharmacy to ensure
clinical monitoring) proper patient and caregiver training, and to monitor
the clinical care of the patient in the home. Alter-
Data from: Lima HA. Pharmacy Practice News 1999; (July) 33, and
natively, home nursing services required for the safe
National Association for Home Care and Hospice. Basic Statistics About
provision of home infusion therapy can be provided
Home Care, 2010. Available at: http://www.nahc.org/facts/10HC_
Stats.pdf (accessed July 1, 2011). by a qualified home health agency.
Home infusion pharmacy services differ dramat-
ically from most retail pharmacy operations. While
1980s, the US healthcare system underwent dra- retail pharmacies primarily dispense oral medications,
matic changes. In particular, with the introduction infusion pharmacies must have the equipment neces-
of diagnosis-related groups (DRGs) as a cost-control sary to safely prepare and store sterile parenteral
measure, home care offered a cost-effective alterna- preparations. This includes: laminar flow hoods or
tive following the post-acute hospital stage.122 Driven isolators and clean room complexes to reduce the
by heightened emphasis on cost-effectiveness and risk of microbial contamination, modified storage
cost-containment, technological advances have been areas for certain drugs, and additional compounding
developed that enabled the safe and effective adminis- equipment and supplies for the sterile preparation of
tration of complex treatments in the home, including parenteral drugs. In addition to sterile preparation
home infusion therapy. expertise, home infusion pharmacists must have the
Home infusion is an important component of knowledge and commitment to provide pharmaceuti-
the home care industry and accounts for approx- cal care within an interdisciplinary team to a broad
imately $9 to $11 billion annually. This service cross-section of patients treated in their homes and in
provides therapies to patients in their homes or alter- alternate site settings.128 A summary of home infusion
nate settings, such as ambulatory infusion clinics. pharmacists’ responsibilities is outlined in Table 11.6.
Home infusion therapy involves the prolonged inter-
mittent or continuous parenteral administration of
pharmaceutical products (e.g., medications, nutrients, Specialty pharmacy
or other solutions) most often delivered intravenously,
subcutaneously, intramuscularly, or epidurally. Com- Specialty pharmacy is a unique pharmacy practice
monly prescribed home infusion therapies include: that has its origins in the home infusion practice
antibiotics, antifungals, parenteral nutrition (PN), setting. Although an accepted industry standard and
pain management, hydration, chemotherapy, immune FDA definition are lacking, specialty pharmaceuticals
globulins, corticosteroids, inotropics, blood clotting were originally defined as those products produced
factors, other intravenous drugs, as well as enteral by recombinant DNA technology (biotech drugs) and
nutrition.122,126 According to the ASHP Minimum administered via injection.129 Early specialty drugs
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484 | An Introduction to Pharmacy

In fact, one universally accepted characteristic

Table 11.6 Home infusion pharmacist
of specialty pharmaceuticals is their high cost.
responsibilities
Recombinant insulin does not fit the definition of
• Preadmission Assessment a specialty pharmaceutical, but interferon beta-1a
• Initial Assessment (Avonex®), a $17,000+ -a-year product used to treat
• Product, Devices, and Ancillary Supply Selection
multiple sclerosis (MS) that requires a refrigerated
• Care Plan Development
chain of distribution, clearly does.131 The US Centers
• Patient Education and Counseling
• Clinical Monitoring for Medicare and Medicaid (CMS) will put a drug
• Communication with Patient, Caregiver, Nurse, Dietitian, and on its specialty tier if the monthly cost of the drug
Prescriber exceeds $600.132 This cost is misleading because
• Coordination of Drug Preparation, Delivery, Storage, and most specialty medications cost well over $1,000
Administration
per month for one drug. Consider the multiple
• Precautions for Employee and Patient Safety
• Home Care Record Documentation
• Adverse Event Reporting
• Performance Improvement Activity Participation
• Policy and Procedure Development and Implementation Table 11.7 Characteristics of specialty
• Legal, Regulatory and Accreditation Compliance pharmaceutical130
• Training, Continuing Education and Competence
High cost
Data from: ASHP Guidelines on the Pharmacist’s Role in Home Care. Am Developed using biotechnology/recombinant technology
J Health-Syst Pharm 2000; 57:1252–7. Requires specific, detailed patient education on administration of the
drug
Administered as a self-injectable
Office-administered injectable or self-infused
were used to treat complex genetic conditions includ- Administered orally (often as a monoclonal antibody)
ing: cancer, hemophilia, hepatitis C, multiple sclero- Requires special handling, such as refrigeration storage, inventory,
sis, and pulmonary hypertension. However, specialty or distribution
drug dosage forms have expanded and can include Limited distribution
Used to treat complex genetic diseases that require special
high-cost oral, injectable, infused, and inhaled biotech
monitoring and therapy management
drugs, and are sometimes called biologicals or biolog- Often times, is an orphan drug used to treat rare diseases
ics. The newer specialty pharmaceuticals are targeted Requires high-touch service model, complex care and continuous
to more common chronic conditions such as rheuma- patient management
toid arthritis and asthma. Many specialty drugs are Used in the treatment of specific diseases including but not limited
to:
not biologics and conversely, many biologic drugs are
Crohn’s disease
not considered specialty drugs. Insulin is a biologic
Growth hormone deficiency
but is not considered a specialty drug. Many specialty Hemophilia, von Willebrand disease and other bleeding disorders
drugs are orphan drugs or are used to treat diseases Hepatitis C
for which there are no other available treatments. Hereditary angioedema
An increasing amount of specialty drugs on the mar- HIV/AIDS
Immune disorders
ket today and in the FDA pipeline can be taken
Lysosomal (metabolic) storage disorders (LSDs)
orally. Specialty drugs require intensive ‘‘therapy
Multiple sclerosis (MS)
management’’ by health professionals due to a high Neuroimmunological disorders (e.g., CIDP, Guillain Barré)
incidence of adverse effects and compliance issues that Oncology
require dosage adjustments and monitoring. Char- Pulmonary arterial hypertension (PAH)
acteristics of specialty pharmaceuticals are listed in Psoriasis
Respiratory syncytial virus (RSV)
Table 11.7.
Rheumatoid arthritis (RA)
Specialty medications typically require ‘‘high- Transplant
touch’’ services in the forms of distribution, Not managed under traditional outpatient prescription drug benefit
administration, or patient management: all of these
factors add costs for the purchaser or consumer. Adapted from 129,130
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The scope of pharmacy practice | 485

medications a hepatitis C or an HIV/AIDS patient positions in 2004–2005.135 In 2010–2011, 47% of

may take where monthly costs can exceed $4,000. pharmacy faculty members were in non-tenure-track
Traditionally, specialty drugs are used to treat positions.134 This rise in non-tenured faculty most
relatively small numbers of patients who have rare, likely reflects the increasing curricular need for
chronic and oftentimes genetic or orphan diseases. academicians with expertise in clinical arenas, such
These drugs require special handling and clinical as critical care, infectious diseases, internal medicine,
monitoring and are very expensive, ranging from cardiology, oncology, and other practice disciplines.
$10,000 to over $250,000 per year. Typically, departments and divisions in colleges of
pharmacy have guidelines for promotion and tenure,
as well as guidelines for promotion of non-tenure-
Pharmacists in academia track faculty. A level of excellence is expected in
primary categories (e.g., teaching, scholarly/research
Pharmacists in academia, like other academicians, activity, patient care, service) to support promotion
have responsibilities in the categories of teaching; and tenure of a given faculty member. With respect to
scholarly/research activity; patient care; and service to teaching, the ‘‘teaching load’’ may be calculated in dif-
their department, college, and/or university. Within ferent ways (e.g., lecture contact hours, student credit
most colleges of pharmacy, there are faculty members hours: course credit hours multiplied by the number
in tenure-track positions and those in non-tenure- of students in that course). For pharmacy practice
track positions, whereas some colleges are non-tenure faculty, the number of weeks precepting students per
granting institutions only. The choice to pursue a year are also included. Of note, most pharmacy fac-
given academic appointment track is based on the ulty (tenured and non-tenured) may not have been
individual’s preference to focus on a specific aspect ‘‘taught to teach.’’ Thus, they require professional
of academia, as well as the university’s expectations development support from their institutions to gain
of that faculty member. That is, some individuals experience in pedagogy and scholarly activity. A few
may prefer the classroom setting focusing on teach- of these faculty members may have had teaching
ing, whereas others prefer involvement in patient care requirements or experiences in their graduate school
and service. Tenure-track faculty are expected to be or residency programs, which gives them some formal
more productive in the area of scholarship, with less teaching experience prior to taking a faculty position.
time devoted to patient care than non-tenure-track Professional practice or patient care responsibil-
faculty.133 According to the AACP, for colleges that ities necessary for promotion may include evidence
do offer both tracks of academic appointments, 53% of substantial commitment to pharmaceutical care
of pharmacy faculty are either tenured or are in a (e.g., time commitment and duration of service),
tenure-track position.134 When considering the dis- leadership in practice policy and protocol develop-
cipline of pharmacy practice as a whole, where the ment, participation in activities to ensure the optimal
vast majority of individuals are pharmacists, 34% of use of medications, publication of scholarly articles
these faculty members are tenured or in tenure-track concerning professional practice, efforts to maintain
positions. professional competence, and presentations of educa-
However, the majority (65%) of pharmacy tional programs. A faculty member’s workload may
practice faculty members are in contractual, non- constitute all of the aforementioned metrics, as well
tenure-track positions.134 These tracks are often as other institution-specific requirements.
defined as ‘‘clinician-educator’’ positions, where Evaluation of scholarly/research activity may
individuals may have an annual contract agreement include the number of manuscripts a faculty member
or ‘‘rolling’’ agreements of various time length (e.g., publishes annually in peer-reviewed journals and/or
4 year renewal). The number of non-tenured faculty, in other professional publications. Other types of
including clinical faculty members, continues to rise. publications that may be considered scholarly include
During the 1991–1992 academic year, 22% of all books, book chapters, and continuing professional
faculty members were in non-tenure-track positions, education articles, among others. Research efforts in
compared to 42% of faculty members in such the realm of scholarly activity include the number
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486 | An Introduction to Pharmacy

of federal and/or non-federal grants submitted and

Table 11.8 Responsibilities for pharmacy
approved/funded, as well as grant dollar amounts.
practice faculty in tenure and non-tenure tracks
Scholarly activity also includes presentations made
(e.g., ‘‘podium/poster presentations’’ at meetings, Discipline Tenure track Non-tenure track
invited lectures, and continuing professional educa-
tion presentations at the local, state or national level). Number of weeks per year 26 + 9.4 (n = 48) 34.1 + 6.8 (n = 49)
precepting students
The service component of a faculty member’s
responsibility would include university and school
Number of clerkship 12.1 + 6.0 (n = 47) 16.5 + 6.3 (n = 47)
committee work, as well as other types of professional students per year
and community service (e.g., advising student organi-
zations, holding leadership positions in a professional Number of didactic hours 34.8 + 23 (n = 47) 29.5 + 24 (n = 47)
organization). Typically, pharmacists’ service to the taught per year

profession, in academia, means participating in intra-

Number of peer-reviewed 1.7 + 1.3 (n = 48) 0.6 + 0.7 (n = 48)
and inter-professional organizations (e.g., the Amer- articles published per year
ican Pharmacists Association (APhA), the American
Society of Health-Systems Pharmacists (ASHP), Number of committees 2.2 + 0.9 (n = 48) 1.8 + 0.9 (n = 48)
American Associations of Colleges of Pharmacy assigned to per year

(AACP), the American College of Clinical Pharmacy

n, Number of pharmacy practice departments responding.133
(ACCP), and the American Public Health Association
(From Glover ML, Deziel-Evans L. Comparison of the responsibilities of
(APHA), among others). Further, academic pharma- tenure versus non-tenure track pharmacy practice faculty. Am J Pharm
cists may hold many leadership positions in these Ed 2002; 66: 388–391.)
organizations. This provides a critical link between
professional organizations and academia. and clinical knowledge to pharmacy practice.136
Those pharmacists in academia on tenure-track A study published in 2002 investigated faculty
appointments, like other academicians, strive for pro- member commitment to the categories of teaching,
motion and tenure over a 6-year period and typically scholarly activity, service, and patient care for tenure-
apply for promotion with tenure at the time of track individuals versus non-tenure-track individuals
advancement from the rank of assistant professor in pharmacy practice departments (Table 11.8).133
to the rank of associate professor (e.g., the 7th year).
Once the rank of associate professor is achieved, the
pharmacist academician may strive to attain the high- Nutrition in pharmacy practice
est academic rank of ‘‘full professor,’’ which acknowl-
edges a national and international reputation through Diet and nutritional status are the foundations of
continued outstanding teaching, scholarly/research good health and well-being. Nutrition consists of a
activity and service for their contributions to their complex system of macronutrients, vitamins, minerals
specific discipline, and continued professional growth. and fluids that are essential for growth and develop-
These individuals are recognized nationally or inter- ment. Many chronic diseases such as osteoporosis,
nationally for their expertise. There is no defined time cancer, and coronary artery disease have dietary asso-
frame to be promoted from associate to full professor. ciations. Health-care practitioners need to be aware
Similar teaching, scholarly activity, and service of the importance of proper nutrition in disease pre-
expectations exist for non-tenure-track faculty vention and the interrelationships of the biochemical
members. However, requirements, as far as the roles of nutrients and their impact on deficiency states
number of items in each category, are scaled down and disease processes.
for these individuals, to account for the additional
patient care/clinical responsibilities. These pharmacy
Nutrients and associated substances
clinician-educators in academia are also heavily
involved in experiential education and responsible In both general and specialty practice pharmacists in a
for teaching the student to apply basic science variety of settings are called upon to care for patients
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The scope of pharmacy practice | 487

requiring nutrient-related interventions. Nutrition is specific disorders. Parenteral nutrients can be com-
rarely the primary problem for these patients; rather bined to form a parenteral nutrient admixture used to
an underlying disease process, condition or therapeu- support patients unable to otherwise take or assimilate
tic regimen compromises nutrition status or results nutrients through the gastrointestinal tract.
in outright nutrient deficiencies. For other patients There exists a nutrition continuum from health
preventative care and disease risk reduction may be to disease, across the life cycle, in which pharma-
the goal. In either case nutritional pharmacother- cists have become involved based on their knowledge
apy represents an integration of the principles of set and clinical opportunity. Even many inherited
pharmacotherapy with the pharmaceutical sciences metabolic disorders require close attention with nutri-
and clinical nutrition. It involves the evaluation and ent manipulation. Particularly in the field of nutrition,
implementation of the best therapeutic plan for the where misinformation may endanger the health of
patient in which dietary supplements, enteral nutri- individuals, consumers must be provided opportu-
tion, or parenteral nutrition may be necessary. This nity to learn to make sound decisions regarding
is built on a longstanding history of using food, con- their health and nutrition status. Pharmacists can be
taining traditional nutrients and associated bioactive involved in educating patients on various aspects of
substances, to manage human conditions. In recent nutrition, screening patients for poor nutrition status,
years more attention has been given to the specific suggesting referral to other healthcare providers for
aspects of the diet that not only prevent deficien- more specific needs, and managing therapeutic regi-
cies but also can be used to prevent chronic disease, mens that contain dietary supplements, enteral nutri-
augment growth and development, and treat select tion, or parenteral nutrition. Furthermore, depending
disorders of health. It is valuable to appreciate that on the setting, pharmacists may be involved in clinical
nutrients and associated substances may be delivered or basic research that involves nutrients and asso-
in fresh foods, processed and fortified foods, dietary ciated substances. Pharmacists can be involved to
supplement products, medical foods, and drugs. With varying degrees in helping consumers and patients
the exception of food these are all pharmaceutical alike with preventive strategies as well as therapies
preparations. involving nutrients.
Nutrients and associated substances found in
foods or pharmaceutical ‘‘delivery systems’’ are phys-
iologically active substances. The chemical struc-
Veterinary pharmacy
ture and structure–activity relationships of individual
nutrients are no different than any other natural
Scope of veterinary pharmacy practice
or synthetic drug. In fact the kinetic behavior of In 1977, a survey of agricultural sector veterinarians137
some nutrients is more complex than that of many demonstrated the need for pharmacist involvement in
drugs. Nutrient bioavailability can vary greatly with veterinary medicine and recommended the establish-
the delivery vehicle and dosage form. Additionally ment of a veterinary pharmacy specialty that required
nutrient absorption, distribution, and elimination will specialized education and examination for licensure.
vary with an individual’s nutrition status. Dietary More than three decades after this recommendation,
supplement products may contain nutrients or asso- the Board of Pharmaceutical Specialties (BPS) does
ciated substances as the sole ingredient, but more not yet recognize veterinary pharmacy as a pharmacy
often are included in multi-ingredient products. The specialty practice. However, veterinary pharmacy
latter sometimes combine nutrients with botanical certainly qualifies for consideration in light of BPS’s
and other non-nutrient ingredients. Meal replacement overriding concern to ‘‘ensure that the public receives
formulas and medical foods intended for patients the level of pharmacy services that will improve a
unable to consume adequate nourishment orally are patient’s quality of life.’’138 BPS’s stated concern
additional delivery vehicles for nutrients and asso- does not characterize patients as being limited to
ciated substances. Some nutrients are found as drug the human species, and society expects a competent
products – in oral and parenteral dosage forms. These performance from pharmacists when providing
nutrient-containing products are often intended for pharmaceutical care for all family members, human
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488 | An Introduction to Pharmacy

or otherwise. As human reliance on animals increases revenue.139 Some veterinary pharmacists in these
(e.g., companionship, service, research, food, settings are species specialists and are noted for their
agribusiness, and entertainment), most pharmacists expertise and skills in providing pharmaceutical care
will eventually find themselves providing some degree for a single species, such as pharmacists caring for
of pharmaceutical care and drugs to a non-human horses in exclusively equine veterinary practices.
patient. Many pharmacists have devoted a large A typical day for a veterinary specialty referral
portion, if not all, of their professional practice to center pharmacist involves many of the distributive
providing pharmaceutical expertise and specialized and consultative duties that are performed by the
skills to caring for animals. Pharmacists desiring veterinary teaching hospital pharmacist but with less
to effectively participate in animal care have many emphasis on teaching or research.
career options. The current scope of veterinary
pharmacy practice includes, but is not limited to, Community pharmacy
veterinary academia, veterinary specialty referral
One of the most rapidly growing areas of veterinary
centers, community and online (Internet) pharmacies,
pharmacy practice is in the community pharmacy
the pharmaceutical and agricultural industry, and
setting. When the Animal Medicinal Drug Use Clar-
governmental public health and regulatory sectors.
ification Act of 1996 codified the extra-label use of
Veterinary teaching hospitals human drugs in animals, veterinarians began prescrib-
ing more and more human drugs for use in animal
The most well-established practice of veterinary phar-
patients. As a result, pharmacists in chain and inde-
macy resides in veterinary academic teaching hospi-
pendent pharmacies were presented with an unprece-
tals. Pharmacists in these roles provide expertise in
dented number of prescriptions for animals. The
areas of service (drug selection, distribution, and con-
professional rewards of helping animals combined
trol), teaching (didactic, incidental exchanges, client
with the financial rewards of cash-paying customers
counseling, in-service education, and continuing edu-
caused community pharmacists to focus more on the
cation programs for pharmacists and veterinarians),
animal prescription market. Independent pharmacies
and research (clinical trial development and adminis-
began collaborating with veterinarians to provide
tration, compounded preparation quality assurance,
compounded preparations for animal patients, and
adverse drug reaction and medication error reporting,
large retail chains began allowing pets into the dis-
publication of articles in scientific and professional
counted generics plans traditionally offered for human
journals, and drug information query requests). A typ-
prescriptions. The result has been the emergence of
ical day for a veterinary teaching hospital pharmacist
several veterinary-only pharmacies catering solely to
involves rounding with clinical faculty, house offi-
animal patients, and most recently, veterinary-only
cers, and students; preparing and delivering lectures
online pharmacies are beginning to become more
for veterinary, pharmacy, and veterinary technology
prevalent.
students; providing drug utilization review and ther-
apeutic interventions; maintaining hospital pharmacy
operations (inpatient and outpatient drug distribu- Industry (pharmaceutical, agricultural)
tion, preparing sterile and nonsterile compounds, Pharmacists with veterinary expertise are also valu-
admixture of intravenous and chemotherapeutic ther- able to the animal health industry. Because of their
apies); and engaging in a variety of incidental teaching unique training that combines pharmacological exper-
and consultative activities with students, veterinary tise, clinical decision making, and marketing skills,
practitioners, and animal owners. pharmacists with specialized veterinary training make
excellent professional representatives for the veteri-
Veterinary specialty referral centers nary pharmaceutical industry. They can easily explain
Increasingly, veterinary specialty referral centers are the pharmacodynamics and clinical advantages of new
employing veterinary pharmacists. Interventions by drugs to veterinarians and can serve as consultants
these pharmacists have a direct and positive impact for adverse event monitoring and reporting. Veteri-
on patient care, patient well-being, and practice nary pharmacists also serve a role in research and
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The scope of pharmacy practice | 489

development in the veterinary pharmaceutical indus- Extemporaneous prescription

try and design and oversee pre- and post-marketing
compounding
clinical trials for veterinary drugs. Many veterinary
pharmacists also possess an expertise in livestock ani-
Historically, pharmaceutical compounding was the
mal medicine and are contracted by producers to
beginning of pharmacy and has been an integral part
consult in areas of medication management, special- of pharmacy practice throughout its history. This is
ized compounding, and avoidance of drug residues demonstrated by some definitions and references to
in the tissues of food-producing animals. As pharma- pharmacy, including:
cists are well trained in pharmacokinetic principles,
they are able to collaborate with producers to predict
drug depletion profiles for therapeutic agents used in
• Pharmacy is the art or practice of preparing and
preserving drugs and of compounding and dis-
food-producing animals.
pensing medicines according to the prescriptions
of physicians.140
Government sectors (FDA, CDC, NIH, disaster • Pharmacy is (1) the art or practice of preparing,
preserving, compounding, and dispensing drugs
relief)
or (2) a place where medicines are compounded or
Veterinary pharmacists are also impacting the gov-
dispensed.141
ernmental and regulatory sectors. The Center for
• Pharmacy is the science, art, and practice of
Veterinary Medicine of the Food and Drug Adminis- preparing, preserving, compounding, and dispens-
tration (FDA CVM) employs many veterinary phar- ing medicinal drugs and giving instructions for
macists in areas of compliance, surveillance, adverse their use.142
event reporting, and medication error prevention. The
• And thou shalt make it an oil of holy ointment, an
Centers for Disease Control and Prevention (CDC) ointment compounded after the art of the apothe-
also employ veterinary pharmacists who are charged cary; it shall be an anointing oil.143
with overseeing the distribution and use of biological • Even today, the definitions of pharmacy include
agents and drugs used to prevent or treat rare diseases the preparation of drugs.144,145
that are zoonotic between animals and humans. The
National Institutes of Health (NIH) employ a vet-
The heritage of pharmacy, spanning some 5000
erinary pharmacist responsible for providing drugs,
years, has centered around the provision of pharma-
compounds, and consultation for research animals ceutical preparations for patients. Pharmacists are the
in NIH funded protocols. This pharmacist focuses only healthcare professionals that possess the knowl-
his/her efforts on minimizing the stress that drug edge and skill required for compounding and prepar-
administration can cause to research animals, and ing medications to meet the unique needs of patients.
has developed combination drug dosage forms and The responsibility of extemporaneously compounding
transmucosally absorbed drugs for nasal and buccal safe, effective prescription preparations for patients
administration. who require special care is fundamental to the phar-
Veterinary pharmacists also serve on disaster relief macy profession.
teams. These specially trained pharmacists are parts The nineteenth century saw more consistency in
of multidisciplinary teams of veterinarians, veteri- compounding formulations through the establishment
nary technicians, and pharmacists. Regional teams of the United States Pharmacopeia (USP). In the twen-
of disaster relief veterinary professionals remain on tieth century, it has been estimated that a broad
alert and are deployed to stricken areas to provide knowledge of compounding was still essential for
triage, care, and treatment for displaced and injured 80% of the prescriptions dispensed in the 1920s.
animals. One of the largest deployments of a Veteri- The middle part of the century did not see an end
nary Medical Assistance Team (VMAT) was during to the art and science of compounding, but it did
the hurricane Katrina recovery in 2005 and involved give way to newer technology, allowing for manu-
many veterinary pharmacists. factured products. In the latter part of the century,
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490 | An Introduction to Pharmacy

a broad knowledge of compounding was still essen- pharmacist’s expertise to adjust dosage quantities,
tial. In the twenty-first century, a broad knowledge of frequencies, and even dosage forms for enhanced
compounding is essential and will become even more compliance. All pharmacists should understand the
so with more individualized medication prescribed in options presented by compounding.
the field of biologics.140 Pharmaceutical compounding is increasing for a
The pharmaceutical industry began to take over number of reasons, including the availability of a lim-
the production of most medications used by the ited number of dosage forms for most drugs, a
medical profession. In many ways, this has provided limited number of strengths of most drugs, home
superior service, new methods, and a vast array healthcare, hospice, the non-availability of drug
of innovative products that could not have been products/combinations, discontinued drugs, drug
provided on a one-on-one basis. Research and devel- shortages, orphan drugs, new therapeutic approaches,
opment have been the hallmarks of pharmaceutical and special patient populations (e.g., pediatrics; geri-
manufacturers. However, the very nature of provid- atrics; bioidentical hormone replacement therapy for
ing millions of doses of a product requires the dosage postmenopausal women and andropause in men;
forms (e.g., capsules, tablets, suppositories) and doses thyroid patients; pain management; dental patients;
(individual strengths of each dose) be limited and environmentally and cosmetic sensitive patients;
results in a one-sided approach to therapy. In the sports injuries; limited distribution system drugs; and
twenty-first century, it is no longer economical for a veterinary compounding, including small, large, herd,
pharmaceutical company to manufacture a product exotic, and companion animals).
in several doses or in several dosage forms to meet Newly evolving dosage forms and therapeutic
the needs of the entire range of patients receiving approaches suggest that compounding of pharmaceu-
therapy. Marketing strategies determine the majority ticals and related preparations, specifically for individ-
of patient needs, but the very nature of the process ual patients, will become more common in pharmacy
cannot meet all patient needs. practice. Compounding pharmacy is unique, as it
We must also recognize that some individuals and allows the compounding pharmacist to use much of
their healthcare needs do not fall in the windows their scientific, mathematics, and technology back-
of theoretical dosage strength and dosage forms and ground to a fuller extent. Compounding pharmacists
that large-scale manufacturers cannot cost-effectively develop a special and unique relationship with the
tailor-make a medication for a handful of patients patients they serve. They work hand-in-hand with
and meet the ever-changing needs of a given patient, physicians to solve problems not addressed by com-
disease state, or institution. The skills of pharma- mercially available dosage forms.
cists practicing compounding fill this gap to meet In institutional healthcare environments there is
individualized needs. By this assessment, the phar- quite a bit of batch production of sterile and nonsterile
macist may, through understanding of the principles preparations performed to meet individual patients’
of compounding and recognition of their skill level needs or prescribers’ clinical investigational proto-
in working secundum artem, recommend therapy be cols. Many institutions are now outsourcing some
provided that is not provided by the pharmaceuti- of their compounding to specialty pharmacies spe-
cal industry but that is individualized for a specific cially equipped to address changing patterns of drug
patient’s needs at a specific time. therapy. Some of this results from the impact of the
Compounding has always been a basic part of new USP standards enhancing the facility, equipment,
pharmacy practice; the drugs, dosage forms, and personnel, and process requirements.
equipment or techniques used are the variables. Phar-
macists possess knowledge and skills that are unique
The compounding pharmacist
and not duplicated by any other profession. Pharmacy
activities to individualize patient therapy include com- Pharmacists are unique professionals: well trained
pounding and clinical functions. Either function in the in the natural, physical, and medical sciences and
absence of the other results in placing pharmacy in sensitized to the potential tragedy that may result from
a disadvantaged position. It is important to use a a single mistake that may occur in the daily practice
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The scope of pharmacy practice | 491

of their profession. Pharmacists have developed the patient care through extemporaneous compounding?
reputation of being available in the local community The pharmaceutical sciences, especially chemistry and
to interact with patients, provide needed medications, pharmaceutics, serve as the foundation for pharma-
and work with patients to regain or maintain a certain cists’ ability to formulate specific dosage forms to
standard or quality of health, as well as just being meet patients’ needs.
there in time of need.
Pharmacy is a complex mixture of different prac- Definitions
tices and practice sites. No longer is pharmacy simply Pharmacy is united in the sense that pharmacists
community pharmacy or hospital pharmacy. Phar- have a responsibility to serve their patients and com-
macy is diverse and offers many opportunities for pound an appropriately prescribed preparation in the
those willing to look around, find their niche, and course of their professional practice. It is the right
practice pharmacy to meet the needs of their own com- and responsibility of pharmacists to compound med-
munity of patients. Most compounding pharmacists ications to meet the specific needs of patients. Phar-
appear interested and excited about their practices. In macists are ultimately responsible for the integrity
fact, many pharmacists intimately involved in phar- of the finished preparation compounded under their
maceutical care have now realized the importance immediate supervision.
of providing individualized patient care through the Compounding has been defined by the USP as:
preparation of patient-specific preparations. Com- the preparation, mixing, assembling, altering, pack-
pounding pharmacy is not for everyone, but, as it aging, and labeling of a drug, drug-delivery device
grows, it will provide for an increasingly significant or device in accordance with a licensed practitioner’s
number of pharmacists the excitement and fulfillment prescription, medication order, or initiative based on
of using their innovative and creative skills to help the practitioner/patient/pharmacist/compounder rela-
solve patient problems. tionship in the course of professional practice. Com-
As mentioned, pharmaceutical compounding pounding includes the following:
requires the use of training in mathematics, science,
and technology more than some of the other practices
of pharmacy. It has been stated that: • Preparation of drug dosage forms for both human
and animal patients
‘‘The sciences are what support pharmacy’s exper-
tise in drug distribution and drug use. Recent history • Preparation of drugs or devices in anticipation of
prescription drug orders based on routine, regu-
leads one to question whether we in the profession,
larly observed prescribing patterns
and some in pharmaceutical education, recognize and
appreciate the contribution that the pharmaceutical • Reconstitution or manipulation of commercial
products that may require the addition of one or
sciences have made and continue to make to the phar-
more ingredients
macy profession and health care. The pharmaceutical
sciences are what make us unique. They provide • Preparation of hazardous drugs or devices for the
us the special value that we bring to the bedside. purposes of, or as an incident to research (clinical
No other health professional is capable of bringing or academic), teaching, or chemical analysis
to the pharmacotherapeutic decision-making table • Preparation of drugs and devices for prescriber’s
such concepts as pH, particle size, partition coeffi- office use where permitted by federal and state
cient, protein binding, structure-activity relationships, law.147
economics, and epidemiology. The pharmaceutical
sciences, combined with pharmacy’s infrastructure, Compounding may hold different meanings to dif-
including pharmaceutical education, are what make ferent pharmacists. It may mean the preparation of
the pharmacist an indispensable participant on the oral liquids, topical creams/ointments, and suppos-
health care team.’’146 itories; the conversion of one dose or dosage form
And what area of pharmacy practice has the into another; the preparation of select dosage forms
opportunity of using the scientific education and train- from bulk chemicals; the preparation of intravenous
ing as much as pharmacists involved in individualizing admixtures, parenteral nutrition solutions, pediatric
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492 | An Introduction to Pharmacy

dosage forms from adult dosage forms; the prepa- 8. Is there a bona fide prescriber–pharmacist–
ration of radioactive isotopes; the preparation of patient relationship?
cassettes, syringes, and other devices with drugs for 9. Does the patient have the necessary storage facil-
administration in the home setting; or compounding ity, if required, to assure potency of the prepara-
for animal patients. tion until its beyond-use date?
There are two different types of compounded 10. Can I perform the necessary calculations to com-
prescriptions, including the extemporaneous and the pound the preparation formula?
batch prepared. The extemporaneous prescription 11. Am I willing to complete the necessary documen-
is one that is unexpected or one the pharmacist tation to compound the preparation?
may expect to receive on a fairly routine basis on a 12. Is there a literature reference that might pro-
small scale. The batch prepared prescription is one vide information on use, preparation, stability,
in which multiple identical units are prepared as administration, etc.?
a single operation in anticipation of the receipt of 13. How long will the patient be using the prepara-
prescriptions. There may be some benefits to quality, tion, and what is the expected duration of ther-
if preparation protocols are on file or standardized apy consistent with an appropriate beyond-use
preparations are established based on stability, to date? Alternatively, should the preparation be
decrease medication errors. compounded in small quantities and dispensed
Finally, the USP uses the term ‘‘preparation’’ for a to the patient in short time intervals?
compounded drug dosage form or dietary supplement 14. Can I do some basic quality control to check
or a device to which a compounder has introduced the preparation prior to dispensing (e.g., cap-
a drug. The term ‘‘product’’ is used to describe a sule weight variation, pH, visual observations,
manufactured pharmaceutical dosage form. smell)?
15. Am I assured of ingredient identity, quality, and
Evaluating the need purity?
When considering whether to compound a prescrip- 16. What procedures do I have for investigating and
tion, one might wish to consider the following ques- correcting out of specifications preparations?
tions: 17. Are the physical, chemical, and therapeutic prop-
erties of the individual ingredients consistent
1. Is a product commercially available in the exact with the expected properties of the ordered drug
dosage form, strength, and packaging? preparation?148
2. Is the prescription rational, concerning the ingre-
dients, intended use, dosage, and method of Evaluating the feasibility of batch compounding
administration? The following questions may be considered prior to
3. Am I qualified to prepare this prescription by batch compounding activities:
education, skill development, and expertise?
4. Do I have the proper equipment, supplies, and 1. Will the processes, procedures, compounding
chemicals or drugs? environment, and equipment used to prepare this
5. Is there documentation for assigning a beyond- batch produce the expected qualities in the fin-
use date for the prescription preparation, or do ished preparation?
I use the guidelines delineated in USP Chapters 2. Will all the critical processes and procedures be
<795> and <797>, Pharmacy Compounding carried out exactly as intended for every batch of
– Nonsterile Preparations and Pharmacy Com- the compounded preparation to produce the same
pounding – Sterile Preparations, respectively? high-quality preparation in every batch?
6. Is there an alternative by which the patient will 3. Will the finished preparation have all the qualities
receive a benefit? as specified, on completion of the preparation and
7. Will this compounded preparation satisfy the packaging of each batch?
intent of the prescribing physician and meet the 4. Will each batch retain all the qualities within
needs of the patient? the specified limits, until the end of the labeled
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The scope of pharmacy practice | 493

beyond-use date (i.e., is it chemically, physically, involving nursing time to administer multiple single
and microbiologically stable?) drugs.
5. Can I monitor and trace the history of each batch, Another example concerns the economic use of
identify potential sources of problems, and insti- expensive drug products. Some drug products are
tute appropriate corrective measures to minimize expensive and may have short shelf-lives. If a patient
the likelihood of their occurrence? does not need the entire contents of a vial or dosage
6. Do I have a program of potency testing in unit, in many cases, the remaining drug product is
place?148 discarded and wasted. However, there are numerous
instances in which the pharmacist can divide the com-
Pharmacists who perform batch compounding should mercial product into smaller, usable units, store it
be capable and willing to do so properly, particu- properly, and dispense the required quantity on indi-
larly when performing sterile compounding. Trends vidual prescriptions. Compounding can include the
indicate that more batch compounding may occur in repackaging of drug products into smaller packages
more pharmacies in the future. suitable for patient use.
Another obliquely related economic question can
Economic considerations be addressed regarding the commercialization of com-
There are, at least, two different economic consider- pounded preparations. Over the years, it has been
ations in making the decision to compound prescrip- interesting to note that many compounded prepara-
tions; these include (1) pharmacist compensation and tions, eventually, become commercially manufactured
(2) healthcare costs. products. Examples include:
Pharmaceutical compounding is a cognitive ser-
vice; hence, cognitive services reimbursement is justi- • Fentanyl Lozenges
fied. In the same manner as a surgeon uses cognitive, • Minoxidil Topical Solution
technical, and manipulative skills, so does the pharma- • Nystatin Lozenges
cist use cognitive, technical, and manipulative skills • Clindamycin Topical Solution
in extemporaneous compounding to meet individ- • Dihydroergotamine Mesylate Nasal Spray
ualized patient needs. The pricing of a compounded • Buprenorphine Nasal Spray
prescription should include consideration for pharma- • Buffered Hypertonic Saline Solution
codynamic and pharmacotherapeutic decision mak- • Erythromycin Topical Solution
ing, formulation expertise, time, reimbursement of • 17P-Hydroxyprogesterone Caproate Injection
materials, and the use of facilities and equipment. • Testosterone Topical Gels
Compounding prescriptions can be attractive profes- • 4-Aminopyridine Capsules (Fampridine)
sionally and financially. Historically, it has been said • Nitroglycerin Rectal Ointment
that compounding is an act whereby the professional • Colchicine Injection
and scientific knowledge of a pharmacist can find its
expression. For those pharmacists dedicated to doing as well as numerous other dermatological and pedi-
a quality job in compounding, the professional, psy- atric oral liquids and some premixed intravenous
chological, and financial rewards can be substantial. solutions. It is inevitable that a very stable, com-
Compounding prescriptions can be a way of low- pounded preparation will become a manufactured
ering the cost of drug therapy. In some cases, it is product, when it becomes economically profitable for
less expensive for the pharmacist to prepare a spe- a pharmaceutical manufacturer to produce it.
cific prescription for the patient, which may mean
the difference between the patient actually obtaining Compounding factors
the drug or doing without it. If compounding a pre-
scription results in a patient being able to afford the Stability
drug therapy, it must be considered. In hospitals, it One key factor in compounding prescriptions is
is less expensive to prepare an intravenous admix- stability. The more common types of stability of
ture for administering multiple drugs as compared to which compounding pharmacists should be aware are
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494 | An Introduction to Pharmacy

chemical, physical, and microbiological. Whereas For low-risk preparations

commercially manufactured products are required In the absence of passing a sterility test, the storage
to possess an expiration date, compounded prepa- periods cannot exceed the following time periods,
rations are assigned a beyond-use date. There are provided that, before administration, the CSPs are
numerous sources of information that can be used for properly stored and are exposed for not more than
determining an appropriate beyond-use date, such 48 hours at controlled room temperature, for not
as chemical companies, manufacturers’ literature, more than 14 days at a cold temperature, and for 45
laboratory data, journals, and published books days in solid frozen state between −25◦ C and −10◦ C.
on the subject. Most pharmacists prepare or dis-
pense small quantities of compounded preparations For medium-risk preparations
and recommend storage at room, cool, or cold In the absence of passing a sterility test, the storage
temperatures. periods cannot exceed the following time periods,
The standards published in the USP 35/NF 30 provided that, before administration, the CSPs are
Chapter <795>, Pharmacy Compounding – Nonste- properly stored and are exposed for not more than
rile Preparations, explain that: ‘‘In the absence of sta- 30 hours at controlled room temperature, for not
bility information that is applicable to a specific drug more than 9 days at a cold temperature, and for 45
and preparation, the following maximum beyond-use days in solid frozen state between −25◦ C and −10◦ C.
dates are recommended for nonsterile compounded
drug preparations that are packaged in tight, light- For high-risk preparations
resistant containers and stored at controlled room In the absence of passing a sterility test, the storage
temperature unless otherwise indicated; and for sterile periods cannot exceed the following time periods,
preparations for which a program of sterility testing provided that, before administration, the CSPs are
is in place.’’ properly stored and are exposed for not more than
24 hours at controlled room temperature, for not
For nonaqueous formulations more than 3 days at a cold temperature, and for 45
The beyond-use date is not later than the time remain- days in solid frozen state between −25◦ C and −10◦ C.
ing until the earliest expiration date of the active phar-
Quality control
maceutical ingredient (API) or 6 months, whichever
is earlier. One of the fastest growing and most important areas
of pharmaceutical compounding is that of quality
control. Quality must be built-in to the prepara-
For water-containing oral formulations
tion from the beginning steps to evaluating the final
The beyond-use date is not later than 14 days, when
preparation. USP 35/NF 30 Chapter <1163> Quality
stored at controlled cold temperatures.
Assurance in Pharmaceutical Compounding has been
newly revised and is official. The chapter discusses
For water-containing topical/dermal and mucosal the composition of a quality assurance program that
liquid and semisolid formulations should include, at least, the following nine separate
The beyond-use date is not later than 30 days. but integrated components: (1) training; (2) standard
These maximum beyond-use dates may be operating procedures (SOPs); (3) documentation; (4)
exceeded, when there is supporting valid scientific verification; (5) testing; (6) cleaning, disinfecting, and
stability information directly applicable to the specific safety; (7) containers, packaging, repackaging, label-
preparation (e.g., the same drug concentration range, ing, and storage; (8) outsourcing, if used; and (9)
pH, excipients, vehicle, water content).147 responsible personnel.
The standards published in the USP 35/NF 30 There are several quality control tests that can
Chapter <797>, Pharmacy Compounding – Non- be done within the pharmacy, and others can be
sterile Preparations, for beyond-use dates relate the sent to a contract laboratory. The following quality
beyond-use date to the risk level of the compounded control tests can be considered for the respective
sterile preparations (CSPs). dosage forms:
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The scope of pharmacy practice | 495

1. Oral and Topical Liquids (solutions, suspen- include formulas, as well as consulting expertise by
sions, emulsions) – Weight/volume, pH, specific telephone or via the Internet. This service can assist in
gravity, active drug assay, globule size range, rhe- the process of compounding a particular preparation
ological properties/pourability, physical observa- that may be difficult.
tion (color, clarity), and physical stability (discol-
oration, foreign materials, gas formation, mold
Training and experience
growth)
Pharmacists involved in upgrading and enhancing the
2. Hard Gelatin Capsules – Weight–overall aver-
age weight, weight–individual weight variation, traditional aspects of extemporaneous compounding
dissolution of capsule shell, disintegration and/or need to keep current with all the new tools of their
dissolution of capsule contents, active-drug assay, trade, retrieve the old from storage, and put in a bit
physical appearance (color, uniformity, extent of of practice using their scientific background and tech-
fill, locked), and physical stability (discoloration, niques, before they will be comfortable in exhibiting
changes in appearance) their skills.
3. Ointments, Creams, and Gels – Theoretical Because there is an expectation that pharmacists
weight compared to actual weight, pH, specific can compound, there is a need that pharmacists be
gravity, active drug assay, physical observations able to compound. Due to the decrease in instruction
(color, clarity, texture–surface, texture–spatula in compounding pharmacy in colleges of pharmacy,
spread, appearance, feel), and rheological graduating pharmacists may not feel comfortable
properties in their ability to compound. They can be advised
4. Suppositories, Troches, Lollipops, and Sticks – to seek training, if their practice may encompass
Weight, specific gravity, active drug assay, physi- compounding activities. The need for pharmaceutical
cal observation (color, clarity, texture of surface, compounding training and experience is addressed by
appearance, feel), melting test, dissolution test, short courses, continuing education, increased cur-
and physical stability ricular requirements, and apprenticeships. Additional
5. Parenteral Preparations – Weight/volume, phys- training areas for compounding are needed to pro-
ical observation, pH, specific gravity, osmolality, vide the experience needed to compound prescriptions
assay, color, clarity, particulate matter, sterility, accurately and safely. Many pharmacists who com-
and pyrogenicity. pound become actively involved in the practicums
and rotations of the colleges of pharmacy in their
Compounding support respective states.
Numerous agencies, companies, and organizations Only properly educated and trained pharmacists
are available to assist pharmacists in compound- should be involved in pharmaceutical compounding.
ing. Information, chemicals, supplies, and equipment If pharmacists wish to compound, they should partic-
are readily available. Chemical and supply compa- ipate in continuing professional education programs
nies have increased in size and number in recent designed to properly train them, including the sci-
years, and many provide information on compound- entific basis and practical skills necessary for sound,
ing, incompatibilities, and stability. Specialty com- contemporary compounding.
pounding organizations have developed over recent The practice of pharmacy is regulated by individ-
years and provide full-line services and products to ual state boards of pharmacy. Pharmacy compound-
the compounding pharmacist. Many national and ing is inherent in the practice of pharmacy; hence, it
international organizations provide continuing pro- is governed in the United States by the state boards
fessional education programs in both nonsterile and of pharmacy. Compounding is a part of the ‘‘practice
sterile compounding. of pharmacy’’ and is not a ‘‘product,’’ consequently,
These entities provide services to compounding traditional compounding does not come under the
pharmacists, ranging from selling a complete line of direct auspices of the FDA. Also, the FDA consid-
compounding supplies to providing only chemicals or ers all compounded medications as ‘‘non-approved.’’
compounding aids. Others offer additional services to Actually, there are many common medications on the
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496 | An Introduction to Pharmacy

market that have never been FDA-approved, includ- Formulas

ing the pre-1938 drugs, as well as any drug product Consistency of compounded preparations is impor-
that has been altered in any way not described in tant. Formulas should be developed or obtained and
the labeling. Other examples of non-FDA-approved tried, to assure that each time an extemporaneous
drugs include all intravenous admixtures and extem- preparation is prepared the methods used, ingredi-
poraneous pediatric and geriatric formulations, and ents added, and the order of steps is documented.
cancer cocktails, as well as others. This accomplishes three things. First, it provides the
methodology for each person involved or requested
Equipment
to provide such service the information necessary to
The equipment needed will be determined by the do so properly. Second, it provides consistency from
type and extent of the services one provides. Many batch to batch. Third, if the preparation does not turn
pharmacies already have clean air environments (e.g., out the way expected, a stepwise methodology exists
laminar air flow hoods, isolation barrier systems) for reviewing and determining what happened and
in which aseptic compounding of sterile solutions is what revisions and improvements are needed.
performed. These same units can be used to com-
pound other sterile preparations, such as eye drops. Chemicals and supplies
A balance, preferably electronic, is essential. Oint- If one is going to prepare a topical preparation, a
ment slabs (i.e., pill tiles), along with spatulas of vehicle (e.g., cream, ointment, gel) and the active
different types and materials, should be purchased. A pharmaceutical ingredients (e.g., either finely ground
few mortars and pestles (i.e., glass, ceramic, plastic, product from an available tablet or injection or
disposable) and some glassware should be secured. It pharmaceutical-grade chemicals) would be required.
may not be necessary to buy a roomful of equipment, One needs proper dispensing containers for the med-
but one should purchase what is needed to start the ication. In short, a relationship with providers that
service and should build on it as the service grows carry chemicals and supplies is important.
and expands to different arenas. Pharmacists have been using raw chemicals
Much of the equipment used today in compound- and other materials for prescription compounding
ing has changed. Today, electronic balances are throughout history. In the past, these chemicals
used more often than torsion balances; micropipets and materials have been obtained from natural
are commonplace; and ultrafreezers are some- sources, raw materials, and household ingredients.
times required in addition to standard refrigerator Today, compounding pharmacists use chemicals
freezers. This area is constantly changing, and the from various reliable commercial sources, depending
compounding pharmacist should be aware of the on their availability.
available technology to prepare accurate and effective Some chemical companies place a disclaimer on
prescriptions. Becoming acquainted with the local rep- their chemicals for various reasons, including, but not
resentative for a laboratory supply company is helpful. necessarily limited to:

Environment
1. The companies do not want to be required to pro-
A separate area for traditional compounding is recom- vide complete labeling of the materials as required
mended, rather than simply cleaning off a small area by the Food Drug and Cosmetic (FD&C) Act;
of the dispensing counter. The compounder needs a consequently, they state they are not to be used
clean, neat, well-lit, and quiet working area. If aseptic as drugs. This exempts the companies from having
compounding is considered, a clean air environment to comply with the FD&C regulations.
(e.g., laminar air flow hood, isolation barrier system) 2. The source of the chemicals may not be companies
should be used. The actual facility used depends on meeting current Good Manufacturing Practices;
the level and volume of compounding done. consequently, when the drugs are repackaged,
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The scope of pharmacy practice | 497

only selected information concerning the level overfills) or from the standards set in the individual
of potency, impurities, and other miscellaneous New Drug Approval (NDA).
characterization data is provided. Compounding using manufactured products can
3. The disclaimer is to protect the companies place the pharmacist in a situation in which the final
from the use of their supplies, without the full preparation may not be in compliance with the USP
compendial-type testing, as required by the FDA standards. The pharmacist has no way of knowing
for drug ingredients for manufacturing. what the actual allowable range of the API may be
in the manufactured product or of its actual analyzed
Historically, the FD&C Act has not applied to potency. It may be 90.0 to 110.0%, or it may be 80.0
chemicals used for pharmaceutical compounding, but to 120.0%, or even a broader or different range. If the
it does apply to chemicals used for manufacturing. pharmacist does not know what the ‘‘actual’’ potency
The selection of the chemical source for compound- of the API is in the commercial product, then there
ing is a judgment call on the part of pharmacists. is a possibility that the compounded preparation will
When selecting a supplier of compounding chemi- be outside the allowable USP standards. Obviously,
cals, certificates of analysis should be obtained and in many clinical situations, this variation will not
reviewed for purity and impurities, as part of the be significant, but it is important nonetheless. This
decision-making process. situation occurs in all practice sites and involves both
Chapter <795> Pharmacy Compounding–Nons- nonsterile and sterile compounding.
terile Preparations in USP 35/NF 30 is summarized In recent years, ‘‘compounding kits’’ have become
here as follows:147 commercially available in which the ingredients for a
A USP, NF, or Food Chemicals Codex (FCC) specific compounded preparation are pre-weighed and
substance is the recommended source of ingredients each individual kit contains the necessary supplies for
for compounding all drug preparations. If that is compounding. The kits are labeled with instructions
not available, the use of another high-quality source, to the pharmacist for compounding the preparation.
such as analytical reagent (AR) or certified Ameri- For busy pharmacies, these kits can save time.
can Chemical Society (ACS) grade, is an option for In summary, it is the responsibility of the pharma-
professional judgment. If the substance is not an offi- cist to select the most appropriate quality of chemical
cial preparation or substance, additional information, for compounding, beginning with the USP/NF as
such as a certificate of analysis, should be obtained by the first choice and, if this is not available, then
the pharmacist to ensure its suitability. descending the list of purity grades (Table 11.9),
A manufactured drug product may be a source using professional judgment and discretion. A certifi-
of active ingredient. Only manufactured drugs from cate of analysis for the chemicals should be obtained
containers labeled with a batch control number and and kept on file in the pharmacy for these selected
a future expiration date are acceptable as a potential chemicals.147,149
source of active ingredients. When compounding with
manufactured drug products, the pharmacist must Compounding information sources
consider all ingredients present in the drug prod-
uct relative to the intended use of the compounded Numerous sources are now available for compound-
preparation. There are issues when compounding with ing information, including books, journals, pam-
commercial products, however. phlets, brochures, and electronic media. Some of these
USP standards for pharmaceutical compounding reference sources should be accessible by compound-
require the API be present in an amount equal to 90.0 ing pharmacies, including the following:
to 110.0% of the label. This can pose a problem,
Pharmacy and medical libraries
when compounding using commercially manufac-
tured products, due to the variation in allowable Compounding databases
strengths by USP dosage form monographs (and http://www.CompoundingToday.com
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498 | An Introduction to Pharmacy

Thompson JE. A Practical Guide to Contemporary

Table 11.9 Description of chemical grades
Pharmacy Practice, 3rd edn. Baltimore MD: Lip-
Grade Description pincott Williams and Wilkins, 2009.
Trissel LA. Trissel’s Stability of Compounded For-
Technical or commercial Indeterminate quality mulations, 4th edn. Washington, DC: American
Pharmaceutical Association, 2009.
CP (Chemically Pure) More refined, but still of unknown quality
Trissel LA. Handbook on Injectable Drugs, 16th
USP/NF Meets minimum purity standards;
edn. Bethesda, MD: American Society of Health-
conforms to tolerances set by the USP/NF Systems Pharmacists, 2010.
for contaminants dangerous to health United States Pharmacopeia 35/National Formulary
30. United States Pharmacopeial Convention,
ACS reagent High purity; confirms to minimum
Rockville, MD, 2012.
specifications set by the Reagent
Chemicals Committee of the American
Chemical Society
Journals
Australian Journal of Hospital Pharmacy
Analytical reagent Very high purity Canadian Journal of Hospital Pharmacy
European Journal of Hospital Pharmacy
HPLC Solvents purified for use in
high-performance liquid
International Journal of Pharmaceutical Compound-
chromatography (HPLC); very high purity ing
Journal of the American Society of Health-System
Spectroscopic grade Very high purity Pharmacists
Lippincott’s Hospital Pharmacy
Primary standard Highest purity; required for accurate
Pharmacy Times
volumetric analysis (for standard
solutions) Secundem Artem
The Annals of Pharmacotherapy
US Pharmacist
References Pharmaceutical manufactures
Allen Jr LV. The Art, Science and Technology of Phar- Package insert information
maceutical Compounding, 4th ed. Washington
DC: American Pharmaceutical Association, 2012. Compounding types
Allen Jr LV et al Ansel’s Pharmaceutical Dosage
Forms and Drug Delivery Systems, 9th Ed. Media, Ambulatory-care compounding
PA: Lippincott Williams and Wilkins, 2010. If individuals can walk, they are considered mobile or
Jackson M, Lowey A, eds. Handbook of Extempo- ambulatory (i.e., not bedridden). Consequently, most
raneous Preparation. London: Pharmaceutical pharmacists are involved in ambulatory care, and
Press, 2010. most ambulatory patients are outpatients. Actually,
Langley C, Belcher D. Pharmaceutical Compounding the term can also be applied to homecare patients and
and Dispensing. London: Pharmaceutical Press, even institutionalized patients who are mobile. One
2008. general characteristic of ambulatory patients is that
Marriott JF et al. Pharmaceutical Compounding and they are responsible for obtaining their own medica-
Dispensing. London: Pharmaceutical Press, 2006. tion, storing it, preparing it (if necessary), and taking
Merck Index, 15th ed. Whitehouse Station, NJ: it.150 It seems almost incongruous that in health-
Merck and Co, 2013. care today, as we become more aware that patients
Remington: The Science and Practice of Pharmacy, are individuals, respond as individuals, and must be
22nd edn. London: Pharmaceutical Press, 2012. treated as individuals, that some healthcare providers
Shrewsbury R. Applied Pharmaceutics in Contem- appear to be grouping patients into categories. They
porary Compounding, 2nd edn. Englewood, CO: are grouped in categories for treatment, for reim-
Morton, 2008. bursement from a third party, or for determining
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The scope of pharmacy practice | 499

levels of care in managed-care organizations and using patient, using the best means to do so, and providing
fixed-dose products provided by pharmaceutical man- that care in a conducive environment. This must
ufacturers that are available because the marketing be sufficiently economical to not put the institution
demand is sufficiently high to justify their manufac- in jeopardy of being unable to continue to provide
ture and production. Why should the availability or the services to the community they serve. This
the lack of availability of a specific, economically requires cooperation on the part of the institutional
profitable, commercially available product dictate the administration, the medical staff, and the employees
therapy of a patient? (nurses and pharmacists, in particular, as regards
Pharmacists have an opportunity to extend their to medication usage) and must involve the patient.
activities in patient care as the emphasis continues to One of the effective means by which institutions
shift from inpatient care to ambulatory care. Ambula- can meet these challenges is to consider expanding
tory care, however, is so diverse and involves so many extemporaneous compounding services within the
disciplines that it is sometimes difficult to under- institutional pharmacy. Pharmaceutical care and
stand, and it changes rapidly. Also, ambulatory care pharmaceutical compounding can provide cost sav-
could encourage a team approach to health improve- ings to the institution, while providing needed options
ment, prevention, health maintenance, risk assess- to the physician through problem-solving approaches
ment, early detection, management, curative therapy, and stimulating the institutional pharmacist through
and rehabilitation.151 Ambulatory care offers various new challenges that allow the expression of both his
opportunities for individualizing patient care through or her skills and his or her art.
pharmaceutical compounding. In fact, it is the area in Institutional pharmacists have always been
which most compounding pharmacists practice. actively involved in compounding, or producing
Pharmacists’ roles in ambulatory care patients can medications for the patient. Daily intravenous
include, among others: (IV) therapy is provided through compounding of
medications. Antibiotic piggybacks, TPN solutions,
1. Dispensing IV additives, and many others are calculated,
2. Compounding compounded, dispensed, and then administered by
3. Counseling and compliance enhancement the nursing staff daily. The preparation of pediatric
4. Minimizing medication errors dosage forms has also been an area of extensive
5. Disease state management activity in some hospitals.
6. Therapeutic drug monitoring To assist institutional administrators in support-
7. Minimizing expenditures.150 – 152 ing the provision of extemporaneous compounding
services, they should be aware that:153
Most reimbursement for ambulatory patients
comes from dispensing the product or the com- 1. The patients’ needs are better served
pounded preparation. Little financial consideration 2. The economic implication is favorable to the insti-
is given to counseling, minimizing medication tution, or at least no less favorable than other
errors, compliance enhancement, and therapeutic alternatives
monitoring. However, these activities are important, 3. The provision of such alternative care improves
and they all should be performed. Due to the unique and does not detract from the image of the institu-
nature of compounded medications, counseling is an tion for the purpose of public relations
absolute must for these patients. 4. Making such services available enhances the abil-
From this discussion of the activities of ambu- ities of the physician to meet the patients’ specific
latory care pharmacists, it should be evident that needs
extemporaneous compounding is a vitally important 5. The services fall within regulatory guidelines
in ambulatory patient care. 6. The pharmacy staff is capable of performing such
services.
Institutional pharmacy compounding
The ever-present responsibility of the healthcare Members of the institutional staff are constantly
industry is to provide the best available care for the reading journal articles and are aware of innovative
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500 | An Introduction to Pharmacy

thought and practice by their peers. When physi- Individualized dosage forms, dosage strengths, and
cians become aware of the skill, availability, and alternative routes of administration can often help
awareness of pharmaceutical compounding and that attain these goals. There are many easily accessi-
they can have almost any medication they need, ble organizations specializing in helping meet these
in the form and strength they need for a specific needs. The public relations aspect of meeting these
situation, they request it more often. As the institu- needs may enhance community support. Improving
tional pharmacy staff demonstrates their expertise and outcomes assists the medical staff, by allowing them
problem-solving skills, the medical staff consistently to spend their time dealing with new problems, as hos-
depends upon them. pital pharmacy meets the challenge of past problems.
Guidelines are essential in determining any Nursing and pharmacy have the enhanced opportu-
changes within an institutional pharmacy. Policies nity to use the skills they have developed and to
and procedures must be written to indicate the types provide opportunities for pharmacy to have more
of services made available. The two most important patient involvement and job satisfaction. Due to some
aspects to consider when making both the decision cost considerations in meeting the new USP com-
and the guidelines are:153 pounding standards, some hospitals outsource part
of their compounding activities. In evaluating an out-
1. Keep intact the triad relationship. The medical sourcing pharmacy, the institutional pharmacy needs
staff (physician), the hospital staff (pharmacist to confirm that the outsourced facility is USP Chapter
and nurse), and the patient should all be informed <795> and <797> compliant.
of the decision to approach patient care by the
use of institutionally compounded products. The Veterinary compounding
patient is already aware that much of this occurs Veterinary compounding is necessary for many rea-
in the preparation of their TPN solutions or their sons. For example, with multiple species, ranging
IV antibiotic piggybacks. Patient awareness that from small to large, it would be impossible to practice
the institution has recognized a special need they effective medicine without compounded preparations.
might have and that the institution is going the Treating exotic species, small and large animals (birds
extra mile to meet those needs enhances public to whales; land and aquatic), and animals with cancer
relations. The patient, recognizing that he or she is requires compounding. There is no ideal anesthetic
being treated as an individual, is receiving treat- drug, which has led veterinarians to devise anesthetic
ment benefit that may have a placebo effect in combinations, inducing good-quality anesthesia with
enhancing their improvement, especially when minimal risk to the animal. Compounding is essential
handled in a caring manner. for safe and effective veterinary anesthetic practice.
2. Do not overstep one’s bounds. When products Veterinarians are called on to anesthetize elephants,
are commercially available to meet the needs of gorillas, tigers, ostriches, sharks, horses, cows, and
the institution, the patient, and the physician, use poisonous snakes, among others.
them. When the physician desires a pharmaceuti- Other reasons veterinary compounding is neces-
cal that is different for any number of reasons than sary include:
anything commercially available, then one should
consider extemporaneous compounding. 1. The necessity for multiple injections in the absence
of a compounded multi-ingredient preparation
In consideration of meeting patient specific needs, 2. Rapid changes in management and disease prob-
the institutional pharmacist must look at various lems in veterinary medicine
modalities as potential solutions. When traditional 3. Problems associated with the treatment of large
institutional processes and procedures are not meet- numbers of animals with several drugs within a
ing the patient’s need, extemporaneous compound- short period
ing should be a consideration. Improving outcomes 4. Cost-prohibitive factors associated with the large
and getting patients well and out of the institu- volume of some large-volume parenterals required
tion as quickly as possible should be the end goal. for animals
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The scope of pharmacy practice | 501

5. The need for previously prepared antidotes for use Chapter <797> Pharmacy Compounding – Sterile
in cases of animal poisoning. Preparations
Chapter <1163> Quality Assurance in Pharmaceuti-
Veterinary compounding will continue to exist in cal Compounding
the future for the same reason it does now: to fulfill
therapeutic needs in veterinary medicine.154 The following are summaries of USP Chapters
<795>, Pharmacy Compounding – Nonsterile Prepa-
Nuclear pharmacy compounding rations and <797> Pharmacy Compounding – Sterile
Preparations.147
Nuclear pharmacy is a specialty practice of phar-
macy that is a patient-oriented service and embodies
USP Chapter <795> Pharmacy Compounding –
the scientific knowledge and professional judgment
Nonsterile Preparations
required for improving and promoting health through
This material in this section is divided into (1)
assurance of the safe and efficacious use of radioac-
Introduction, (2) Definitions, (3) Categories of Com-
tive drugs for diagnosis and therapy. Radioactive
pounding, (4) Responsibilities of the Compounder,
drugs, commonly referred to as radiopharmaceuti-
(5) Compounding Process, (6) Compounding Facili-
cals, are a special class of drugs regulated by the
ties, (7) Compounding Equipment, (8) Component
FDA. They are unique in that they contain an unsta-
Selection, Handling, and Storage, (9) Stability
ble nuclide (radioactive nuclide) as a part of the
Criteria and Beyond-Use Dating, (10) Packaging and
compound designed to localize in an organ or tis-
Drug Preparation Containers,(11) Compounding
sue. Since radiopharmaceuticals are radioactive, the
Documentation, (12) Quality Control, (13) Patient
Nuclear Regulatory Commission, or a similar state
Counseling, (14) Training, and (15) Compounding
agency, is heavily involved in regulatory matters rele-
for Animal Patients.
vant to radiopharmaceuticals.
A nuclear pharmacist is expert at preparing Introduction
(compounding) radiopharmaceuticals with Tc-99m
The Introduction explains the purpose of the chapter,
sodium pertechnetate and reagent kits. The kits are
which is to provide compounders with guidance on
multiple dose vials, containing the compound to be
applying good compounding practices for the prepa-
labeled with the radioactive nuclide Tc-99m to create
ration of nonsterile compounded preparations for
the radiopharmaceutical. The contents within the
both humans and animals. The chapter also provides
vial are sterile and pyrogen free, as is the Tc-99m
general information to enhance the compounder’s
sodium pertechnetate. Most radiopharmaceuticals are
ability to extemporaneously compound preparations
administered intravenously, so a nuclear pharmacist
of acceptable strength, quality, and purity.
must be proficient at maintaining aseptic conditions
during compounding. Definitions
Today, there are several hundred commercial,
The Definitions section defines how certain terms are
centralized nuclear pharmacies providing a signifi-
used in the chapter and includes terms, such as active
cant fraction of radiopharmaceuticals used in nuclear
pharmaceutical ingredient, added substances, beyond-
medicine procedures.155
use date, component, compounder, compounding,
hazardous drug, manufacturing, preparation, stabil-
Regulations and guidelines ity, and vehicle.

The documents of special importance in providing Categories of compounding

guidelines and standards for pharmaceutical com- The chapter defines three categories of compounding:
pounding are the USP 34/NF 29 chapters: Simple, Moderate, and Complex. Simple is making a
preparation that has a USP compounding monograph
Chapter <795> Pharmacy Compounding – Nonster- or appears in a peer-reviewed journal article with spe-
ile Preparations cific details and stability data for that formulation,
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502 | An Introduction to Pharmacy

as well as reconstituting or manipulating commercial Packaging and drug preparation containers

products that require the addition of one or more Containers and closures used in packaging com-
ingredients as directed by the manufacturer. Moder- pounded preparations must meet USP requirements.
ate includes making a preparation that requires special They shall be of a suitable clean material that does
calculations or procedures to determine quantities of not alter the quality, strength, or purity of the com-
components per preparation or per individualized pounded drug preparation.
dosage units or making a preparation for which sta-
bility data is not available. Complex compounding is Compounding documentation
making a preparation that requires special training, Compounding Documentation describes the Formu-
environment, facilities, equipment, and procedures to
lation Record, the Compounding Record, Standard
ensure appropriate therapeutic outcomes.
Operating Procedures and the Material Safety Data
Sheets and how they are used.
Responsibilities of the compounder
This section states that the compounder is responsible Quality control
for compounding preparations of acceptable strength,
Quality Control is included to ensure the accuracy
quality, and purity, along with other requirements.
and completeness of the compounding process. Com-
It goes further to detail ten General Principles of
pounded preparations must meet the USP/NF stan-
Compounding.
dards, and the pharmacist should review each proce-
Compounding process dure in the compounding process as a final check.

This section is a step-by-step presentation on the com-

Patient counseling
pounding process to ensure uniformity of activities in
This section explains that, at the time of dispensing,
preparing each formulation.
certain details need to be discussed with the patient,
Compounding facilities including the proper use, storage, and evidence of
instability of the compounded preparation(s).
This section discusses the standards for the facility.
It must be adequate and appropriate for the com-
Training
pounding activities performed, and the area should
be separate from other functions that occur in the A discussion of the steps that should be included in a
pharmacy and maintained in a clean and sanitary detailed training procedure is presented, along with a
condition. discussion of what is important, and the training and
evaluation of personnel requirements is presented.
Compounding equipment
Compounding for animal patients
Equipment used must be of the appropriate design
and capacity for the preparations being compounded. Compounding standards apply to those preparations
There should be procedures for its selection, purchase, that are compounded for animal patients, just as
storage, cleaning, maintenance, and calibration, as they do for human patients. Because animals are
well as procedures to minimize any mix-ups and different, a discussion of some of the considerations
cross-contamination. is presented.

Component selection, handling, and storage USP Chapter <797> Pharmacy Compounding –
The sources of the ingredients were previously cov- Sterile Preparations
ered in this chapter. Also included are 11 guidelines USP Chapter <797> involves procedures and require-
that must be followed when selecting, handling, and ments for compounding sterile preparations (CSPs).
storing components for compounded preparations. This chapter is divided into the following sections:
(1) Introduction,(2) Organization of this Chapter,
Stability criteria and beyond-use dating (3) Definitions, (4) Responsibility of Compounding
This section was previously discussed in this chapter. Personnel, (5) CSP Microbial Contamination Risk
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The scope of pharmacy practice | 503

Levels, (6) Personnel Training and Evaluation in Asep- packaged, sealed, labeled, stored, dispensed, and
tic Manipulation Skills, (7) Immediate-Use CSPs, (8) distributed. The section lists 14 objectives that
Single-dose and Multiple-dose Containers, (9) Haz- must be achieved by supervisory compounding and
ardous Drugs as CSPs, (10) Radiopharmaceuticals as dispensing personnel.
CSPs, (11) Allergen Extracts as CSPs, (12) Verifica-
CSP microbial contamination risk levels
tion of Compounding Accuracy and Sterility, (13)
Environmental Quality and Control, (14) Suggested Included is a discussion on the various risk levels
Standard Operating Procedures (SOPs), (15) Elements determined by the corresponding probability of con-
of Quality Control, (16) Finished Preparation Release taminating a CSP with (1) microbial contamination
Checks and Tests, (17) Storage and Beyond-Use Dat- and (2) chemical and physical contamination. Three
ing, (18) Maintaining Sterility, Purity, and Stability of risk levels are identified: Low, Medium, and High,
Dispensed and Distributed CSPs, (19) Patient or Care- along with examples of each. The characteristics
giver Training, (20) Patient Monitoring and Adverse described for each level are intended as a guide to the
Events Reporting, (21) Quality Assurance (QA) Pro- breadth and depth of care necessary in compounding.
gram, (21) Abbreviations and Acronyms, and (22) The section discusses the conditions, personnel and
Appendices. process requirements, examples, and quality assur-
ance associated with each risk level. The beyond-use
Introduction dates associated with each level are also described.
The objective of this chapter is to describe condi-
Personnel training and evaluation in aseptic
tions and practices to prevent harm, including death,
manipulation skills
to patients that could result from improperly com-
pounded sterile preparations. It lists five conditions This section describes the requirements for training
that might occur and includes nonsterility, excessive personnel involved, as well as how these individuals
bacterial endotoxins, variability in intended strength are validated in aseptic manipulations using media-fill
challenge testing.
of the correct ingredients, unintended chemical and
physical contaminants, and ingredients of inappropri- Immediate-use CSPs
ate quality. The standards in this chapter are intended
This is a new category, intended for situations in
to apply to all persons who prepare CSPs and in all
which emergency or immediate patient administration
places CSPs are prepared.
of a CSP is required. Since this is an exempt category,
Organization of this chapter there are six listed requirements that must be met to
utilize it.
This chapter is organized to facilitate the practitioners
understanding of the accuracy and quality practices Single dose and multiple dose containers
involved in preparing CSPs. In addition to the main The ‘‘use times’’ of single and multiple dose containers
sections, there are five appendices to assist the practi- are described, along with whether or not the multiple-
tioner. dose containers contain preservatives.

Definitions Hazardous drugs as CSPs

This section contains 29 definitions applicable to the The requirements for compounding with hazardous
compounding of sterile preparations. drugs are described. It details their storage, handling,
preparation, and the use of newer technology to allow
Responsibility of compounding personnel
safer handling of these drugs. Also discussed are activ-
This section discusses the various procedures, ities involving containment and disposal.
requirements, and performance responsibilities of
those involved in compounding sterile preparations. Radiopharmaceuticals as CSPs
Compounding personnel are responsible for ensuring These general comments refer to USP Chapter <823>
CSPs are accurately identified, measured, diluted, Radiopharmaceuticals for Positron Emission Tomog-
and mixed and are correctly purified, sterilized, raphy – Compounding and some of the technology
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504 | An Introduction to Pharmacy

used in this type of compounding. In addition, some Storage and beyond-use dating
requirements related to equipment and facilities are Storage and beyond-use dating provides background
discussed. and rationale for the determination of beyond-use
dates for CSPs. The beyond-use dates for CSPs are
Allergen extracts as CSPs associated with the end-preparation testing for these
Allergen extracts are single dose or multiple dose preparations, as well as the monitoring of controlled
intradermal or subcutaneous injections that are CSPs storage areas. It also discusses beyond-use dating for
and may be exempt from the CSP requirements, proprietary bag and vial systems, as well as monitor-
if 11 different conditions described in this section ing controlled storage areas to ensure that potency is
are met. retained throughout any storage time.

Maintaining sterility, purity, and stability of dispensed

Verification of compounding accuracy and sterility
and distributed CSPs
Verification of compounding accuracy standards,
This section discusses both sterile preparations for
methods of sterilization, and depyrogenation are
institutional use and packing and transporting CSPs.
discussed in this section. Sterilization by filtration,
Topics included are packaging, handling and trans-
autoclaving, and dry heat are described.
portation, administration, education and training,
and storage in locations outside CSP facilities (i.e.,
Environmental quality and control
in patients’ homes). This section also discusses re-
Environmental Quality and Control presents discus- dispensed CSPs involving returned and unopened
sions on critical site exposure, clean rooms, barrier preparations.
isolators, facility design, primary engineering con-
trols, viable and nonviable environmental sampling Patient or caregiver training
testing, personnel requirements, cleaning and disin- Detailed topics are provided that should be a part
fecting the compounding area, personnel cleansing of a training program to ensure the patient or care-
and garbing, personnel training and competency eval- giver understands and complies with the many special
uation of garbing, aseptic work practices and clean- and complex responsibilities involving the storage,
ing/disinfection procedures and action levels, and handling, and administration of CSPs.
documentation and data evaluation.
Patient monitoring and adverse events reporting
Suggested standard operating procedures (SOPs) Explanations are provided for monitoring patients
Twenty-three suggested SOPs are presented, but the and any adverse events that might occur, including
compounding pharmacy must have SOPs written to the establishment of SOPs for reporting these events.
cover every significant activity in the pharmacy.
Quality assurance (QA) program

Elements of quality control

The Quality Assurance section describes the standard
of a formal program intended to provide a mechanism
Quality control standards are presented for sterile and
for monitoring, evaluating, correcting, and improving
nonsterile ingredients, devices, and equipment. This
the activities and processes involved with CSPs.
section also discusses the training and performance
evaluation program for those involved in aseptic com- Abbreviations and acronyms
pounding activities. This section describes the abbreviations and acronyms
used in this chapter.
Finished preparation release checks and tests
This section describes physical inspection, compound- Appendices
ing accuracy checks, sterility testing, bacterial endo- There are five different appendices used to assist in
toxin (pyrogen) testing, and identity and strength understanding and implementing these standards in
verification of ingredients. compounding pharmacies.
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The scope of pharmacy practice | 505

Other compounding-related USP chapters to State Licensed Pharmacies (Appendix B), Model
There are two additional General Chapters in Rules for Nuclear/Radiologic Pharmacy and Model
the USP/NF, prepared specifically for pharmacy Rules for Sterile Pharmaceuticals are other documents
compounding: Chapter <1160> Pharmaceutical Cal- designed to apply to the compounding of drugs by
culations in Prescription Compounding and Chapter state-licensed pharmacies. Some state boards of phar-
<1163> Quality Assurance in Pharmaceutical macy use it as a model, and others use the USP
Compounding.156 chapters integrated into their regulations.

NABP good compounding practices applicable to state

USP Chapter <1160> Pharmaceutical Calculations in
licensed pharmacies
Prescription Compounding
The different subparts and their titles include:
This chapter is provided as a reference and review of
pharmaceutical calculations that may be used in com-
1. Subpart A – General Provisions and Definitions
pounding pharmacies.147 It discusses topics, such as
2. Subpart B – Organization and Personnel
weighing, buffer solutions, dosage calculations, per-
3. Subpart C – Drug Compounding Facilities
centage concentrations, specific gravity, dilution and
4. Subpart D – Equipment
concentration, potency units, reconstitution, alliga-
5. Subpart E – Control of Components and Drug
tion, molar, molal and normal concentrations, mil-
Product Containers and Closures
liequivalents and millimoles, isoosmotic solutions,
6. Subpart F – Drug Compounding Controls
flow rates in intravenous sets, temperature, and others
7. Subpart G – Continuous Quality Improvement
related to pharmaceutical compounding.
Program
8. Subpart H – Labeling Control of Excess Products
USP Chapter <1163> Quality Assurance in
9. Subpart I – Records and Reports.
Pharmaceutical Compounding
This chapter is designed to provide compounders with NABP model rules for sterile pharmaceuticals
information related to establishing a quality assurance
The different parts and their titles include:
program in their facility. It discusses (1) Training, (2)
SOPs, (3) Documentation, (4) Verification, (5) Test-
1. Part 1 – Purpose and Scope
ing, (6) Physical testing of dosage units, (7) Weight
2. Part 2 – Definitions
assessment, (8) Microbiological testing, (9) Cleaning,
3. Part 3 – Policy and Procedure Manual
disinfecting, and safety, (10) Containers, packaging,
4. Part 4 – Physical Requirements
repackaging, labeling and storage, (11) Outsourcing,
5. Part 5 – Records and Reports
(12) Responsible personnel, and (13) Summary.
6. Part 6 – Delivery Service
7. Part 7 – Disposal of Cytotoxic and/or Hazardous
Other applicable chapters
Wastes
Numerous other General Chapters in the USP/NF are 8. Part 8 – Emergency Kits
related to compounding and directly impact it, such 9. Part 9 – Cytotoxic Drugs
as Chapters <1151> Pharmaceutical Dosage Forms, 10. Part 10 – Patient Education and Training
<1176> Prescription Balances and Volumetric Appa- 11. Part 11 – Quality Assurance/Compounding and
ratus, <1219> Stability Considerations in Dispensing Preparation of Sterile Pharmaceuticals
Practice, and <1231> Water for Pharmaceutical Pur- 12. Part 12 – Pharmacist Care Outcomes.
poses.

Model State Pharmacy Act and rules of the Special considerations in

National Association of Boards of Pharmacy extemporaneous compounding
(model act) General considerations in compounding various
The National Association of Boards of Pharmacy dosage forms are discussed in chapters contained in
(NABP) Good Compounding Practices Applicable Remington Part 5: Pharmaceutical Dosage Forms:
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506 | An Introduction to Pharmacy

Manufacturing and Compounding.157 However, Compounding with hydrates and solvates158

there are aspects of compounding that should be Concerning whether or not a drug is a hydrate,
discussed to compound preparations that are of a solvate, or just contains some amount of water,
acceptable strength, quality, and purity, including common sources would be the USP/NF, Certificates
of Analysis, and looking at the chemical structure
1. Compounding with hydrates and solvates or empirical formula of the drug (for solvates and
2. Compounding with inorganic salts hydrates).
3. Compounding with salts An example of a USP/NF monograph is shown in
4. Compounding with esters Fig. 11.4. It is apparent that this is a hydrate. The
5. Compounding with aliquots more molecules of water present in the molecule, the
6. Compounding with ‘‘potency-designations’’ more of the chemical that must be weighed to obtain
active ingredients the actual active drug. An example of a Certificate of
7. Compounding with commercial products. Analysis is shown in Figure 11.5.
As a drug example that is available with different
It is important to know the purity and form of all amounts of water, let us look at different forms of
ingredients used in compounding, especially of APIs. dexamethasone.
Is the quantity of drug per dosage unit calculated on
the anhydrous or hydrated form and, if so, which
• Dexamethasone contains less than 0.5% of its
hydrated form? Is it calculated on the ‘‘base’’ or weight in water
the ‘‘salt’’ form of the drug; or, on the ‘‘base’’ or
• Dexamethasone acetate has one molecule of water
the ‘‘ester’’ form? Some drugs are either obtained of hydration and contains between 3.5 and 4.5%
as an ‘‘aliquot’’ or a ‘‘dilution’’ or are prepared as of water; the anhydrous form contains less than
aliquots or dilutions to be later weighed or measured 0.4% water
for compounding purposes. Also, a number of drugs
• Dexamethasone sodium phosphate contains
are available with labeled potency designations; for a sum of water and alcohol that may be up to
example, Gentamicin Sulfate USP ‘‘has a potency 16.0%.
equivalent to not less than 590 mcg of gentamicin per
mg, calculated on the dried basis.’’ Another example is Lidocaine Hydrochloride.
Sources of information that can be used to deter- Lidocaine hydrochloride occurs as a monohydrate
mine the ‘‘form’’ of the drug (base, salt, or ester), if and as the anhydrous form. The water content may
it is commercially manufactured, would be the com- be between 5.0 and 7.0%.
mercial products, the USP/NF monographs, etc. For
example, Albuterol Sulfate Tablets USP, are based
on the ‘‘albuterol’’ content (present as the sulfate
form). The USP states ‘‘Albuterol Tablets USP con-
tain an amount of albuterol sulfate equivalent to not
H
less than 90.0% and not more than 110.0% of the N—CH3
labeled amount of albuterol (C13 H21 NO3 ).’’
H
Diphenhydramine Hydrochloride Capsules USP, H2SO4 5H2O
are based on the total molecule (i.e., diphenhydramine
hydrochloride). The USP states ‘‘Diphenhydramine
HO O OH
Hydrochloride Capsules USP contain not less 2
than 90.0% and not more than 110.0% of the
labeled amount of diphenhydramine hydrochloride Figure 11.4 USP 35/NF 30 monograph chemical structure
(C17 H21 NO.HCl).’’ for morphine sulfate.
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The scope of pharmacy practice | 507

CERTIFICATE OF ANALYSIS

Morphine Sulfate, USP CAS 62111-15-0

(C17H19NO3)2.H2SO44.5H2O Lot No.___XYZ______

MW 758.83

TEST LIMIT RESULTS

Min. Max.

Assay 98.0% 102.0% 100.5%

(anhydrous basis)

Identification To Pass Test Passes Test

Specific rotation –107 º 109.5º 108.1°

Acidity To Pass Test Passes Test

Water 10.4% 13.4% 12.5%

Residue on ignition nmt 0.1% 0.06%

Chloride To Pass Test Passes Test

Ammonium salts To Pass Test Passes Test

Limit of foreign alkaloids To Pass Test Passes Test

Physical Appearance:
White, feathery, silky crystals,
cubical masses of crystals, or white,
crystalline powder. To Pass Test Passes Test

Manufacturer Name
Manufacturer Address
Manufacturer Telephone

Signature of Certificate of Analysis Coordinator _________________________

Figure 11.5 Typical certificate of analysis for morphine sulfate.

Example Example

How much adjustment should be made, if using If a prescription for lidocaine hydrochloride 2% gel
lidocaine hydrochloride monohydrate in place of lido- (100 g) is to be made, then 2 g of anhydrous lidocaine
caine hydrochloride anhydrous for a compounded HCl could be used, OR:
prescription? 2 g × 1.066 = 2.132 g of lidocaine HCl monohy-
Lidocaine HCl monohydrate C14 H22 N2 O.HCl. drate.
H2 O MW 288.81
Lidocaine HCl anhydrous C14 H22 N2 O.HCl MW
270.80
A comparison of the molecular weights reveals a
Also, a direct comparison of the molecular weights
factor of 1.066 can be used for the adjustment:
and the physical quantity required can be used, as
(288.81)/(270.80) = 1.066
follows:
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508 | An Introduction to Pharmacy

Compounding with inorganic salts159

MW Hydrate Weight of Hydrated form
= Inorganic salts may not always be 100% of their
MW Anhydrous Weight of Anhydrous form
288.81 X composition. Topics involving inorganic salts include
= the effects of physical and chemical properties, and
270.80 2g
incompatibilities and solubilities of inorganic salts.
X = 2.133g
Physical and chemical properties include parti-
Further, the USP monograph for Lidocaine cle size, tendencies to absorb/give off water, pH
Hydrochloride Jelly USP, states ‘‘It contains not properties, and others. Eutectic formation is another
less than 95.0% and not more than 105.09% phenomenon that results when certain materials are
of the labeled amount of lidocaine hydrochloride mixed together and become pasty or even liquefy.
(C14 H22 N2 O.HCl).’’ Note that this is the anhydrous Eutectic mixtures can be advantageous or deleterious,
form. depending on how they are used. There are numerous
It is important to also check the Certificate of methods (keeping problematic ingredients separate,
Analysis (C of A) for the lidocaine hydrochloride addition of drying powders, etc.) to overcome these
used to determine the water content. Fortunately, occurrences that can be utilized by the pharmacist.
most pure powders (anhydrous) only contain 0.2 to Incompatibilities are defined as the inability of a
0.5% moisture, which can be insignificant, but needs substance to maintain its identity or to exercise its
to be checked, nevertheless. inherent properties when brought into contact with
Solvates and hydrates must be packaged in ‘‘tight’’ or into the sphere of influence of another substance
containers to prevent the loss or gain of moisture. In or a physical force. From the pharmacist’s position,
fact, it is best to have all chemicals used in compound- incompatibilities fall into two classes: the desirable
ing in ‘‘tight’’ containers, kept thoroughly closed at and the undesirable. Effervescent salts added to water
all times, except for the short time when a weighing represent the desirable, whereas a pH change resulting
step is involved. Storage at the indicated temperatures in hydrolysis and drug degradation represents the
is also important to minimize any exposure to very undesirable.
high humidity levels. There are three classes of incompatibilities: phys-
ical, chemical, and physiologic. Only the first two
• Hygroscopic powders are those that tend to absorb are of interest here. Physical incompatibilities include
moisture from the air. insolubility, immiscibility, heat, pressure, cold, light,
• Deliquescent powders are those that absorb mois- and percussion (violent reactions). Chemical incom-
ture from the air and even liquefy. patibilities commonly include hydrolysis, condensa-
• Efflorescent powders are those that may give up tion, oxidation, reduction, precipitation, gas evolu-
their water of crystallization and may even become tion, heat liberation, and heat absorption.
damp and pasty. Regarding solubility of inorganic salts, there are
some general rules that may be of interest.
When working with these powders, extra care
must be taken. The USP description of a powder 1. If both the cation and anion of an ionic com-
will state whether it has hygroscopic, deliquescent, or pound are monovalent, the solute–solute attrac-
efflorescent properties. For these types of powders, tive forces are easily overcome, and, therefore,
storage in ‘‘tight containers’’ will decrease property these compounds are water soluble (e.g., NaCl,
changes in the chemicals. LiBr, KI, NH4 NO3 , NaNO2 ).
One other factor is that if a hygroscopic or del- 2. If only one of the two ions in an ionic compound
iquescent powder is weighed on a balance and the is monovalent, the solute–solute interactions
compounder leaves for a short time and then returns, are also easily overcome and the compounds
the powder may have absorbed moisture from the air are water soluble (e.g., BaCl2 , MgI2 , Na2 SO4 ,
and weigh heavier than it should. Therefore, weigh Na3 PO4 ).
quickly after opening the bulk chemical containers, 3. If both the cation and anion are multivalent, the
and then reseal them. solute–solute interaction may be too great to be
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The scope of pharmacy practice | 509

overcome by the solute–solvent interaction, and words, sufficient albuterol sulfate is present to provide
the compound may have poor water solubility the labeled amount of the albuterol base.
(e.g., CaSO4 , BaSO4 , BiPO4 ; exceptions: ZnSO4 ,
FeSO4 ).
Example
4. Common salts of alkali metals (e.g., Na, K, Li,
Cs, Rb) are water soluble (exception: Li2 CO3 ). A prescription calls for 10 mL of fentanyl
5. Ammonium and quaternary ammonium salts are 1 mcg/0.1 mL (as the citrate) topical gel. How
water soluble. much fentanyl citrate will be required?
6. Nitrates, nitrites, acetates, chlorates, and lac-
tates are water soluble (exceptions: silver and 1. 50 mcg/0.1 mL = X mcg/10 mL
mercurous acetate). X = 5 mg
7. Sulfates, sulfites, and thiosulfates are water solu- 2. Fentanyl MW = 336.47
ble (exceptions: calcium and barium salts). 3. Fentanyl citrate MW = 528.59
8. Chlorides, bromides, and iodides are water sol- 4. 336.47/5 mg = 528.59
uble (exceptions: salts of silver and mercurous Y = 7.85 mg
ions). 5. Each mg of fentanyl equals 528.59/336.47 =
9. Acid salts corresponding to an insoluble salt will 1.57 mg fentanyl citrate
be more water soluble than the original salt.
10. Hydroxides and oxides of compounds, other
than alkali metal cations and the ammonium ion, In another scenario, Diphenhydramine
are water insoluble. Hydrochloride Capsules USP, are based on the
11. Sulfides are water insoluble, except for their total molecule (i.e., diphenhydramine hydrochloride).
alkali metal salts. The USP states ‘‘Diphenhydramine Hydrochloride
12. Phosphates, carbonates, silicates, borates, and Capsules USP contain not less than 90.0% and
hypochlorites are water insoluble, except for not more than 110.0% of the labeled amount of
their alkali metal salts and ammonium salts. diphenhydramine hydrochloride (C17 H21 NO.HCl).’’
As one can see, the weight of the ‘‘HCl’’ is considered
in the dose of the drug.
Compounding with organic salts160
Many drugs are ‘‘salts,’’ and the dose may be based
on the ‘‘total salt’’ form or just the ‘‘base’’ form of the Example
drug. The purity and form of all ingredients used in
A prescription calls for 30 capsules of diphenhy-
compounding, especially of APIs, must be known and
dramine hydrochloride 35 mg each. How much
considered during formulation. If a number of factors
diphenhydramine hydrochloride will be required?
are not considered, the final compounded preparation
Since the total salt molecule is part of the dose, 30
may not fall within the strength requirements (e.g.,
× 35 mg = 1.05 g of diphenhydramine hydrochloride
90 to 110% for compounded preparations or the USP
is required.
monographs).
Sources of information that can be used to deter-
mine the ‘‘form’’ of the drug (i.e., base, salt, or ester), Because many drugs are either weak acids or weak
if it is commercially manufactured, would be the com- bases and have limited water solubility, they are often
mercial products; also, the USP/NF can be used. For used as their ‘‘salts’’ to increase their aqueous solubil-
example, Albuterol Sulfate Tablets USP, are based ity. When salts are placed in an aqueous environment,
on the ‘‘albuterol’’ content (present as the sulfate they dissolve to some extent, based on their solubil-
form). The USP states ‘‘Albuterol Tablets USP con- ity in the aqueous media and the pH of the media.
tain an amount of albuterol sulfate equivalent to not There will be a portion of the drug that is dissolved,
less than 90.0% and not more than 110.0% of the and some may remain undissolved. Of the dissolved
labeled amount of albuterol (C13 H21 NO3 ).’’ In other portion, there will be a part that is ‘‘ionized,’’ and the
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510 | An Introduction to Pharmacy

remainder will be ‘‘unionized,’’ depending on the pH aromatic compounds; the term ‘‘aromatic’’ was origi-
of the media. It is the ‘‘unionized’’ portion of the drug nally used to describe compounds that ‘‘smelled’’ but
in solution that will be absorbed for systemic effect. were later found to contain either benzene or fused
This is described by the ‘‘dissociation constant’’ or benzene rings in the structure. The term has been gen-
‘‘pKa ’’ of the drug. eralized to include aromatic heterocyclic structures.
As is evident from this discussion, the purpose of The dehydration of a molecule of an alcohol and
the ‘‘salt’’ form is to enhance the solubility of the a molecule of an organic acid can form an ester. For
drug, but it may also enhance the stability and change example, ethanol reacts with acetic acid to form ethyl
other attributes of the drug that make it easier to acetate, an ester:
handle and manipulate for producing dosage forms.
Why do we have some drugs that are dosed on the C2 H5 OH + CH3 COOH → CH3 CH2 –O–CO–CH3
‘‘base’’ form of the drug (whether they be weak acids
or weak bases) and some drugs that are dosed on the Following salts, esters are the most important acid
total weight of the ‘‘salt’’ form of the drug? derivatives used in pharmacy. Esters can be prepared
In reviewing older US Pharmacopeia revisions, it for a number of reasons, including solubility, stability,
appears this has been an issue for many years with resistance to degradation after administration, and use
no apparent basis for which way the salts are dosed. as prodrugs.
However, both the official monographs and the FDA Some drugs are very soluble but tend to degrade
approved drug products appear inconsistent in how rapidly when in solution. One approach to increase
they determine how a drug is dosed. Pharmacists their stability, and shelf-life, is to prepare esters that
involved in compounding must be aware of the correct are poorly soluble. This results in a ‘‘suspension’’
use of the verbiage, as follows: dosage form in place of a ‘‘solution’’ dosage form.
It is the responsibility of the formulator (com- A drug in a suspension dosage form degrades at a
pounding pharmacist) to determine whether or not much slower rate than one in solution. After oral
the base/acid of salt form of the drug is to be used in administration, the ester is cleaved, and the active
the calculations for the amount of API to actually be drug moiety released for absorption.
used. It should be routine procedure, when receiving Some drugs may cause pain at the site of injection,
a prescription, to correctly determine whether or not especially if they precipitate and damage the sur-
the salt or base/acid form of the drug is to be used rounding tissue. This can be overcome by preparing
as the basis for the dose. Resources include the USP, a drug with increased solubility. Chloramphenicol
product package insert, and a call to the manufacturer has low water solubility, but the succinate ester is
or physician, as appropriate. formed to increase the water solubility of the drug
and facilitate parenteral administration. This succi-
Compounding with esters161 nate ester is inactive but is hydrolyzed to release the
Many drugs are available as the base form or as an active chloramphenicol moiety.
‘‘ester,’’ and the dose may be calculated on the total Esters are an important means of preparing pro-
ester form or just the base form of the drug. Some drugs, due to the number of esterases present in
drugs are esters by virtue of their internal chemical various parts of the body that will cleave the ester
structure (atropine, cocaine, many local anesthetics, linkage, releasing the active moiety. Carboxylic acid
etc.), and others are esters by the addition of a moiety esters are common in pharmacy and are neutral liq-
that will form an ester for certain purposes. Only the uids or solids that can be hydrolyzed slowly by water
latter are discussed here; those that are esters, due to and rapidly by acids or alkalais into their components.
their basic molecular structure, are not included. Some of the simple esters are soluble in water,
An ester is a compound of the general formula but those with more than four carbon atoms are
R–C–O–R1, where R and R1 may be the same or practically insoluble in water.
different and may be either aliphatic or aromatic. One cannot simply look at the title and determine
The term ‘‘aliphatic’’ refers to acyclic or cyclic, sat- whether or not the drug is a salt or an ester. For
urated or unsaturated carbon compounds excluding example, ‘‘acetate salts’’ include calcium acetate,
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The scope of pharmacy practice | 511

chlorhexidine acetate, desmopressin acetate, fle- 424.39. Therefore, 1 mg of cefuroxime is con-

cainide acetate, gonadorelin acetate, guanabenz tained in 510.47/424.39 = 1.2 mg of cefuroxime
acetate, leuprolide acetate, lysine acetate, mafenide axetil. A 250 mg cefuroxime tablet will contain
acetate, and zinc acetate, and ‘‘acetate esters’’ 250 × 1.2 = 300 mg of cefuroxime axetil.
include cortisone acetate, desoxycorticosterone 7. Therefore, if using a commercial product to
acetate, dexamethasone acetate, fludrocortisones prepare a dosage form, no conversion should be
acetate, fluorometholone acetate, hydrocortisone required. However, if using a bulk active ingre-
acetate, isoflupredone acetate, medroxyproges- dient, then the required amount of cefuroxime
terone acetate, megestrol acetate, melengestrol axetil that is equivalent to the desired dosage of
acetate, methylprednisolone acetate, norethindrone cefuroxime must be calculated.
acetate, paramethasone acetate, prednisolone acetate,
trenbolone acetate, and betamethasone acetate. Dexamethasone labeled strengths pose an inter-
Further, ‘‘succinate salts’’ include sumatriptan esting challenge, as they are not consistent in naming
succinate, doxylamine succinate, loxapine succinate either the base or the ester form, for example:
and metoprolol succinate and ‘‘succinate esters’’
include chloramphenicol sodium succinate, hydro- • ‘‘Dexamethasone’’ dosage form monographs are
cortisone sodium succinate, hypromellose acetate based on the labeled amount of ‘‘dexamethasone.’’
succinate, methylprednisolone sodium succinate, and • ‘‘Dexamethasone Acetate’’ dosage form mono-
prednisolone sodium succinate. graph is based on the labeled amount of ‘‘dexam-
Cefuroxime axetil is an example of an ester dosed ethasone.’’
on the base form. • ‘‘Dexamethasone Sodium Phosphate’’ dosage form
monographs are based upon the labeled amount
1. Cefuroxime axetil is C20 H22 N4 O10 S, with a of ‘‘dexamethasone phosphate’’, not ‘‘dexametha-
molecular weight of 510.47. Cefuroxime axetil is sone.’’
described as a mixture of the diastereoisomers of
cefuroxime axetil and contains the equivalent of There are a number of important sources of infor-
not less than 745 mcg and not more than 875 mcg mation that can be used to determine the ‘‘form’’
of cefuroxime (C16 H16 N4 O8 S) per mg, calculated of the drug (i.e., base or ester). If it is commercially
on the anhydrous basis. manufactured, the package insert terminology will
2. Cefuroxime Axetil Tablets, USP, contain the provide the information. If it is a USP/NF mono-
equivalent of not less than 90.0% and not more graphed dosage form, then the USP/NF can be used.
than 110.0% of the labeled amount of cefuroxime Since some drugs may occur as salt forms, ester
(C16 H16 N4 O8 S). forms, and/or salt–ester forms, it is important to doc-
3. Ceftin Tablets (cefuroxime axetil tablets) provide ument what form is used and whether it is a salt, ester,
the equivalent of 250 or 500 mg of cefuroxime as or combination. An example of a drug that occurs as
cefuroxime axetil. both salt and ester forms is the drug erythromycin:
4. Ceftin for Oral Suspension (cefuroxime axetil erythromycin estolate is a salt; erythromycin ethyl-
powder for oral suspension), provides the succinate is an ester; erythromycin gluceptate is a salt;
equivalent of 125 mg or 250 mg of cefuroxime as erythromycin lactobionate is a salt; and erythromycin
cefuroxime axetil per 5 mL of suspension. stearate is a salt.
5. After oral administration, cefuroxime axetil is
absorbed from the gastrointestingal tract and Compounding with aliquots, dilutions,
rapidly hydrolyzed by nonspecific esterases in the and concentrates162
intestinal mucosa and blood to cefuroxime; the Substances are available as aliquots, dilutions, and
axetil moiety is metabolized to acetaldehyde and concentrates for a number of reasons. First, the quan-
acetic acid. tities required for dosing or compounding are so small
6. The molecular weight of cefuroxime axetil is they cannot be accurately weighed, so dilutions are
510.47. The molecular weight of cefuroxime is prepared, assayed, and utilized. Second, some items
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512 | An Introduction to Pharmacy

(e.g., nitroglycerin) are explosive and must be diluted whether or not International Units or ‘USP
in order to be safely handled. Third, many substances, Units’ have been defined.
such as acids and bases, are commercially available
in percentage strengths that vary from one acid to
There is no relationship between the units of
another and depend on the solubility and stability of
potency of one drug with that of another different
the solute in water and on the manufacturing process.
drug. In the case of potency-designated drugs, there
The diluted acids are aqueous solutions 10% w/v,
must be a ‘‘reference standard’’ for comparison. In
but diluted acetic acid is 6% w/v. The concentrations
of the official undiluted acids are expressed as per- actual usage, the potency specifications often include
centages weight in weight (w/w), but the strengths a range or ‘‘not less than __’’ and ‘‘not more than
of official diluted acids are expressed as percentages ___.’’ In some cases, only a lower range is given, and,
weight in volume (w/v). Therefore, it is necessary in a few cases, there is no upper limit.
to consider the specific gravities of the concentrated The determinations of potency are done on the
acids, when calculating the volume required to make ‘‘dried or anhydrous basis.’’ In the case of hygroscopic
a given quantity of diluted acid. APIs, one must exercise precautions to maintain the
substance in a dried state in tight containers. In some
Compounding with potency-designated cases, there is a designation of specified solvent-free
ingredients163 conditions.
In the case of ‘‘potency-designated’’ drugs, the bulk In the case of dihydrostreptomycin, there are dif-
substance, or API, is not 100% active drug in all cases. ferent potencies, depending on the use of the API. The
It is important to know the assayed-potency designa- potency may be not less than 450 mcg, 650 mcg, or
tion of the ingredient, so appropriate allowances can 725 mcg, depending on its form or usage (route of
be made to obtain the correct amount. administration).
Some APIs, including some antibiotics, endocrine In some cases, as in erythromycin ethylsucci-
products, biotechnology-derived products, and bio- nate and erythromycin stearate, the potency is based
logics, have potencies that are based on ‘‘activity’’ on the sum of the percentages of three different
and are expressed in terms of ‘‘units of activity,’’ erythromycins that make up the API. The potency-
‘‘micrograms per milligram,’’ or other standard terms designation is determined on the ‘‘base’’ of the drug,
of measurements. These are described for each API in but, in a few instances, the salt or ester form is used.
the USP (see Table 11.9). The potency of antibiotics is commonly expressed
Regarding biologicals, the following is found in as ‘‘mcg of activity per mg of substance.’’ Obviously,
the General Notices of the USP: there will be different equivalents for the base versus
5.50.10 Units of Potxency (Biological) the salt forms of the drug. For example, tobramycin
For substances that cannot be completely has not less than 900 mcg of tobramycin per mg, and
characterized by chemical and physical means, tobramycin sulfate has a potency of not less than 634
it may be necessary to express quantities of mcg of tobramycin per mg, all on the anhydrous basis.
activity in biological units of potency, each As another example, ampicillin contains not less than
defined by an authoritative, designated refer- 900 mcg and not more than 1050 mcg of ampicillin
ence standard. per mg, and ampicillin sodium contains not less than
Units of biological potency defined by 845 mcg and not more than 988 mcg of ampicillin
the World Health Organization (WHO) for per mg, both calculated on the anhydrous basis. So,
International Biological Standards and Inter- one can tell that it is extremely important to check
national Biological Reference Preparations are the labels accompanying each batch of each API for
termed International Units (IU). Monographs the necessary values used in calculations.
refer to the units defined by USP Reference In some drugs, the actual dose may be expressed
Standards as ‘USP Units.’ For biological prod- in units, instead of mg. Examples of this include
ucts, units of potency are defined by the cor- heparin and insulin. Other examples include enzymes
responding US Standard established by FDA, (pancreatin, pancrelipase, papain), and antibiotics.
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Each container must be labeled with the actual 0.1 M. An increase in the buffer concentration means
potency, and this information is to be used in cal- an increase in pain on injection, so it is kept as low as
culations involving dosing prior to compounding reasonable.
activities. These calculations must be performed and Chelating agents are incorporated to bind trace
checked and documented, as different lots of the same metals, such as copper, iron, calcium, and man-
API may have different potencies. An example of a ganese, and minimize rates of degradation. Ethylene-
calculation follows: diaminetetraacetic acid (EDTA) is commonly used at
a concentration of about 0.01 to 0.05%.
Since oxidation is one of the major factors in pro-
Example
tein degradation, antioxidants are often incorporated.
A formula calls for 500 mg of neomycin sulfate. The Examples include ascorbic acid, sodium disulfide,
label on the API shows 650 mcg of neomycin activity monothioglycerol, and α-tocopherol, which are fre-
per mg of powder. How much of this powder is quently used at a concentration of about 0.05 to
required to provide the 500 mg of neomycin sulfate? 0.1%.
650 mcg/1000 mcg = 500 mg/X mg Especially if multiple dose vials are prepared,
X = 769 mg of the powder is required to provide preservatives are necessary, if the active ingredient is
500 mg of actual neomycin sulfate. compatible. Example preservatives can include phe-
nol (0.3 to 0.5%), chlorobutanol (0.3 to 0.5%), and
benzyl alcohol (1.0 to 3.0%).
Compounding with complex organic Other excipients may include the polyols, which
molecules164 are good stabilizers and are commonly used in con-
Most complex molecules and biotechnology prod- centrations from 1% to 10% and tonicity-adjusting
ucts are proteins; however, some may be smaller agents, which include sodium chloride and dextrose
peptide-like molecules. Proteins are inherently unsta- in concentrations necessary to achieve isotonicity of
ble molecules and require special handling; also, their approximately 290 mOsm/L.
degradation profiles can be quite complex. Pharma-
cists involved in compounding with biologically active Preparation
proteins must be knowledgeable of their stabilization, Complex molecule formulations and procedures
formulation, and delivery to the site of action. should be kept as simple as possible. Sterility must
In compounding with complex molecules, one be achieved and maintained in many preparations,
must be cognizant of both the active drug constituent and, since most do not contain a preservative, it is
and the total drug formulation in which it is con- recommended that only one dose be prepared from
tained. Protein drugs are very potent and are used in each vial or container to minimize contamination.
quite low concentrations. The bulk of many manufac- Sometimes, this may not be practical, and specific
tured products and compounded preparations may be manipulations are needed to meet patient needs. Also,
the excipients, including the vehicle, buffers, stabiliz- there are two special considerations in working with
ers, and others that are often incorporated in these biotechnologically derived preparations – the use of
products. A number of different stabilizers can be used filters and the sorption of these drugs to containers.
from different chemical classes and include buffers, The use of filters in manipulating biotechnology
surfactants, amino acids, polyhydric alcohols, fatty products can result in ‘‘sorption’’ or the loss of some
acids, proteins, antioxidants, reducing agents, and of the drug available to the patient. Sorption is ‘‘stick-
metal ions. ing’’ either by ‘‘absorption’’ into the filter or by
‘‘adsorption’’ onto the surface of the filter. Special
Factors filters have been prepared to minimize this problem.
pH is one of the key important factors in formulating For example, muromonab-CD3 (Orthoclone OKT3)
a stable preparation. The optimal pH range can be injection should be filtered with a low protein-binding
achieved through the selection of appropriate physio- filter of 0.2 to 0.22 μm. Many biotechnology products
logic buffers, in buffer concentration ranges of 0.01 to should not be filtered at all. If a filtration device is
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514 | An Introduction to Pharmacy

part of the intravenous (IV) administration apparatus, • Interaction of the product with the inner wall of
large molecule drugs should be administered distal to the glass vial or bag and with the elastomeric clo-
the site of the filter. Filters shown to minimize pro- sure
tein adsorption are those made from polyvinylidene • Effectiveness of the preservative if a multiple dose
difluoride, polycarbonate, polysulfone, and regener- product is mixed with other products
ated cellulose. As a precaution, low protein-binding • Immunogenic potential, because some are pro-
filters should be used. duced by a fermentation-type process and proteins
Sorption of proteins to containers (glass or plastic) can co-purify with proteins.
can result in drug loss. This loss can be minimized
either by the use of albumin or by siliconization. Also, physicochemical factors considered in com-
Adding about 0.1% albumin to the preparation can pounding with protein drug products include the
decrease the sorption of proteins to containers. If glass structure of the protein drug, isoelectric point, molec-
or plastic containers are used, the albumin solution ular weight, solubility and factors affecting solubility
should be added and manipulated to coat the interior (e.g., surfactants, salts, metal ions, pH), stability and
surface before adding the drug. If siliconization is factors affecting stability (e.g., pH, temperature, light,
used, one can prepare a silicon solution or emulsion oxygen, metal ions, freeze–thaw cycles, mechanical
and soak or rinse the glass vials in it. The drained stress), polymorphism, stereoisomers, filtration media
vials should then be placed in an oven at about compatibility, shear, and surface denaturation.
250◦ C for 5 to 6 hours. This procedure will minimize Solubility can vary with changes in chemical struc-
protein adsorption to glass; it can be used for both the ture, pH, and temperature. Proteins are more soluble
preparation equipment and the packaging containers. in their native environment or medium or in a matrix
that is similar to their native environment, which may
include sodium chloride, trace elements, lipids, and
Physicochemical considerations
other proteins in an aqueous medium. One must con-
Several factors must be considered to ensure retention sider the ingredients’ effects on the solubility of the
of a large molecule drug’s activity up to the time of active drug, especially since most of the products are
administration to the patient and include selecting currently administered parenterally. This is critical,
an appropriate vehicle for drug delivery, individu- because the actual drug is present in a small quantity
alizing dosages, administering drugs through novel and can go unnoticed if it precipitates.
drug-delivery systems, preparing drugs for delivery The pH of the compound should be maintained
through these systems, monitoring their efficacy, and close to the pH of the original approved, manufac-
counseling patients on their use. Specific issues rele- tured product. Changes in pH can affect proteins in
vant to large molecule drugs include the: numerous ways and result in altered activity. Chem-
ical degradation rate constants are pH related, and
hydrogen ion concentration can affect the actual struc-
• Effect of agitation and/or frothing on a prepara- ture of proteins (i.e., quaternary structure). Buffer
tion’s stability systems may be needed in compounding; they should
• High molecular weight and potential for aggrega- be prepared at the minimum buffer strength required
tion (i.e., a small change in structure can result in a to produce the most stable drug preparation, as pre-
change in activity) viously mentioned.
• Assignment of potency to the reference standards, Chemical and physical instability must be consid-
(when traditional pharmaceuticals are about 98% ered and addressed appropriately. Chemical instabil-
pure, these materials may be only 0.1 to 1% active, ity of proteins is the modification of protein struc-
with their activity assigned by potentially variable tures by bond formation or cleavage to yield a new
assays) compound. Physical instability involves changes in
• Use of micropipets, which can require frequent structure, conformation, or behavior in a particular
calibration environment. Stability, both chemical and physical,
• Stability may be less than lyophilized preparations depends on pH, temperature, and agitation, as well
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The scope of pharmacy practice | 515

as the overall environment in which the drug is con- of certain products; for instance, the activity of fil-
tained. grastim decreases if frozen. Some products can retain
Sorption is a problem with colony-stimulating fac- potency at room temperature after reconstitution. Sar-
tors and with aldesleukin (Proleukin) at low concen- gramostim retains potency for up to 30 days at 25◦ C.
trations. To minimize ‘‘sticking’’ of the protein to the However, most manufacturers recommend refrigera-
glass or plastic, the addition of about 0.1% albumin tion at 2 to 8◦ C, regardless of the product’s potency
to the product to occupy the potential binding sites at room temperature.
in the container is often helpful. Pharmacists must The short shelf-life of these products after recon-
consider this problem before making any changes in stitution can be due to chemical, physical, or micro-
packaging. biological instability. The manufacturer’s recommen-
Agitation resulting in frothing can create difficul- dations or those validated by the published litera-
ties in two ways. First, frothing can cause difficulties ture should be followed for products after they are
in using a syringe to withdraw the required amount reconstituted and manipulated into preparations. One
of drug from a vial. To avoid this problem, the for- example is tPA (alteplase), which has been used in
mulator should mix the product by rolling the vial treating intraocular fibrin formation after a vitrec-
in the hands or gently swirling it. Second, excessive tomy and in managing subconjunctival hemorrhage
agitation can cause changes in a protein’s quaternary after glaucoma filtration surgery. The prepared solu-
structure that often reduce or eliminate a drug’s ther- tion is stable in a pH range of 5 to 7.5 and is
apeutic activity. Some products, such as filgrastim incompatible with bacteriostatic agents. To prepare
(Neupogen) and sargramostim (Leukine), are recon- a compounded preparation, the commercial prod-
stituted by directing a soft stream of diluent against uct is reconstituted according to the manufacturer’s
the inside of the container wall. Others, such as recom- directions, using sterile water for injection without
binant tissue plasminogen activator (tPA; alteplase), preservatives to yield a concentration of 1 mg/mL.
are reconstituted by directing a stream of diluent This solution is further diluted with 0.9% sodium
directly into the product at the bottom of the vial. chloride injection to yield a concentration of 25
mcg/100 mcL. Aliquots of 0.3 mL are withdrawn into
Packaging 1 mL tuberculin syringes and capped. The syringes
The container used for packaging and storage after are stored in an ultrafreezer at −70◦ C. This product
compounding must be chosen carefully. For example, has been shown, by both bioassay and clinical use,
the manufacturer’s directions for interleukin-2 to retain its activity for at least 1 year. This type
(aldesleukin) suggest the use of a plastic bag, because of specific preparation information is not included in
that type of dilution container enhances consistent the manufacturer’s label information and is obtained
drug delivery. Unless otherwise specified, USP type I from the literature or by asking the manufacturer
glass should be used for packaging, when storage for directly.
extended time periods is indicated. The pharmacist
should be aware of the potential for sorption of the Stability
drug to the glass walls. Closures and stoppers should Physical stability can involve degradation by aggre-
be selected that are compatible and flexible, have low gation, denaturation, and precipitation. Aggregation
levels of particulates, and have few problems with can be the result of covalent or non-covalent pro-
adsorption, absorption, and permeation. cesses and can be either physical or chemical in nature.
Aggregate formation can actually begin when primary
Storage/labeling particles are formed from protein molecules as a result
The recommended storage temperature depends on of Brownian movement.
the specific preparation and may include room tem- Denaturation can result from heat, cold,
perature (15◦ to 25◦ C), refrigerator temperature (2◦ extreme pH values, organic solvents, hydrophilic
to 8◦ C), frozen (−20◦ C), or ultrafrozen temperature surfaces, shear, agitation, mixing, filtering, shaking,
(down to −80◦ C). Freezing does affect the activity freeze–thaw cycles, ionic strength, and other factors.
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516 | An Introduction to Pharmacy

Denaturation can be quite complex and can be either injection to 48 mL of 5% dextrose in water and has
reversible or irreversible. just compounded a drug preparation that does not
Precipitation can result from shaking, heating, meet the USP compounding specifications of 90.0 to
filtration, pH, and chemical interactions. The first step 110.0% of the labeled quantity. In other words, 2 mL
in a precipitation process is aggregation. When the of 40 mg/mL at 120% of labeled quantity equals
aggregates gain a sufficient size, they precipitate out 96 mg of gentamicin present. The acceptable range
of solution and are clearly evident. Precipitation can would only be 72 to 88 mg of gentamicin present.
occur on membrane filters, in equipment, in tubing, Since there is 96 mg of drug present and it exceeds
and in contact with other equipment and supplies. the maximum 88 mg, this preparation does not meet
the USP standard for compounding. If this solution
Issues related to compounding with commercial was selected to be analyzed by a regulatory agency,
products it would be reported as ‘‘out of specification’’ and
Pharmacists have a choice for the source of ingredi- ‘‘superpotent.’’ This is the system currently in effect
ents used in compounding prescriptions for humans: that must be followed until such time that most com-
bulk drug substances (APIs) or commercial prod- pounding can be done using compendial standard
ucts. Veterinary compounding may require the use of (USP/NF) or other high quality bulk drug substances.
commercial products. Different dosage forms have historically been used
Is compounding using commercial products wise? as the source of active drugs and the different dosage
Can one be assured of a quality preparation, if com- forms that they have been used to prepare. Oral tablets
pounded marketed products are used? Can one meet and capsules are commonly used to prepare oral liq-
the USP standards of USP Chapters <795> and uids (solutions and suspensions) for pediatric use, and
<797> by using commercial products as the source of injectable drugs to prepare intravenous admixtures.
drugs? The answer to these questions is, ‘‘sometimes, Another fact to consider is that FDA-approved com-
but not always.’’ Pharmacists are placed in an inter- mercial products are used, but the final compounded
esting situation, when required to use commercial preparation is not FDA-approved. There are many
products in compounding veterinary preparations, considerations and variables of which to be aware
because this sometimes results in preparations outside in using commercial dosage forms. Some commer-
USP standards and specifications. cial dosage forms are inappropriate for use in some
In compounding for human patients, pharmacists situations in compounding.
have the choice to use bulk chemicals (APIs) or com- Considerations when working with commercial
mercial products. When using commercial products products include the following:
as the source of active drugs, one does not really
know if the final compounded preparation meets USP 1. The use of commercial products as a source of
standards. As an example, one may prepare a rela- active drugs will result in a higher prescription
tively simple intravenous admixture containing 80 mg cost to the patient, as compared to bulk drug sub-
gentamicin injection in 50 mL of 5% dextrose solu- stances (APIs). This is especially true if injectables
tion. To prepare this, 2 mL of gentamicin injection are used as the drug source.
(40 mg/mL) is added to 48 mL of 5% dextrose in 2. Uncertainties in compounding using commercial
water in a piggyback bag to make a final volume of products involve the presence of excipients and
50 mL. In compounding, one is allowed a variance actual assay potency.
of 90.0 to 110.0% of the labeled potency of the 3. When using commercial solutions as a source of
finished compounded preparation. The USP specifica- drugs, one must be aware of the pH of the solution
tion for gentamicin injection is not less than 90.0% and the pH of the compounded preparation. If the
and not more than 125.0% of the labeled amount pH range is significantly different (i.e., about 2 to
of gentamicin. If the specific batch analyzed at the 3 pH units different), this may result in changes in
manufacturer was at 120%, it met the USP spec- the solubility and stability of the drug and formu-
ifications and entered the marketplace distribution lation. Regarding solubility, instead of a solution
system. A pharmacist adds 2 mL of that gentamicin being prepared, it may result in a suspension if
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The scope of pharmacy practice | 517

the pH of the final compounded preparation is Summary

insufficient to keep the drug in solution.
Pharmacy compounding is providing pharmacists
4. The presence of buffers in the commercial drug
with a unique opportunity to meet the needs of
product may influence and dictate the pH of the
physicians and their patients by individualizing
final compounded preparation.
medications. It will become an even more important
5. If compounding large batches, it may be advisable
part of pharmacy practice in the future in all practice
to assay the commercial product used for potency.
areas for humans and animals. Pharmaceutical com-
This is especially true if the allowable range in the
pounding is a practice in which the clinical expertise
USP for the commercial product is outside the
of pharmacists can be merged with the scientific
90.0 to 110.0% acceptable range in compound-
expertise of pharmacists to make pharmaceutical
ing. Some USP monographs for commercial prod-
care a reality.
ucts go much higher, but this is unusual. However,
Pharmacists should not hesitate to become
it is important to know the variables one is work-
involved in pharmacy compounding but should
ing with. Most commercial drugs are in the 95 to
be aware of the requirements and uniqueness of
105% and 90 to 110% range, with some in the 80
formulating a specific drug product for a specific
to 120% range; however, in some cases, it is even
patient. This is an important component in pro-
more. Compounded preparations are limited to a
viding pharmaceutical care. After all, without the
90.0 to 110.0% standard. In summary, it may be
pharmaceutical product or preparation, there is no
that the pharmacist did everything exactly correct,
pharmaceutical care.
but, if the final preparation was assayed, it would
be out of specifications (OOS), due to the use of
the commercial product where a wide variability
was allowed. References
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12
Social, behavioral, economic and
administrative sciences

Laws governing pharmacy 523 Pharmacist credentialing 533

Pharmacoeconomics 525 Medical claims and basic billing terminology 534

Product recalls and withdrawals, and disposal of Claims for pharmacist services 537
unused medicines 528
Future directions 538
Marketing pharmacy care services 529
Pharmaceutical risk management 540
Clinical pharmacy services 529
Pharmacoepidemiology and pharmacovigilance 542
Current billing methods for pharmacists 530
References 544
Documentation: The SOAP System 532

Laws governing pharmacy State agencies, such as a Board of Pharmacy, also

adopt rules or regulations that have the force of law.
Pharmacists, whether community practitioners Another source of law comes from court decisions that
employed by an institution, or working for a phar- either interpret statutory and regulatory laws or make
maceutical manufacturer, must be aware of the legal new laws based on judicial decisions; the latter type of
requirements that apply to their daily professional rulings are often called ‘‘judge made’’ or ‘‘common’’
activities. The laws pertaining to the practice of laws derived from the English court system.
pharmacy arise from a variety of sources, including Besides the various sources of laws, there are a
statutory laws, such as the Food, Drug and Cosmetic multitude of types of law. Civil law governs the rela-
Act (FDCA), the Controlled Substances Act (CSA), tionship between individuals within society, whereas
the Poison Prevention Packaging Act (PPPA) at the criminal law governs the relationship of the individual
federal level, and Pharmacy Practice Acts or Codes at to society as a whole. Two important subdivisions of
the state level. In addition, several regulatory agencies civil law are the law of contracts and tort law. The for-
in the federal government, including the Food and mer concerns relationships that the individuals enter
Drug Administration (FDA), the Consumer Product into voluntarily, whereas the latter embodies relation-
Safety Commission (CPSC), and the Drug Enforce- ships that exist automatically by virtue of law. Each
ment Administration (DEA), have the authority to type and source of law is applicable to pharmacists
promulgate regulations that have the force of law. and pharmacy practice.
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524 | An Introduction to Pharmacy

Laws governing the practice of pharmacy states to enact. Animosities between the FDA and
compounding pharmacies finally cumulated in a US
Relationship between state and federal laws
Supreme Court decision in April, 2002 that should
Differentiating between state and federal laws govern- have settled the issue in favor of state authority to reg-
ing the practice of pharmacy can be a daunting task, ulate compounding. Undaunted by the Supreme Court
because some areas of the law are reserved exclu- decision, within days, the FDA reissued guidelines to
sively to state governments, whereas other topics are its field officers to distinguish between acceptable
governed exclusively by federal authorities. Compli- compounding activities and unlawful manufacturing
cating the subject even more, there are numerous by pharmacies without a federally issued manufactur-
issues that both the state and federal laws address. ing license.
In the latter case, when both federal and state laws The authority for states to regulate pharmacy
speak to the same issue, the governing bodies are originates in the 10th Amendment to the US Con-
said to have ‘‘concurrent jurisdiction.’’ Determining stitution, which reserves most ‘‘police powers’’ to
which of the two sets of laws to apply to any given the states. The terminology could be misleading, if
situation is sometimes difficult, especially in cases ‘‘police power’’ were thought to refer to law enforce-
in which the two laws differ in their obligations ment officers only. In fact, as the term is used in the
or prohibitions. As a general rule, when there is a law, the ‘‘police power’’ reserved exclusively to the
‘‘conflict of laws,’’ it is safer to apply and follow states means the states have the authority to pass laws
the more strict law. An example will help illustrate designed to protect the health, safety, and welfare of
the point: DEA regulations require pharmacies to its citizens. Note that the Constitution reserves most
keep controlled substances records, including pre- ‘‘police powers’’ to the states. As might be expected,
scriptions, for at least 2 years. Several states have there are exceptions that permit the federal govern-
laws that all prescriptions be stored in a pharmacy for ment to ‘‘pre-empt’’ inconsistent state laws, if the
a longer period. In Michigan, for example, pharma- federal government determines it will ‘‘occupy the
cies must retain prescriptions a minimum of 5 years field’’ of a particular subject matter. Another example
from the date of last refill. Because record retention is is offered to clarify the point. Every state has laws
a subject of ‘‘concurrent jurisdiction’’ between state regarding the labeling and packaging of drugs dis-
and federal governments, a pharmacist would follow pensed pursuant to a prescription. Some states even
the ‘‘stricter’’ law and, at least in Michigan, keep have laws regarding the type of container used to con-
all prescriptions, including those for controlled sub- tain prescription drugs. The CPSC, a federal agency,
stances, for a minimum of 5 years from the date of acting under the auspices of the federal PPPA has
the last refill. Another area of ‘‘concurrent jurisdic- ‘‘pre-empted’’ inconsistent state laws dealing with the
tion’’ that has sparked over a decade of controversy packaging of ‘‘household substances,’’ which include
involves the compounding of drugs by pharmacists. prescription drugs. Under the applicable regulations,
Historically, compounding was thought to be exclu- nearly every drug dispensed by prescription must be
sively in the realm of state jurisdiction. In the early in a child resistant container, unless the patient or pre-
1990s, the FDA began an aggressive approach to regu- scriber requests otherwise. Due to the pre-emption,
late pharmacies engaging in large scale compounding any state law not consistent with the demands of
more akin to manufacturing. Viewed another way, the CPSC regulations would have no force of law,
the FDA was attempting to regulate pharmacies that and pharmacists are required to follow the federal
were manufacturing, and, therefore, subject to federal mandates.
laws, under the guise of state regulated compound- Perhaps it is too simplistic to put it this way, but
ing practices. The furor over the subject led to an another general rule to use in determining which juris-
amendment to the FDCA that gave the FDA some dictional body controls a subject matter is to think
regulatory authority over compounding, while leav- of state laws as regulating the practice of pharmacy
ing other aspects of compounding subject to state law. and the federal government as regulating pharma-
This, in turn, led the National Association of Boards ceuticals, including their marketing, production, and
of Pharmacy (NABP) to adopt model guidelines for distribution. As with all laws, there are exceptions
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Social, behavioral, economic and administrative sciences | 525

to this general rule. Nonetheless, it should help read- services and must develop priorities for those inter-
ers better comprehend the scope of the jurisdictional ventions to successfully compete in the ever-changing
authority of the different governmental bodies. healthcare landscapes.
As a general background, it is important to appre-
ciate the types of evaluations involved when exam-
Pharmacoeconomics ining costs and consequences in health interventions.
To facilitate an understanding of terminology used
Practitioners and managers face a multitude of eco- in this section, the reader is referred to the glossary
nomic challenges as the discovery of new thera- of terms in Table 12.1. In addition, Table 12.2 pro-
pies seems boundless, whereas payers’ and patients’ vides a concise framework which differentiates the
resources to purchase these cures are limited. How key pharmacoeconomic methods. Drummond et al.13
does a person decide which are the best medicines to emphasize that full economic evaluations involve the
use within restricted budgets? The continuing impact comparison of at least two interventions and an exam-
of cost containment is causing administrators and pol- ination of all costs and consequences.
icy makers in all health fields to closely examine the
costs and benefits of both proposed and existing pro-
Community pharmacy economics
grams. It is increasingly evident that private employers
and management
and public agencies demand that health programs be
evaluated in terms of clinical and social outcomes The economic effect of the healthcare industry on our
related to costs incurred. Cost–benefit analysis and society is difficult to evaluate. However, recognizing
other pharmacoeconomic tools are ways to analyze that healthcare currently represents more than 17%
the value of interventions and services to patients. of national gross domestic product (GDP) should give
These methods supplement the traditional market- some indication of its effect.14 It is accepted that
place value as measured by the prices the patient advances made by the industry during the past few
or patron is willing to pay. As public and private decades have reduced morbidity and mortality rates
insurance agencies continue to pay for a higher per- that, in turn, have increased productivity and added
centage of prescriptions dispensed, pharmacists are to the gross domestic product. At the same time, the
very cognizant that pharmacy services and therapeu- cost of healthcare is rising at a faster rate than the
tic interventions require substantial cost justification consumer price index (CPI) for all items, and this
to survive and thrive in the future.1 – 7 cost continues to represent an increasing share of
Pharmacy entrepreneurs have established numer- the GDP.
ous innovative roles for pharmacists, such as home
intravenous therapy, drug-level monitoring, par-
Economics of pharmaceuticals
enteral nutrition management, hospice care, and
self-care counseling, among others. The use of valid The magnitude of healthcare expenditures in the
economic evaluation methods (e.g., cost–benefit and United States and the growing governmental involve-
cost-effectiveness analysis) to measure the value and ment as a third-party payer of healthcare costs are
impact of new services, such as medication therapy evidence of society’s commitment to providing the
management (MTM), can increase acceptance and best care possible for all citizens. Those involved in
benefit of such programs by the medical profession, the delivery of healthcare share society’s commitment
third-party payers, and consumers.8 – 10 and, therefore, must be concerned with the economics
There is increasing competition among health of the delivery system.
professionals for the limited dollars and resources In 2011, recent market trends in prescription drug
available. Within institutions and communities, phar- sales continued together with important new develop-
macists have to increasingly compete with nursing, ments in the treatment of several diseases. Spending
medical, and other groups for adequate reimburse- grew slowly, in line with the trend of annual growth
ment and payment.11,12 Therefore, pharmacy must of 5% or less since 2007. Total healthcare spending
document the cost-benefits of distinct pharmacy reached $320 billion, up by about $50 billion since
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526 | An Introduction to Pharmacy

Table 12.1 Glossary of terms

Contingent valuation A method for evaluation of benefit or value to individuals of therapy that uses survey methods to
establish willingness-to-pay.

Cost–benefit analysis (CBA) A type of analysis that measures costs and benefits in pecuniary units and computes a net monetary
gain/loss or a cost–benefit ratio.

Cost-effectiveness analysis (CEA) A type of analysis that compares interventions or programs having a common health outcome (e.g.,
reduction of blood pressure, life-years saved) in a situation in which, for a given level of resources,
the decision maker wishes to maximize the health benefits conferred to the population of concern.
This type of analysis can be used to assess cost-effectiveness efficiency.

Cost-minimization analysis (CMA) A comparison in which inputs are measured in monetary values and outputs are assumed to be
identical.

Cost-utility analysis (CUA) A type of analysis that measures benefits in utility-weighted life-years (QALYs) and that computes a
cost per utility-measure ratio for comparison between programs.

Decision analysis An explicit quantitative approach for prescribing decisions under conditions of uncertainty.

Decision tree A framework for representing alternatives for use in decision analysis.

Direct costs Those costs that are wholly attributable to the service in question, for example, the services of
professional and paraprofessional personnel, equipment, and materials.

Discount rate Rate of discount used to convert future costs and benefits into equivalent present values; typically
2–6% per annum.

Equity Fairness in the allocation of resources or treatments among different individuals or groups

Indirect costs (1) Societal, economic, and productivity losses due to morbidity and early mortality; also (2)
sometimes used to refer to overhead costs based on costs that are shared by many services
concurrently, for example, maintenance, electricity, and administration.

Net benefit Total benefit (in monetary units) minus total cost (in monetary units); a basic decision criterion in
cost–benefit analysis.

Opportunity cost The opportunity cost of a commodity is the value of the best alternative use to which those resources
could have been put; the value of the productive opportunities foregone by the decision to use
them in producing that commodity.

Pharmacoeconomics The study of how individuals and societies choose to allocate scarce pharmaceutical and health
resources among competing alternative uses and to distribute the products and services among
members of the society.

Preference-based measures Also referred to a utility measures or quality-adjusted life year measures. Patients are asked to
imagine possible health states and provide score to reflect their preferences for various scenarios,
on a scale of 1.0 (perfect health) to 0 (worst possible health state or death).

Quality of life (QOL) Physical, social, and emotional aspects of a patient’s well-being that are relevant and important to
the individual.

(continued overleaf)
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Social, behavioral, economic and administrative sciences | 527

Table 12.1 (continued)

Quality-adjusted life year (QALY) A common measure of health improvement used in cost-utility analysis; combines mortality and
quality of life gains (outcome of a treatment measured as the number of years of life saved, adjusted
for quality).

Sensitivity analysis A process through which the robustness of an economic model is assessed by examining the
changes in results of the analysis when key variables are varied over a specified range.

Utility A measure of value of an outcome that reflects attitudes toward risk. Utility scores are often obtained
from patients with questionnaires (EQ-5D) or instruments, such Visual Analog Scales (VAS), Standard
Gamble (SG), or Time Trade Off (TTO).

Willingness-to-pay The maximum amount of money an individual is prepared to give up to ensure that a proposed
healthcare intervention is undertaken.

For a more comprehensive glossary see Berger ML et al. Health Care Cost, Quality, and Outcomes. ISPOR Book of Terms. Lawrenceville, NJ: International
Society for Pharmacoeconomics and Outcomes Research, 2003.1

Table 12.2 Types of pharmacoeconomic evaluations

Are both costs and consequences of the alternatives examined ?

NO YES

Examines only consequences Examines only costs Examines both

Is there comparison of two or NO Outcome description Cost description Cost-outcome description

more alternatives?

YES Efficacy description Cost analysis Full economic evalution

(CBA, CEA, CUA, etc.)

Adapted from Drummond MF et al. Methods for the Economic Evaluation of Health Care Programs. Oxford: Oxford University Press, 2005.13

2006 and $125 billion since 2002, representing an obligation to their beneficiaries to ensure access and
increase in nominal spending of 3.7%, but when cal- the delivery of quality services at reasonable prices.
culated on a real per capita basis an increase of only In this regard, health professionals, including com-
0.5%.15,16 munity pharmacists, find their products and services
The share of prescription drug spending by third- under scrutiny by a sophisticated group of agencies
party payers has increased significantly over the past representing a large portion of the general public.
15 years.17,18 Although some look on third-party Today, approximately 85 to 90% of prescrip-
payment as a mechanism for solving the high cost of tions filled in a community pharmacy are partially or
healthcare, including the drug-cost segment, it should completely paid by a third-party payer.17,18 Private
be understood that third-party payment does not insurance funds about 42% of the nation’s prescrip-
reduce the cost. It simply spreads it over a larger popu- tion costs, the government funds 37%, and the con-
lation. Actually, third-party payment may increase the sumer funds 21% through out-of-pocket expenses.17
total cost of healthcare as additional administrative The implementation of Medicare Part D in 2006 has
costs and increased use of products and services are increased the public funding of prescription drugs.
inherent in these programs. It follows that third-party Those who provide pharmacy services must con-
payers, whether governmental or private, have an sider economic and professional factors as they make
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528 | An Introduction to Pharmacy

decisions about participation in these programs. Phar- reports and the implementation of Medicare Part D,
macy owners and managers face the challenge of there is increased focus on the appropriate and safe
maintaining the economic practicality of their phar- use of pharmaceuticals. A 2009 study found that the
macies when contracting with pharmacy benefit man- cost of drug-related morbidity in the United States
agers and other payers. Participation in such contracts is nearly $289 billion annually, representing 13%
often increases administrative expenses for the phar- of total healthcare expenditures.21 Poor medication
macy, while providing reimbursement that may not adherence leads to emergency room visits and hospi-
be adequate to cover the costs of providing quality talizations, and ultimately poor patient outcomes.22
pharmacy services. The Medicare Prescription Drug, Improvement, and
Previously, the cost of healthcare was given little Modernization Act included medication therapy man-
attention by the providers of health services. It was agement (MTM) in the regulation to improve med-
assumed that the primary obligation of the provider ication use and reduce unnecessary costs. MTM is
was to ensure the physical well-being of the patient, defined as ‘‘a distinct service or group of services
without regard to cost. It is now apparent that it does that optimize therapeutic outcomes for individual
little good to develop a level of healthcare unsurpassed patients.’’23 MTM includes conducting medication
in the world, if a sizable segment of the population reviews, developing personal medication records and
cannot afford to pay for it. The obligation of health medication action plans, and intervening to prevent
professionals to consider the economic dimensions of or resolve medication-related problems. Studies, such
healthcare is now recognized. as the Asheville Project, have shown that MTM ser-
In 2010, the average generic prescription, both vices provided by community pharmacists can reduce
for short-term and 90 day medications, cost $72, direct medical costs and improve patient outcomes.24
compared with $198 for the average brand-name Community pharmacists have an important role in
drug. Average co-payments for that year were $6 ensuring appropriate use of medications and reducing
for generics, but brand-name drugs given preferred unnecessary healthcare costs.
status by an insurer were four times as expensive, and
non-preferred brands almost six times as costly.19 Product recalls and withdrawals,
Pharmacy practice laws in all states have been and disposal of unused medicines
amended to allow pharmacists to practice generic sub-
stitution. These amendments allow the pharmacist, Occasionally, pharmaceutical manufacturers must
under specified conditions, to choose drug prod- recall or withdraw products from wholesalers, phar-
ucts with due regard for both the physical and macies, and/or patients. In the preceding two decades
the economic well-being of the patient. The generic we have seen the number of drug recalls range from
substitution amendments are tangible evidence of approximately 300 per year, to over 400 per year.
societal concern with the cost of healthcare. Addi- (In the year 2009 the number of recalls jumped to
tionally, pharmacy and therapeutic committees who over 1700. Approximately 1000 of them were due
develop formularies and recommend prescription ben- to one repackaging firm that is no longer a going
efit designs consider cost in their decision-making. concern. That year is an anomaly, and as such will
The concern of health professionals with the cost not be addressed further.) The reasons for recalls and
of healthcare now reinforces the efforts of consumer withdrawals range from life-threatening situations
groups, government, and others involved in financing (e.g., a product that is supposed to be sterile but
healthcare, to the end of providing the best care for is instead contaminated with bacteria) to situations
all, regardless of economic status. where there is no health hazard or risk, but simply, the
The Institute of Medicine (IOM) is an independent product does not measure up to the quality control
organization that conducts studies and issues reports standards that the pharmaceutical community wishes
to provide unbiased and authoritative advice to pol- to present to the public (e.g., a label that appears
icy makers and the public.20 The IOM has issued upside-down on its container).
several reports related to medication safety problems It is impossible to anticipate every situation, and it
in the United States. With the publication of these is unwise to have a ‘‘cookie cutter’’ solution for every
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Social, behavioral, economic and administrative sciences | 529

recall or withdrawal.25 It is hoped that pharmacists need for most patients is to have good health. If
will take these guidelines and then enhance or modify their health deteriorates, a need exists to return to
them to fit their particular practice. a healthy state. Patients have many alternative prod-
It is helpful to employ a simple aid that the ancients ucts, services, and providers to help them achieve this
used in analyzing rhetorical thoughts and questions.26 healthy state, including pharmacists and pharmacy
Today a vast number of people seem to be familiar care services. Patients choose healthcare options that
with them as a journalistic tool for gathering facts and they believe will best fit their needs and desires at an
circumstances: The ‘‘W’’s; Who What When Where acceptable price. To compete with the various options
Why How. available to patients, pharmacists should incorporate
the marketing process into the planning, design, and
management of their operations.
Marketing pharmacy care services
To successfully implement pharmacy care ser-
vices, pharmacists need to effectively market these
‘‘Marketing is a discipline that promotes the reso-
services. The steps of the marketing process pro-
lution of problems by identifying and meeting the
vide a basic framework that can be applied to any
needs of customers. In pharmacy practice, the cus-
practice. Each step of the marketing process may
tomers served by marketing may be patients, physi-
be individualized to a particular practice site, demo-
cians, nurses, or anyone else who interacts with
graphic area, patient base, competitive environment,
pharmacists.’’27
‘‘Marketing can be used to solve almost any prob- and recognized financial constraints. Regardless of the
lem in pharmacy. It can be used in personal career pharmacy involved, however, the key to success lies in
management, in influencing change in practice set- knowing the customer through market research and
tings, and in enhancing job effectiveness. Marketing systematic planning of strategies to reach and serve
can help persuade patients to adhere to medication targeted individuals.
plans, physicians to prescribe medicines appropri- A thorough analysis of one’s environment is essen-
ately, and management to support pharmacy practice tial to identify key targets and stakeholders, recognize
initiatives. It can be used to recruit good employees, opportunities and threats to the practice’s success,
attract and keep patients, provide innovative services, and ensure that marketing resources are used in the
and compete with other health professions for a por- most cost-effective manner.
tion of the health care pie.’’28 When implementing the marketing plan in an
Marketing is a proven approach that can be individual pharmacy, pharmacists should use goals,
used by pharmacists to better serve their patients. objectives, and individual tasks to give direction to
As pharmacists work to expand their role in provid- the marketing process. Including all employees in
ing pharmacy care services, the process of marketing this process, from clerks to pharmacists, helps to
can be used to influence demand for these services. In ensure consistency and commitment from all involved.
recent years practitioners have worked to re-engineer During the implementation phase of the marketing
their practices to incorporate a philosophy of phar- plan, regularly scheduled meetings should be held to
macy care into their practices. This re-engineering keep employees updated and informed on the mar-
has resulted in pharmacies presenting a new look to keting efforts. By carefully considering the concepts
their patients by incorporating patient consultation described in this section and by involving all employ-
areas, workflow improvements, and the increased use ees of the pharmacy in the process, pharmacists can
of pharmacy technicians within the practice. Along achieve the optimal results from their marketing plan.
with the new look, pharmacists are performing new
activities in their practices as new services are offered
to their patients. To reach their full potential, phar- Clinical pharmacy services
macists must effectively market their services.
An understanding of patients’ needs and wants The addition of clinical pharmacy services to health-
is essential for developing and implementing a suc- care teams has demonstrated significant improvement
cessful plan for marketing pharmacy services. The in therapy outcomes, as well as patient and provider
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530 | An Introduction to Pharmacy

satisfaction, and promotes cost savings for the 1. medication therapy review (MTR),
healthcare system.29,30 Pharmacy services designed 2. personal medication record (PMR),
to improve patients’ access to care, provide disease 3. medication-related action plan (MAP),
management, and that are focused on quality-related 4. intervention and/or referral, and
outcomes contribute to optimizing drug costs within 5. documentation and follow-up.
the total costs of patient care. Despite efforts by
national pharmacy organizations, lack of recognition MTM services can be provided by pharmacists at
by Medicare of pharmacists as providers under Part B any point along the continuum of healthcare. Patients
limits pharmacists’ ability to obtain reimbursement with potential to benefit from MTM provision by
for such services and remains a major barrier for a pharmacist can be identified by physicians, phar-
continued expansion or justification of new clinical macists, or self, and who are at higher risk for
pharmacy services in the ambulatory environment. medication-related problems. Those patients taking
Exploration of mechanisms for reimbursement for multiple medications for disease states associated with
clinical services is needed to further advance the high morbidity, mortality, or low quality of life may
provision of cognitive services in this arena. benefit most from pharmacists’ provision of MTM.
The Medicare Modernization Act of 2003 cre- Other opportunities to improve care by provision of
ated a prescription drug benefit (Part D) for Medicare MTM by a pharmacist include patients transitioned
recipients, and, for the first time, Congress included from the inpatient setting to the ambulatory environ-
an MTM benefit that named pharmacists as the key ment, patients discharged from skilled nursing care
providers.31 The legislation requires payers to reim- and re-integrated into the primary care setting, and
burse providers of MTM services for specific high-risk immediately subsequent to emergency department
patient groups. This is a precedent for reimbursing visits.
pharmacists for patient care services that are not asso- MTM programs are demonstrating positive clin-
ciated with product.31 However, due to the lack of ical, economic, and humanistic outcomes across
recognition of provider status for pharmacists under diverse patient populations in various patient care
Medicare Part B, many state Medicaid plans, and settings. Examples of successful MTM programs
many private payers, it is necessary for pharmacists provided by pharmacists are emerging in the public
to pursue alternative reimbursement mechanisms to and private sector. In the public sector, examples of
create viable ambulatory practice models. Pharmacists state Medicaid reimbursement and Medicare Part
D reimbursement programs exist, whereas, in the
practicing in all settings should become familiar with
private sector, MTM programs are offered to tradi-
opportunities allowing for reimbursement for services
tionally insured groups, managed care populations,
not associated with dispensed drug product (i.e., cog-
and self-insured employers.33
nitive pharmacy services).32 Pharmacists practicing
Codes specific to MTM services have been
in a variety of settings, including ambulatory clinics,
assigned by the American Medical Association Cur-
outpatient pharmacies, and potentially inpatient phar-
rent Procedural Terminology (CPT) Editorial Panel.
macy settings are eligible to obtain reimbursement for
Briefly the codes are as follows:
specific services.

• 99605 – MTM service(s) provided by a pharma-

Current billing methods for cist to an individual patient during a face-to-face
encounter that involve an assessment and interven-
pharmacists
tion if provided; used to code the initial 15 minutes
of an initial encounter with a new MTM patient
Medication Therapy Management (MTM)
• 99606 – Initial 15 minutes with an established
MTM is a term used to describe a broad range of patient
healthcare services provided by pharmacists. In a • 99607 – Each additional 15 minutes of an initial
document developed by the American Pharmacists or subsequent MTM encounter; list separately in
Association, the MTM service model is described as addition to code for primary service and in con-
including the following core elements:33 junction with 99605 or 99606
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Social, behavioral, economic and administrative sciences | 531

‘‘Facility billing’’ ‘‘First-party’’ payment

For those pharmacists practicing in a hospital- First-party payment refers to direct out-of-pocket
associated clinic setting, facility billing has proven payment for clinical pharmacy services. Pharmacists
a viable billing method to sustain existing clinical practicing within their scope, as outlined by state
services, as well as justify expansion of such services pharmacy practice laws under collaborative practice
in the outpatient arena. Facility billing refers to the agreements, can directly bill patients for services ren-
use of the hospital’s technical charge for services dered. This is an often overlooked, yet important,
provided in an outpatient department of a hospital method of billing for services, the importance of which
and represents ‘‘hospital resources utilized.’’ Phar- should not be minimized.
macists can bill for services in hospital-based clinics
using CPT Evaluation and Management (E&M)
Codes 99211–99215 for facility billing. The terms ‘‘Third-party contracting’’
‘‘technical fees’’ and ‘‘facility fees’’ are often used Contracting directly with third-party payers for reim-
interchangeably and represent ‘‘incident-to’’ billing in bursement for cognitive services is becoming more
a hospital-based outpatient clinic. A hospital-based prevalnt. However, a discrepancy still exists among
clinic is a clinic financially tied to the hospital and payers; many third-party organizations do not recog-
appears on the hospital’s cost report.34 nize pharmacists as providers of MTM, and claims
are often denied. Pharmacists should be diligent in
their pursuit of identifying insurers that recognize the
‘‘Incident to’’
benefits realized by pharmacists’ intervention and the
‘‘Incident-to’’ means the pharmacist is billing under profession’s ability to improve clinical outcomes and
a recognized CMS provider, including a physician, decrease inappropriate healthcare resource utilization
clinical psychologist, licensed clinical social worker, and overall healthcare-related costs.
physician assistant, nurse practitioner, clinical nurse
specialist, or certified nurse midwife. The criteria for
billing ‘‘incident to’’ in a hospital-based clinic include Diabetes Self-Management Training
services that are: (DSMT)
Pharmacists involved in diabetes education programs
1. furnished by or under arrangements made by the can receive reimbursement. Diabetes self-management
participating hospital; training (DSMT) is defined as a collaborative process
2. an integral, although incidental, part of a physi- through which people with or at risk for diabetes gain
cian’s or non-physician practitioner’s services; the knowledge and skills needed to modify behavior
3. furnished in the hospital or in a department of the and successfully self-manage the disease and its
hospital; and related conditions. Pharmacists who provide diabetes
4. furnished under direct supervision of a physician care and those interested in initiating services should
or non-physician practitioner.35 be aware of the national standards for diabetes
education. The most recent revision was completed in
Incident-to billing may also be used in a physi- the summer of 2007, and the standards are available
cian office setting for those services provided by online at http://www.diabetes.org/uedocuments/erp-
a non-physician, if the physician determines such national-standards-revised-0707.pdf. The education
services medically necessary. Reimbursement under program must meet all national standards for diabetes
this method of billing tends to be substantially less education.36 Minimum program staff is defined as
than other types of billing methods, and, therefore, one or more instructors. The instructors should be
other justification methods (i.e., cost-reduction, cost- of one of three disciplines: a registered nurse RN,
avoidance, patient/provider satisfaction) are typically registered dietician RD, or a pharmacist. The 2007
employed to substantiate pharmacy services within a standards provide additional opportunities for more
physician office setting. pharmacists to offer ongoing diabetes education
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532 | An Introduction to Pharmacy

programs that are financially sustainable. Medicare Documentation: The SOAP System
will only reimburse for the diabetes education codes
if the program is recognized by one of two accrediting Many advancements in clinical documentation can be
agencies: the American Diabetes Association (ADA) traced to the work of Dr. Lawrence Weed, a physi-
or the American Association of Diabetes Educators cian and pioneer in creating systematic approaches
(AADE). Recently, the Indian Health Service (IHS) to organizing the collection, storage, and use of clini-
was removed as an accrediting agency, and IHS cal information.41 Weed’s intuitive problem-oriented
programs will continue their credentialing with either medical record (POMR) represented a significant
ADA or AADE. More detailed information regard- advance from the fragmented source-oriented record
ing the application process can be found at http:// that had preceded it, in which notes were filed accord-
professional.diabetes.org /Recognition.aspx?typ=15 ing to the source from which they had come, such as
andcid=84040 and http://www.diabeteseducator.org/ physician orders, nursing notes, or laboratory reports.
ProfessionalResources/accred/.37,38 DSMT must be As described by Weed, the POMR consisted of
ordered by the provider (physician or non-physician) four essential components:
managing the patient’s diabetes. DSMT is a stand-
alone provision. This means the ‘‘incident-to’’ 1. defined database,
requirements do not apply to DSMT services. There 2. complete problem list,
are 10 hours of initial training, billed as G0108 3. initial plan, and
(individual) or G0109 (group), in 30 minute incre- 4. progress notes.
ments each. Two additional hours per year are
available thereafter. Diabetes programs exist in mul- Weed recommended that progress notes be further
tiple settings. DSMT can be billed from a hospital, organized to reflect the four types of information
hospital-based clinic, free-standing clinic, or commu- commonly found in clinical documentation. This has
nity pharmacy. Kentucky recently approved licensing come to be known as the SOAP approach to clinical
of diabetes educators. This licensing allows educators documentation SOAP as an acronym for Subjective,
to bill for DSMT directly to all payers. Similar efforts Objective, Assessment, and Plan.
have been proposed on the national level. If certified Subjective information includes a description of
diabetes educators (CDEs) were considered approved the problem and the associated symptoms in the
Medicare providers, pharmacist CDEs would have patient’s own words. These notes often contain ver-
another direct route to Medicare reimbursement, batim quotes from the patient (‘‘I feel hot and achy,
other than as a mass immunizer.36 – 39 and I have a splitting headache’’) and/or those close
to the patient, such as a relative or friend (‘‘She has
been complaining of fever and headache for a couple
Laboratory testing
of days’’).
Pharmacists providing point-of-care laboratory test- Objective information includes observations made
ing can bill for labs by obtaining a Clinical Lab- and data collected and/or considered by the caregiver
oratories Improvement Amendments (CLIA)-waived that is relevant to the problem, including physical
laboratory license. Particularly in chronic disease, exam or assessment or laboratory data (e.g., Patient
point-of-care testing allows for more rapid decision presents to the pharmacy in acute distress, complain-
making. Most often, results are available in less than ing of flu-like symptoms for the past 2 days. Com-
5 minutes, and running the test is minimally complex. plexion is pale, skin is warm and dry to the touch,
All laboratory tests have a specific CPT code, and all and temperature is 101◦ F orally).
laboratory tests must have a matching International The assessment component of the note allows
Classification of Disease (ICD-9) code. For example, the caregiver to express his or her net conclusion or
HbA1c for diabetes assessment is billed 83036 and opinion about the problem based on the subjective
is coded 250.00. A complete guide to establishing and objective information available (e.g., Patient’s
a CLIA waived lab license in outpatient settings is symptoms are consistent with flu). The assessment
available.40 note may be seen as a diagnosis, clinical impression,
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Social, behavioral, economic and administrative sciences | 533

or a change in the condition of the patient for better therapeutic goals should be documented in the
or worse. patient’s care plan. Ideally, an electronic medical
The plan component of the progress note record (EMR) would be utilized, as this is acces-
describes the recommended course of action based sible to all professionals involved in patient care.
on the new information considered by the caregiver. Meticulous documentation of patient care activities
This may include revising a previous plan or estab- performed by pharmacists must be maintained to
lishing a new plan and may contain recommended substantiate the level of service billed by the phar-
treatment, patient education/instruction, and/or the macist. Standardized formatting for documentation
need for additional information (e.g., recommended of MTM services exists; pharmacists engaging in
acetaminophen 650 mg every 4–6 hours, push fluids, the provision of MTM should familiarize themselves
and bed rest. If symptoms worsen, or if not improved with documentation requirements for reimbursement.
in 48 hours, patient is instructed to see physician). Multiple resources and websites available to pharma-
Many permutations of the SOAP approach to cists describe documentation specifically for MTM
clinical documentation have appeared over the years. programs.42 – 44
However, even under different acronyms, most are
essentially minor derivations of Weed’s simple, yet
effective approach. By organizing clinical documen- Pharmacist credentialing
tation in a logical and consistent format, SOAP
maintains significant advantages over unstructured Pharmacists participating in direct patient care activ-
approaches for ensuring greater accuracy and com- ities should demonstrate competency in the areas
pleteness of a patient care encounter. Additionally, of care provided. Board and/or continuing educa-
since the SOAP approach is widely used in the clin- tion certification programs should be completed by
ical training of many different health disciplines, it all pharmacists and documented in a retrievable for-
is likely more familiar and, therefore, more accept- mat. Examples of minimum requirements may include
able to health professionals and claims administrators demonstration of proficient communication skills,
working for third-party payers.42 basic physical assessment skills, laboratory interpreta-
Pharmacists should maintain and adequately doc- tion, and disease- and age-specific competencies. Min-
ument a comprehensive pharmaceutical care plan, imum requirements for level of education, experience,
preferably as a component of a multidisciplinary, col- and/or post-graduate training may be established for
laborative drug therapy agreement. The care plan, specific responsibilities or positions. A model for
if separate, must be accessible to prescribers, phar- ongoing evaluation should be developed to ensure
macists, and other healthcare providers involved in pharmacists remain competent.
patient care. The pharmacist is responsible for com- The Board of Pharmaceutical Specialties (BPS)
municating the plan to the patient and other health- has recognized six specialty areas of pharmacy prac-
care providers. The care plan should document the tice, including ambulatory care, nuclear pharmacy,
following: nutrition support, oncology, pharmacotherapy, and
psychiatry. The newest certification offered by the
1. patient’s medical and medication history; BPS is the Board Certified Ambulatory Care Pharma-
2. medication therapy assessment; cist (BCACP) designation. This exam was offered for
3. medication therapy regimen, including drug the first time in October, 2011.
name, strength, route of administration, and From patient to provider, the value of the
indication for therapy; BPS-certified practitioner registers throughout the
4. goal(s) of therapy; healthcare continuum. For pharmacy professionals,
5. monitoring parameters; and documentation of specialized experience and skills
6. proposed length of therapy. yields the additional benefits of personal satisfaction,
financial rewards, and career advancement.45
Ongoing assessment and evaluation of the Other disease-specific certification may be
patient’s response to therapy and achievement of obtained as a means to increase competency of
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534 | An Introduction to Pharmacy

pharmacists participating in MTM activities. The Medical claims and basic billing
certified diabetes educator (CDE) credential is
terminology
available to pharmacists, physicians, and other allied
health professionals. This credential recognizes a
One significant limitation to written documentation
healthcare professional is competent to provide dia-
is the difficulty in translating it into quantifiable data
betes education. For pharmacists involved in diabetes
consistent with claims administration systems. Sub-
management under collaborative practice agree-
mitting claims for services requires that key data
ments, the Board Certification-Advanced Diabetes
related to the care of the patient be converted by
Management (BC-ADM) credential signifies a phar-
standardized coding systems into recognizable codes.
macist is competent in pharmacologic management
Standardized coding systems exist that allow a claim
of diabetes. The American Association of Diabetes
to reflect what happened in a healthcare encounter.
Educators oversees this exam. To sit for the BC-ADM
examination, candidates must hold a current, active
RN, RD, or RPh license and hold a graduate degree Billing using the CMS-1500
from an accredited program, and, within 48 months
prior to applying, the applicant must complete a The CMS-1500 claim form is the most widely rec-
minimum of 500 clinical practice hours in advanced ognized and accepted format for billing third-party
diabetes management. The BC-ADM exam is offered payers for healthcare services. It is required by Medi-
in June and December of each year. Additionally, care and many other third-party payers for payment
pharmacists involved in anticoagulation management of healthcare services. The form consists of 33 boxes
can apply to the National Certification Board of or fields of required information. Fields 1–13 con-
Anticoagulation Providers to obtain the Certified tain information about the patient and the insured
Anticoagulation Care Provider (CACP) credential. beneficiary. The remaining 20 fields, 14–33, con-
Eligible disciplines include RN, Nurse Practitioner tain information about the provider or supplier of
(NP), registered or licensed pharmacist (BS pharmacy the service. Two fields on the form are particularly
or PharmD), licensed physician (MD or DO), or important for ensuring prompt and correct payment:
physician assistant (PA). The applicant must provide field 21 and field 24D.
documentation of a minimum of 750 hours of The first rule of third-party payment for healthcare
active anticoagulation patient management in the services is there must be a demonstrated medical need
18 months immediately preceding the application for the service performed. On the CMS-1500, need
deadline. is established by the patient’s diagnosis and related
background facts about the condition being treated.

National provider identifier International classification of diseases coding

The Health Insurance Portability and Accountability Field 21 on the CMS-1500 form is labeled ‘Diagnosis
Act (HIPAA) was passed by Congress in 1996 to set a or Nature of Illness or Injury.’ This field contains four
national standard for electronic transfer of all health slots, numbered 1–4, for entering patient diagnos-
data, even medical claims. To meet HIPAA compli- tic information using the ICD-9-CM (International
ance, all health professionals, regardless of discipline, Classification of Diseases, 9th Revision, Clinical Mod-
are required to obtain a national provider identifier. ification) coding system, commonly referred to simply
This number is unique to each provider and health- as ‘ICD-9.’ This reference is available through a vari-
care entity. Every pharmacist and pharmacy should ety of medical publishers.
have an National Provider Identifier (NPI) number. At least one diagnosis code must be reported on
Pharmacists can obtain an NPI by applying online at each claim. Up to four codes may be reported, if
https://nppes.cms.hhs.gov/NPPES/Welcome.do. The needed to accurately represent the reason for the
application process takes approximately 15 minutes, service that was provided. When more than one is
and the NPI number is received electronically within reported, the code that represents the disease, condi-
1 week.46 tion, or problem primarily responsible for the service
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Social, behavioral, economic and administrative sciences | 535

provided should be listed first. Any additional or sup- CPT Coding

plementary codes are listed after, in order of their Field 24D on the CMS-1500 form is labeled ‘‘Pro-
proximal relationship to the primary code. cedures, Services, or Supplies.’’ Payers who require
The ICD-9 coding system contains 19 categories the CMS-1500 require the use of Physician’s Current
of codes. Categories 1 to 15 (codes 001–779) iden- Procedural Terms (CPT) codes or the Centers for
tify diseases and related medical conditions. Category Medicare and Medicaid Services (CMS) Common
16 (codes 780–799) designates symptoms, signs, and Procedure Coding System. Although CMS recently
ill-defined conditions. Category 19 (codes 800–999) changed its name from the former Health Care
relates to injury and poisoning. Each of these cate- Financing Administration (HCFA), these codes are
gories contains numerical codes of three to five digits, still commonly referred to as HCPCS (pronounced
depending on the level of specificity and precision. hick-picks) codes. As with diagnosis, it is essential that
For example, undifferentiated asthma is coded as 493 pharmacists thoroughly understand the codes used in
in the ICD-9 system. For asthma with an allergic this field to describe the service that was performed.
cause, 493.9 would be the appropriate selection. An
The CPT codes were created by the American
additional fifth digit is also available if the patient
Medical Association in 1966 to be a listing of descrip-
does or does not have a history of status asthmaticus
tive terms and identifying codes for reporting medical
(i.e., 493.91 or 493.90, respectively). This system of
services and procedures performed by physicians. In
five-digit codes means the level of diagnostic preci-
1983, HCFA developed HCPCS as a uniform method
sion increases with each successive digit. With few
for healthcare providers and medical suppliers to code
exceptions, payers require the submission of diag-
professional services, procedures, and supplies to meet
noses coded to at least the fourth digit. Failure to
the operational needs of the Medicare and Medicaid
do so often results in payment delay or rejection. In
programs.
addition, other common coding problems include:
The HCPCS classification is organized into three
numbered levels of codes, each of which represents
• the patient’s chronic diagnosis, which is not the
a unique coding system. Most pharmacists who wish
reason for the encounter, is incorrectly billed as the
to bill for their patient care activities will find the
primary diagnosis;
CPT codes the most useful, especially that section
• the ICD-9 code selected is inaccurate or insuffi-
known as the Evaluation and Management, or E&M
ciently precise (i.e., not coded to the fourth or fifth
codes. Each five-digit numerical E&M code begins
digit when appropriate); and
with a ‘‘99’’ prefix (i.e., 99201–99499). The codes
• a supplementary code is used inappropriately as
are divided into several categories, including office vis-
the primary reason for the encounter.
its, hospital visits, and consultations. These categories
are further subdivided into two or more subcategories.
In addition to the previous 19 categories of numer-
For example, separate codes are available for an out-
ical codes, the ICD-9 system provides two cate-
patient office visit with a provider, depending whether
gories of supplementary codes. The first of these
the patient is established or new to the practice.
is the Supplementary Classification of Factors Influ-
E&M code selection is based on three key com-
encing Health Status and Contact with Health Ser-
ponents, with additional considerations becoming
vices (V01–V82), more commonly known as the
relevant only under special circumstances. Once the
‘‘V codes.’’ Of particular interest to pharmacists
appropriate category is selected (e.g., outpatient office
within the V codes are V58.67 – Encounter for long
visit with an established patient), the proper code is
term use of insulin and V58.61 – Long-term (current)
determined on the basis of:
use of anticoagulants. Adding a V-code to the claim is
similar to adding adjectives to further describe nouns.
Because there is no place for narrative description 1. the level of history taken on the patient (the
of the patient’s condition on the CMS-1500, it is par- four levels of history include problem focused,
ticularly important that code selection is as accurate expanded problem focused, detailed, and
and specific as possible. comprehensive;
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536 | An Introduction to Pharmacy

2. the extent of the examination that was performed Five different codes are available to describe an
(the four levels of examination include problem office visit with a new patient (99201–99205). Like-
focused, expanded problem focused, detailed, and wise, five codes are available to describe an office visit
comprehensive); and with an established patient (99211–99215). Many
3. the level of medical decision making that was pharmacists in the community practice setting find
required to perform the service (the four levels of that these ten codes fit most of their needs related to
medical decision making include straightforward, completing a CMS-1500 claim form.
low complexity, moderate complexity and high Table 12.3 illustrates how a provider would use
complexity). the three key components of history, examination, and
medical decision making to select the code that best
Selection of the level of medical decision making represents the nature of a patient care encounter. For
required is itself determined on the basis of three example, 99213 would be the most appropriate code
additional considerations: to describe an office visit with an established patient
that required expanded problem-focused history and
1. the number of diagnosis or management options, examination, and a relatively low level of medical
2. the amount and/or complexity of data reviewed, decision making.
and Under special circumstances, other considerations
3. the risk of complications and/or morbidity or become operative in code selection. For example,
mortality. when counseling or coordination of care activities

Table 12.3 Definitions of selected evaluation and management (E&M) codes

Codes for a new patient

office visit

E & M codes History Examination Medical decision making Time RVUs

99201 Problem focused Problem focused Straightforward 10 min .82

99202 Exp. problem focused Exp. problem focused Straightforward 20 min 1.32

99203 Detailed Detailed Low complexity 30 min 1.80

99204 Comprehensive Comprehensive Mod. complexity 45 min 2.66

99205 Comprehensive Comprehensive High complexity 60 min 3.33

Codes for an established

patient office visit

E & M codes History Examination Medical decision making Time RVUs

99211 Minimal problems 5 min .40

99212 Problem focused Problem focused Low complexity 10 min .71

99213 Exp. problem focused Exp. problem focused Low complexity 15 min 1.00

99214 Detailed Detailed Mod. complexity 25 min 1.55

99215 Comprehensive Comprehensive High complexity 40 min 2.53

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Social, behavioral, economic and administrative sciences | 537

account for more than 50% of a patient encounter, By the early 1980s, government third-party payers
selection of the proper E&M code among a sequence had concluded that the UCR (usual, customary, and
involving different levels of care is based exclusively reasonable) method of compensating physicians and
on the amount of time the provider spent with the other medical care providers was financially unsound
patient. For example, 99204 would be the most and encouraged abuse. This opinion was particularly
appropriate code to describe an office visit with an prevalent in the Medicare program, in which it was
established patient dominated by counseling and decided that a standard fee schedule was needed for
requiring about 45 minutes to complete. physician services. The result was the creation of
Table 12.3 illustrates the relative value unit scores an ongoing research project at Harvard University,
(RVUs) that CMS has assigned to each of the codes known as the RBRVS project.
using the resource-based relative value scale (RBRVS). The RBRVS project was an attempt to create a
The resulting RVU score is then regionally adjusted method of reimbursing physician services based on the
and multiplied by a monetary conversion factor to estimated resource input costs required to perform the
determine the dollar amount a provider will be paid services. The RBRVS used by Medicare to determine
for a particular service or procedure under Medicare. physicians’ fees defines the resource input costs as
As previously discussed, CPT codes specific to consisting of four components:
the provision of MTM are available and should be
1. the time required by the physician before, during,
used by the pharmacist when submitting charges for
and after the service;
services rendered to third-party organizations with
2. the intensity with which the time was spent;
whom contracts exist and who recognize pharmacists
3. the practice costs necessary to supply the service;
as providers of MTM services.
and
Additional information about CPT/HCPCS cod-
4. the opportunity costs of additional training or spe-
ing is available through the American Medical Asso-
cialization the physician may have been required
ciation, CMS, and various commercial publishers of
to complete to provide the service.
medical coding materials.47
The RBRVS combines these resource inputs into
a model intended to reflect the relative costs efficient
Fee setting and the resource-based physicians would incur providing a given service, if
relative value scale (RBRVS) a perfectly competitive market existed. Since it was
At present, there exists no widely accepted standard not considered feasible to gather data on all 7000
for assigning professional fees to pharmacist services. Medicare procedure codes, researchers surveyed 3000
For private pay patients, professional service fees are physicians in 18 specialties to determine the work
set by pharmacists in much the same way that other necessary to perform over 400 medical services. They
products and services are priced. Where these services then grouped the procedures into broad classes of
are covered by insurance or third-party benefit plans, services assumed to be relatively similar in terms
the pharmacist’s professional fees are determined in of resource inputs and extrapolated the results to
negotiation with payers. procedures that were not surveyed.
Many pharmacists who routinely bill major The general approach used in the RBRVS has
medical carriers for their services know that, under received widespread support from policymakers, as
the Medicare program, physicians’ fees are set well as some physician organizations. As a result,
by a resource-based relative value scale (RBRVS). it has been suggested that a similar approach may
Resource based relative value units (RBRVUs) are eventually be applied to determine the professional
assigned to each CPT code and, as such, are a measure fees of other providers, including pharmacists.42,48,49
of physician productivity in some settings. Because
some pharmacists using an ‘‘incident to model’’ pos- Claims for pharmacist services
itively impact the physician’s RVUs by generating the
99211 CPT code, it is useful to describe the RBRVS As discussed previously, most pharmacists success-
system within the context of general medical billing. fully billing third-party payers for their professional
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538 | An Introduction to Pharmacy

services are doing so through the major medical car- involvement in patient education, instruction, or dis-
rier using the CMS-1500 universal claim form. Rou- ease state management activities. Since there are often
tine payment for professional pharmacy services has no ‘‘hard dollar’’ savings to the prescription bene-
simply not made its way into prescription benefit plans fit plan from such services, the value created by the
in any meaningful way, since most prescription benefit pharmacist is likely better recognized and appreciated
managers (PBMs) continue to consider these services by that component of the patient’s medical insurance
beyond the scope of the prescription benefit plans plan concerned with the total care of the patient, and
they manage. Since the X12N 837 claim represents the total cost of that care. This is what is commonly
the electronic equivalent of the CMS-1500 form, the referred to as the ‘‘major medical’’ component of the
HIPAA ruling effectively eliminates National Coun- patient’s health insurance plan.
cil for Prescription Drug Programs (NCPDP) and its Pharmacists should consider filing the claim with
code sets from relevance in the future electronic billing the patient’s major medical insurance carrier when-
for professional pharmacy services, except where the ever they provide a service with which the primary
service is traceable to a particular prescription drug value is likely realized through positive patient health
claim, and is billed to a PBM. Clearly, there exists outcomes or the prevention of negative health out-
a split between prescription-related product billing comes and their related economic sequelae. Although
(NCPDP) and the myriad other professional cognitive each carrier has its own policies and procedures for
services pharmacists perform in their care of patients filing major medical claims, most require a CMS-1500
(CMS-1500, MTM). be submitted.42

Using the CMS-1500 to file pharmacist

care claims Future directions
First issued in the early 1980s, the CMS-1500 (i.e., Patient centered medical home (PCMH)
universal) claim form is the most widely recognized
The PCMH model is based on the premise that the
and accepted format for billing third-party payers
best healthcare is not episodic and illness-oriented.
for healthcare services. It is required by Medicare
Rather, high quality care is patient-centered,
and many other third-party payers for payment of
physician-guided, on-going, and cost-efficient.49 A
healthcare services. Still commonly referred to as the
PCMH is an interdisciplinary practice that promotes
HCFA-1500 (pronounced hickfa), the most recent
a partnership between a patient and his or her
version was released in August, 2005 and is illustrated
healthcare team. The physician, with the assistance
in Fig. 12.1.
of his/her practice team, helps the patient navigate
In deciding whether to use the CMS-1500 to bill
the complex and confusing healthcare system by
for pharmacist care services, the pharmacist should
coordinating and facilitating services with other
consider the nature of the service provided, as well as
qualified medical professionals.49
the payer to whom the claim will be submitted. Many
In 2011, the National Committee for Quality
pharmacist care services are discrete events that occur
Assurance (NCQA) updated the current standards
during the routine process of providing care, particu-
for recognizing a primary care practice as a PCMH.
larly prescription care, to patients. For some of these
The PCMH 2011 program’s six standards align with
services, the value created is confined primarily to the
the core components of primary care:
prescription benefit plan. For example, when a phar-
macist recommends a therapeutically equivalent, but • PCMH 1: Enhance Access and Continuity,
less expensive product to a prescriber, the value cre- • PCMH 2: Identify and Manage Patient Popula-
ated by the pharmacist is restricted to the differential tions,
in the ingredient costs of the two drug products. • PCMH 3: Plan and Manage Care,
In other cases, the value of the pharmacist’s pro- • PCMH 4: Provide Self-Care and Community
fessional service goes beyond, or is less likely to be Support,
recognized as directly relevant to, the prescription • PCMH 5: Track and Coordinate Care, and
drug benefit. An example would be the pharmacist’s • PCMH 6: Measure and Improve Performance.
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Social, behavioral, economic and administrative sciences | 539

Figure 12.1 The most recent version of form ‘‘HCFA-1500.’’

These standards specify that physician-led practices outcomes and promoting safe, cost-effective medi-
implement evidence-based care plans, use non- cation use for patients in medical homes.
physicians in care management, coordinate care Budnitz et al. reported that up to 32% of adverse
transitions, support patient self-management, and events leading to hospitalization were due to medica-
track test results and patient referrals.49 Pharmacists tions; furthermore, only 33 to 50% of patients with
can play important roles in optimizing therapeutic chronic conditions are adherent to their prescribed
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540 | An Introduction to Pharmacy

medications.50 Pharmacists can greatly impact for healthcare professionals and healthcare entities in
medication-related patient outcomes by contributing the years ahead.
to interdisciplinary care as the medication experts. The creation of pharmacy services terminology
Pharmacists can evaluate, through comprehensive and related electronic claims transmissions standards
medication review, the presence of therapeutic dupli- will help speed the evolution of new payment systems.
cation, response to therapy, adverse drug reactions, Likewise, the growing body of research in health out-
suboptimal dosing, and adherence-related issues, and comes assessment will allow the pharmacy profession
intervene to improve patient outcomes. to better communicate value to payers. Demonstrating
As the concept of PCMH continues to develop the value of pharmacists’ services to payers represents
and expand at the core of healthcare reform, pharma- a priority for pharmacy practice-related research in
cists can make substantial contributions to innovative, the years ahead.
collaborative, interdisciplinary primary care models.
Health-care professional teamwork is essential for
care coordination and quality improvement initiatives Pharmaceutical risk management
to optimize chronic disease medication outcomes and
promote medication safety.51 – 53
The new era of risk management
In the United States, drugs are approved only if they
are determined to be safe to use for the conditions
Conclusions
described in their label: This basic tenet of the Food,
Like pharmacy practice itself, documentation is a Drug, and Cosmetic Act (FDCA) has not changed.
learned skill. Increasingly, technology is assisting What has changed, though, in recent years is the
pharmacists to accurately and consistently document interpretation of the term ‘‘safe.’’ Modern concepts
the care they provide. However, repetition and prac- of pharmaceutical risk management are based on the
tice are required for pharmacists to develop good premise that drug manufacturers, healthcare profes-
documentation skills. Until recently, pharmacy curric- sionals, and patients have a responsibility to minimize
ula provided relatively little opportunity for students the risks of using pharmaceutical products. It is not
to develop their written communication skills. The enough to make drugs minimally safe; they must be
same can be said for the professional careers of as safe as possible over the lifecycle of the product’s
most pharmacists. Due to the pharmaceutical care use.54 – 56 This approach represents a role shift for
movement and the economic imperatives now facing the FDA, pharmaceutical manufacturers, and health
the profession, these conditions are rapidly changing. professionals to more proactive risk assessment and
Pharmacists who are participating currently or wish management by using special tools and programs to
to participate in patient-centered care and who expect support a product’s safe use.
to be paid for their activities must master the art of Historically, the FDA interpreted the requirement
clinical documentation and billing. that a drug must be ‘‘safe’’ to mean that the benefits
Pharmacists who wish to pursue compensation of a drug outweigh its risks. The determination was
for their professional services must recognize that suc- made on a ‘‘categorical’’ basis, in which the totality
cessful payment for pharmacist services is relatively of risks was weighted against the totality of benefits
new. Billing department personnel in most settings are when considered for the indications outlined in the
largely unfamiliar with mechanisms for pharmacist drug product’s labeling. If a drug did not meet this cri-
reimbursement. Most government and private third- terion, it was not approved or its label was rewritten to
party payers still do not have well-defined policies narrow the indications for use. This logic was endemic
for paying pharmacists for their professional services. in the FDA for most of the twentieth century. On aver-
This is not to say that payers have no interest in age, two to four drugs over each five-year period were
pharmaceutical care. Rather, for the most part, they withdrawn from the marketplace after post-marketing
simply do not understand what it is or how it will ben- surveillance data uncovered new risks.57 Similarly, on
efit them and their beneficiaries. Health reform will occasion, the FDA would require some special ‘‘tool’’
further define how care is delivered and reimbursed or intervention to improve a product’s safety profile.
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Social, behavioral, economic and administrative sciences | 541

For example, mandatory distribution of patient pack- • Patient monitoring

age inserts was instituted in 1976 to warn women • Patient enrollment in a registry.
about the risks related to birth control pill use,58 and
a special distribution system was instituted in 1990 to ETASUs are not to be ‘‘unduly burdensome on patient
limit the dispensing of Clozaril (clozapine) to patients access’’ to the drug, according to the law. Consid-
who underwent blood testing that demonstrated they erations are to be given to patients with serious
were not having a serious adverse reaction.59 How- or life-threatening diseases, and those in rural or
ever, beginning in the early 1990s, this philosophy medically underserved areas who may have difficulty
started to change as the FDA began to take a more accessing services. ETASUs are also not to be overly
active role in post-marketing surveillance and began burdensome on the healthcare delivery system and
instituting a more aggressive ‘‘management’’ process should be compatible with established systems sup-
to assure greater safety in the use of marketed drugs. ply chain distribution and dispensing systems. REMS
No longer do the manufacturer and FDA provide pas- also may have an implementation system to monitor,
sive oversight and labeling changes to control risks; evaluate, and improve elements to assure safe use.
now the manufacturer must actively monitor for sus- For generic drugs, REMS components are limited
pected, but unquantified, risks and actively manage to MedGuides, patient package inserts, and ETASUs.
and minimize known risks. However, if an innovator drug required a communi-
On September 27, 2007 the President signed into cation plan, then the FDA must require any generic
law the Food and Drug Amendments Act (FDAAA, PL drugs that are approved later to do the same. Generic
110–85).60 This Act granted the FDA new author- drugs use a shared ETASU system with the innovator
ity to require manufacturers to implement a Risk product as well, although a waiver can be granted.
Evaluation and Mitigation Strategy (REMS (can be REMS programs are legally enforceable, with
singular or plural)) when new drugs are approved or monetary implications. All REMS include evaluat-
when new risks are discovered for already approved ing the implemented risk mitigation interventions at
medicines. A REMS is a series of interventions that 18 months, 3 years, and 7 years after they are imple-
companies may implement to presumably lessen the mented. REMS programs may allow some products
risks of their therapies. There are three risk mitigation that might otherwise be withdrawn to remain on the
strategy levels outlined in the FDAAA: market because there are tools in place to manage
the product’s risk. Everyone involved in drug manu-
1. Distribution of a Medication Guide or similar facture, handling, prescribing, dispensing, or dosing
patient information booklet with the medicine, is responsible for ensuring compliance with REMS
2. A communications plan directed to health programs.
professionals, for example letters to healthcare The FDA must consider a number of factors in
providers/pharmacists, professional societies determining if a REMS is necessary according to
messaging, professional education, etc., and FDAAA, including
3. ‘‘Elements to assure safe use,’’ abbreviated as
ETASU, or a plan to control and limit the distri- • The number of people estimated to use the drug
bution of medicines to only qualified prescribers, • The seriousness of the disease or condition the
distribution centers, or patients who meet pre- drug will treat
defined criteria. • The expected benefit of the drug
• The expected or actual duration of drug treatment
The ETASUs may include • The seriousness of the drug’s known or potential
adverse events and the incidence of such events in
• Training/certification of prescribers the population likely to use the drug
• Training/certification of pharmacists/pharmacies • Whether the drug is a new molecular entity.
• Restrictions on where and how the drug is
dispensed If the Agency determines a REMS is necessary, the
• Evidence of patient safe use conditions drug product’s manufacturer has 120 days from
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542 | An Introduction to Pharmacy

Table 12.4 Number of REMS programs approved by the FDA

July 8, 2011 December 29, 2011

REMS element Total Total

Total REMS currently approved 149 105

MedGuide only 77 31

More than a MedGuide 64 57

Of those with more than a MedGuide:

Those with communication plan 46 36

Those with elements to assure safe use 30 31

Those with implementation system 26 26

Communication plan only 8 17

Products releases from REMS requirement 44 94

Source: FDA Web site: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm

notification to develop and submit it for FDA review. requirement.62 Table 12.4 summarizes REMS require-
Manufacturers can file disputes for resolution with ments at mid- and year-end 2011. It is becoming
the FDA Drug Safety Oversight Board, although none increasingly common for some form of risk man-
has been filed. A drug cannot be sold if it is in viola- agement intervention to be required for new chem-
tion of a REMS requirement, and the FDA can find ical entities approved for distribution in the United
it misbranded under the FDCA with accordant civil States.
penalties.
The FDA’s Drug Safety and Risk Management
Advisory Committee evaluates elements of each Pharmacoepidemiology and
REMS program annually and must seek input from pharmacovigilance
physicians, pharmacists, other healthcare profession-
als, and patients about program elements. This may Pharmacoepidemiology, or drug epidemiology, is the
lead to modifications in a REMS program. study of the effects of drugs in populations of people.
As of December 2011, 199 REMS plans have The discipline is an amalgam of clinical pharma-
been approved and implemented, with 94 products cology, clinical epidemiology, medical informatics,
released from REMS requirements, most of those and biostatistics. There are a number of reasons
occurring in mid–late 2011 because the FDA issued pharmacoepidemiology has recently emerged as a
new Guidance on ‘‘Medication Guides-Distribution discipline. Traditional clinical pharmacology directs
Requirements and Inclusion in Risk Evaluation and much of its attention to the pharmacokinetics and
Mitigation Strategies (REMS)’’.61 Of all the REMS pharmacodynamics of drugs. These studies involve
plans, the vast majority have included a Medication small numbers of subjects (6 to 25) who are studied
Guide requirement (88 in December 2011, down from intensively to obtain an understanding of drug absorp-
141 in July). Currently, 53 REMS include a com- tion, distribution, metabolism, or excretion. Studies
munications plan requirement, and 31 include the of these parameters determine the dose and frequency
elements to assure safe use (controlled distribution) of administration of new drugs in the treatment of
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Social, behavioral, economic and administrative sciences | 543

1.0

0.8

0.6

0.4

0.2

0.0
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000

Figure 12.2 Power as a function of sample size in two treatment groups. The study was designed to detect an event that
occurs in four out of 1000 patients in one group and one patient in 1000 in the other group.

patients, and are required before drugs are marketed. Figure 12.2 shows the effect of sample size on
However, such studies tell us little about certain expe- the statistical power of a study. In general terms, the
riences of drugs after they are marketed. It is in this ‘‘power’’ of a test is the ability of a statistical test
post-marketing phase that the tools of clinical epi- used in a study to detect a relationship between an
demiology come into play, especially in determining exposure (drug) and an event or outcome. The highest
the frequency of adverse drug effects. Pharmacovigi- value the power can have is unity, and the lowest is
lance is a subset of pharmacoepidemiology, involving zero. Figure 12.2 shows the power curve for a clinical
surveillance or drug monitoring to detect and assess trial in which the outcome of interest occurs in four
adverse drug events. of every 1000 patients in one treatment group and
Though new drug products undergo the careful in one in every 1000 patients in another treatment
scrutiny of Phase I through III testing, some drug prod- group. For clinical trials, it is desirable to keep the
ucts are recalled soon after they are marketed. There power of a study above 0.80. From Fig. 12.2, it can
are a litany of experiences, including phocomelia from be seen that fewer than 4000 patients in each group
thalidomide, Guillain Barré syndrome from influenza would yield insufficient power to detect a difference
vaccine, endometrial cancer from diethylstilbestrol, between groups, when alpha is 0.05 and a two-tailed
cardiac valve disorders from the combination use test is performed. Another way to interpret the curve
of fenfluramine and phentermine (Fen-Fen), anaphy- is to consider that an adverse effect occurred in 0.4%
laxis from zomepirac, hepatic failure from bromfenac, of patients receiving a drug, and the same adverse
and cardiac arrest from interactions from drugs like effect occurred in 0.1% of patients receiving placebo;
mibefradil or terfenadine when administered with more than 8000 patients would need to be recruited
drugs that inhibit P-450 CYP 3A4, such as ketocona- into the study to detect such an effect. The cost of
zole and erythromycin. More recently, the safety of such a study would be prohibitive.
rosiglitazone, pioglitazone, and a variety of NSAIDs Another important reason adverse events are not
has been called into question by pharmacoepidemiol- identified in the pre-marketing drug experience is
ogists. A major reason for these drug product recalls that, although subjects in pre-marketing studies have
is that premarketing studies treat too few patients the disease or disorder the drug is targeted to treat,
(typically 3000 to 4000) to detect uncommon drug they are otherwise healthy people. Typically, pre-
effects. An adverse effect that occurs in only 1 in marketing studies exclude patients who have compli-
25,000 persons would go unnoticed in only 4000 cating factors, such as renal or hepatic insufficiency,
treated patients in the pre-marketing phase. Yet once diabetes mellitus, or heart failure. Pre-marketing stud-
the drugs are marketed, they often reach millions of ies are conducted to determine the efficacy of a specific
patients and rare events can manifest. Hence, pre- drug often compared to a placebo. Such studies are
marketing studies have insufficient statistical power helpful to ascertain whether a drug works for a specific
to detect rare adverse effects. disease or condition (i.e., ‘‘Does it work?’’), but once
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544 | An Introduction to Pharmacy

the drugs are marketed, they often reach patients surveillance programs, including the FDA Sentinel
with a multitude of comorbidities and complicating Initiative,64 the Observation Medical Outcomes Part-
conditions. In this real world setting of care, treated nership (OMOP; http://www.omop.fnih.org),65 and
patients are sicker, and adverse drug reactions are the European Union Adverse Drug Reporting Program
more common. Post-marketing studies are conducted (EU-ADR; http://www.alert-project.org).66 Pharma-
to determine the effectiveness of a drug or an assess- coepidemiologists involved in these programs pool
ment of the drug’s effect in the typical setting of large claims and electronic health databases, contain-
patient care (i.e., ‘‘Does it work in real world care?’’). ing up to 300 million people, to determine the presence
This scenario has been a driving impetus behind the and magnitude of drug–event associations and detect
interest in comparative effectiveness research (CER), signals that could represent important new problems
which calls for the conduct of studies of commonly with marketed drugs. These programs have spawned
used drugs in the types of patients likely to receive a variety of new methods in pharmacovigilance.
those drugs in typical clinical settings. CER tells us Now that the interface between pharmacoepi-
which drug works best among available, marketed demiology and clinical pharmacology and clinical
alternatives and for what types of patients receiving epidemiology is clearer, the question remains as to
usual care. However, it is an especially broad concept. how medical informatics and biostatistics enter into
An Institute of Medicine panel defined CER as ‘‘the the mix. Health systems, such as managed care orga-
generation and synthesis of evidence that compares nizations, hospitals, clinics, and medical centers, gen-
the benefits and harms of alternative methods to pre- erate a large volume of data on patients. Increasingly,
vent, diagnose, treat, and monitor a clinical condition such data are captured and stored in huge databases.
or to improve the delivery of care. The purpose of Data found in these warehouses often come from
CER is to assist consumers, clinicians, purchasers, many sources, including the pharmacy, laboratory,
and policy makers to make informed decisions that radiology, and patient care clinics and wards. To con-
will improve healthcare at both the individual and duct studies of outcomes of patients who have been
population levels.’’63 The relevance of CER to phar- prescribed drugs requires merging these large files
macoepidemiology is particularly relevant in terms of from disparate sources. Such integrated databases are
determining beneficial and harmful drug effects at the becoming larger and richer. When datasets contain
population level. Several programs have evolved out millions of people with many clinical observations per
of the need for more rapid and valid data pertaining to person, super computers or cloud computing must be
adverse drug effects for new and previously marketed used to analyze the data. When such data are avail-
drugs within the realm of pharmacovigilance. able through time and are linked using a unique
Because adverse effects of drug products are more patient identifier, a variety of longitudinal studies of
commonly observed after marketing, the FDA created the effects of drugs in large populations of patients
the MedWatch Medical Products Reporting Program, (i.e., pharmacoepidemiologic studies) are possible.67
the largest drug and device surveillance program in the The analysis of such large temporal data sets requires
United States (http://www.fda.gov). A similar pro- the tools of biostatistics. The types of statistical
gram is operated by the World Health Organization procedures used in the analysis of data for pharma-
(WHO) for 86 countries, including the United States. coepidemiologic studies can range from simple counts
Such spontaneous report drug surveillance programs of events to sophisticated mathematical models.
are important for drug regulatory agencies to keep
their fingers on the pulse of the adverse drug expe-
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.hrm. (accessed March 2003).
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13
Patient care

Pharmacists and disease state management 547 Pediatric pharmacy practice 583
Development of a pharmacy care plan and Transplant pharmacy practice 585
patient problem solving 558
Pharmacogenomics in pharmacy practice 585
Specialization in pharmacy practice 562
Critical care pharmacy practice 586
Ambulatory care pharmacy practice 575
Infectious diseases pharmacy practice 586
Self care 576
Pain and palliative care 588
Diagnostic self-care 579
Assessing pharmacy-related quality of care 590
Complementary and alternative medical
healthcare 579 Long-term care 591

Preventive care 579 Chronic wound care 591

Substance abuse care 582 References 592

Emergency medicine pharmacy practice 582

targets and emphasizes patient education to encourage

Pharmacists and disease state
self-management. Typically, DSM programs focus
management on chronic disease states, such as diabetes mellitus,
chronic heart failure, and asthma. Only about 55%
Introduction
of Americans with chronic medical conditions receive
Disease state management (DSM) is a systematic care consistent with consensus guidelines, as reported
population-based approach to medical care that is in one study.1 The goal of DSM is to improve treat-
being used with increased frequency in a variety of ment outcomes such as reduction of symptom severity,
healthcare systems as an effort to standardize and morbidity, and hospitalization rate, while controlling
improve provider adherence to treatment guidelines. healthcare costs.
DSM programs tailor population-based outcomes to Both the aging US population and legislative man-
individualized patient care. Success in using the DSM date are promoting DSM growth. Four out of five
format for patient management is demonstrated by Americans live with at least one chronic disease.2 The
improved quality of care and outcomes that outweigh federal Patient Protection and Affordable Care Act
the resources used. (PPACA), passed in 2010, calls for reimbursement
DSM utilizes a multi-disciplinary model that structures that promote the development of DSM
employs evidence-based medicine to set therapeutic programs that improve the quality of care.3
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548 | An Introduction to Pharmacy

DSM has been defined by Zitter as ‘‘a comprehen- formulary management, retail and mail-order delivery
sive integrated approach to care and reimbursement systems, and benefit design and consumer cost sharing
based fundamentally on the natural course of a disease (e.g., copayments and coinsurance).
with treatment designed to address the illness with
maximum effectiveness and efficiency.’’4 Therefore, in
this management system, each patient may be proac-
Historical background
tively triaged at different stages in his or her disease Until the 1970s, the primary mode of healthcare
process, using a defined care plan established from reimbursement was through fee-for-service, whereby
evidence-based protocols or guidelines, rather than the insured enjoyed unrestricted access to all forms
a series of fragmented encounters with various parts of healthcare. In this model, healthcare costs sky-
of the healthcare system. This integrated approach rocketed, physicians relied largely on accumulated
is developed with a quantifiable economic structure individual practice experience for disease treatment,
and a defined quality improvement process. The Care and patient care interventions, rational or not, were
Continuum Alliance (formerly the Disease Manage- reimbursed. New technologies added to the cost of
ment Association of America, DMAA) is a non-profit healthcare, and in a fee-for-service environment their
membership organization founded in 1999 to repre- values were rarely assessed.
sent the disease management community. It defines Managed care was ‘‘born’’ as the diagnosis-related
those components needed for a quality disease man- groups (DRG) system was instituted in the early 1980s
agement program, as shown in Table 13.1.5 by the federal government as a means to rein in
Pharmacists can play an integral role in various healthcare costs, with beneficial results observed by
aspects of disease management care delivery and have the early 1990s (Fig. 13.1).8 Private payers, while
demonstrated success in doing so.6,7 As part of a watching their bottom line, also demanded that costs
prescription drug management program, DSM can be be curtailed. Neither the public nor private sectors,
used as one of the methods to control medication however, were willing to forego quality. Therefore,
utilization and pharmacy expenditures. Other meth- managed care is ever evolving to adapt to the seem-
ods include utilization management (e.g., quantity ingly diametric opposition of cost and quality.
limitations and prior authorizations), open or closed DSM is both an example of and a microcosm
for this evolution. Managed care first targeted hospi-
tal and physician costs, using once-novel approaches
Table 13.1 Disease Management Association of such as disease payment capitation and performance
America (DMAA) definition of what components incentives because these were and are the most costly
need to be included for full service disease components of healthcare. After hospital and physi-
management programs cian cost containment, managed care organizations
(MCOs) addressed prescription drug costs, which are
Components of a disease management program
the third most costly healthcare budget item. By the
• Population identification processes
• Evidence-based practice guidelines mid-1980s most large MCOs had prescription drug
• Collaborative practice models to include physician and management programs, either internally developed
support-service providers or contracted, with cost containment as their primary
• Patient self-management education (may include primary
focus.9 The skyrocketing cost of pharmaceuticals con-
prevention, behavior modification programs, and compli-
ance/surveillance)
tinues to be a driving force behind cost containment
• Process and outcomes measurement, evaluation, and measures employed by MCOs.
management Although quality and cost containment have
• Routine reporting/feedback loop (may include commu- always been mutual goals of managed care, skyrocket-
nication with patient, physician, health plan and ancillary
ing costs, coupled with a ‘‘silo’’ approach to hospital,
providers, and practice profiling)
physician, and pharmaceutical cost containment, had
a neutral – and sometimes negative – effect on quality
Full service disease management programs must include all six
components. Programs consisting of fewer components are disease care delivery. Consumers of healthcare began to
management support services. perceive a sacrifice in the quality of care to maintain
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Patient care | 549

20%
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
60
70
80
90
93
97
98
99
00
01
02
03
04
05
06
07
08
09
10
19
19
19
19
19
19
19
19
20
20
20
20
20
20
20
20
20
20
20
Figure 13.1 National healthcare expenditure as a precentage of gross domestic product 1960–2010.

the bottom line. The healthcare industry responded as a ‘‘minimum essential health benefit’’ to improve
with the development of DSM programs that would, health outcomes and reduce costs.2 However, the
if effective, integrate healthcare services across the theoretical benefits of DSM – improved care quality
patient care continuum, positively influence quality and cost containment – remain to be thoroughly
care, and maximize efficiencies that would lead to vetted through controlled studies. Interim results of
cost containment. the Medicare Health Support pilot program, launched
Initially, DSM programs were focused on sin- by congressional mandate in 2003 to test the viability
gle disease states as out-sourced products developed of DSM programs for improving cost and quality
by stand-alone vendors or by pharmaceutical man- for Medicare fee-for-service enrolees, has so far not
ufacturers. The next phase was characterized by demonstrated benefit.11
the consolidation of multiple disease state manage- Initial start-up costs for DSM are resource-
ment programs under one roof.10 Some industry intensive. It can be argued that health outcomes
examples include Diabetex, with its focus on dia- follow-up in studies to date have not been of sufficient
betes mellitus management, which underwent a name duration to flesh out cost benefit. It may also become
change to XLHealth as it expanded to become a apparent that some diseases are more amenable to
full-service DSM company. Another is Healthways, the beneficial effects of DSM than others. The recent
an internationally-present full service DSM company healthcare reform legislation promoting DSM should
that began as The Diabetes Treatment Centers of provide the DSM industry some breathing room to
America. Most recently, the industry has seen a sort out the answers to these questions.
consolidation of vendors, and increasingly, DSM pro- Certain diseases or treatments lend themselves to
grams are developed and/or operated through health- DSM (Table 13.2). They include those in which the
care systems (e.g., accountable care organizations, or disease course is well-defined and/or propel health-
ACOs) that work to identify proven processes for care costs. Chronicity, prevalence, available bench-
population health management and apply these to the marks or definable, measurable outcomes, variability
care of patients enrolled in their system. in treatment methodology, expensive therapies, and
As healthcare costs are again on the rise as a high incidence of non-adherence or preventable ther-
function of gross domestic product (Fig. 13.1), state apeutic misadventure are common characteristics.
and federal government interest is again keen on ‘‘Rare’’ diseases may qualify because DSM programs
exploring DSM to make inroads on improved cost and can centrally manage a large number of cases drawn
quality. The federal Patient Protection and Affordable from a broad geographic area. Table 13.3 is an adap-
Care Act of 2010 promotes chronic DSM programs tation of the list of most costly medical conditions
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550 | An Introduction to Pharmacy

by a pharmacist;14 significant improvement in A1C ,

Table 13.2 Appropriate medical conditions or
triglyceride, and LDL cholesterol levels in patients
characteristics to be targeted for a disease state
with poorly controlled diabetes, who were previ-
management program characteristics
ously unresponsive to usual care;27 and a reduction
• Well-defined disease course in all-cause mortality in patients with heart fail-
• High cost ure receiving medication evaluation by pharmacy.16
• Chronic diseases or conditions Additionally, models exist showing that pharmacist-
• High frequency
directed care can also serve to improve patient medica-
• Available outcomes benchmarks
tion adherence, ensure appropriate drug use, decrease
• Measurable outcomes
• Treatment methods variable expenditures, and improve access to necessary drug
• High incidence of non-adherence therapy.28,29 There is increasing evidence that the
• Preventable therapeutic misadventure is common or catas- participation and intervention of pharmacists in the
trophic
direct care of the patient has a positive influence on
• Rare occurrence
patient outcomes.30
Schools and colleges of pharmacy voted in 1992
to adopt the six-year Doctor of Pharmacy degree as
the only professional degree in pharmacy. Around the
Table 13.3 Total Expenses for Selected same time, the profession of pharmacy began moving
Conditions by Type of Service: United States, toward a patient-centered, outcome-oriented practice
2010 (the pharmaceutical care model as first outlined
by Hepler and Strand) and away from product-
Condition Ranking Expense ($ million)
orientation as a primary focus.15 This patient-
Heart conditions 1 107,186.40 centered practice resulted from advances in
information technology, the implementation and
Mental disorders 4 73,060.24 increasing role of pharmacy technicians, and the
evolution of pharmacy automation. These changes
COPD, asthma 5 63,782.99
place pharmacists in a unique position to broaden
Diabetes mellitus 7 51,310.57 their scope of practice and to increase services, where
appropriate, as collaborative care providers with a
Hypertension 8 42,943.38 goal toward maximizing health-related outcomes and
minimizing potential drug therapy problems, while
assuring cost-effective care. Healthcare administra-
tors, physicians, ancillary care providers, and the
treated in the United States in 2010 to show DSM- public are increasingly recognizing the unique training
appropriate conditions.12 – 25 and knowledge that pharmacists have in support of
these activities.
Requirements for pharmacists who are involved in
Pharmacists and disease state
DSM vary from state to state and among healthcare
management
organizations. For pharmacists desiring to expand
It is well documented that pharmacotherapy-related their scope of practice into a specialty area, training
outcomes can be improved with implementation of beyond the pharmacy degree and subsequent licen-
protocol-driven disease management programs by sure is becoming increasingly necessary to achieve
pharmacists in collaboration with other healthcare that goal. Typically, pharmacists involved in DSM
providers. Noteworthy examples include an increased have advanced training either through a residency,
percentage of patients achieving National Cholesterol or fellowship, or by acquiring additional skills from
Education Program LDL cholesterol targets following years of experience. Various credentialing and cer-
lipid-optimization;21,22,26 a reduction in the length tification programs exist that provide some of the
of hospitalization in patients taking warfarin guided foundations needed for effective DSM participation.
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Patient care | 551

The Council on Credentialing in Pharmacy (CCP), glucose and cholesterol screening (requiring a Clin-
founded in 1999, is a coalition of 12 national organi- ical Laboratory Improvement Amendments waiver),
zations and serves as a coordinating body for cre- vaccine provision, blood pressure monitoring, and
dentialing programs. CCP serves as a good resource education on smoking cessation or asthma manage-
for currently available credentialing and certification ment. In this role, pharmacists apply ‘‘pharmaceutical
programs, with further information available at http:// care’’ principles to manage patients with chronic med-
pharmacycredentialing.org/ccp/index.htm. ical problems. They may make recommendations to a
The Board of Pharmaceutical Specialties (BPS), primary care or specialty physician or may prescribe
and the Commission for Certification in Geriatric drug therapy under protocol.
Pharmacy (CCGP) are among agencies that offer State law determines the level to which a pharma-
certification to pharmacists in specialty areas. The cist can be involved in DSM or similar services, such
BPS, established by the American Pharmaceutical as when prescribing or changing drug therapy under
Association (APhA) in 1976, certifies pharmacists in protocol, and laws vary between states. In California,
six practice concentrations: ambulatory care, nuclear upon a physician’s patient-specific authorization or
pharmacy, nutrition support, oncology, pharmaco- under protocol, pharmacists are authorized to initiate
therapy, and psychiatric pharmacy. Added qualifica- or adjust a drug regimen and order or perform rou-
tions in either infectious diseases or cardiovascular tine drug therapy-related patient assessments, such
pharmacy are also available for pharmacists certified as vital signs, order drug therapy-related laboratory
in pharmacotherapy. The CCGP, established by the tests, and administer drugs and biologicals by injec-
American Society of Consultant Pharmacists (ASCP) tion, including immunizations. Prior to performing
in 1997, supervises the certification program in any of these activities, the pharmacist shall have
geriatric pharmacy. Additional information for each successfully completed clinical residency training or
of these agencies is available at http://bpsweb.org/ demonstrated clinical experience in direct patient care
specialties/qualification.cfm and http://www.ccgp.org/ delivery.32 While some states require advanced educa-
respectively. tional training, others are more stringent and require
board approval, notification, or registration for col-
laborative practice agreements. It is paramount that
A pharmacist’s role
pharmacists know the precise rules and regulations
Three strategies have been described9 that, if fol- within their home state in order to take advantage of
lowed, should help pharmacists develop practices DSM opportunities.33
that embody pharmaceutical care and DSM. First, Pharmacists’ extensive training in pharmacology,
careful planning of provided services should be car- pharmacokinetics, pharmacodynamics, and pharma-
ried out with buy-in from collaborative partners (e.g., cotherapeutics makes them uniquely qualified to
third party payers, physicians, and ancillary staff) evaluate drug literature. Drug information activities
and patients. Second, close communication should be performed by managed care pharmacists are used
maintained with the primary care physician regard- to support drug utilization review or medication
ing each patient’s care. Finally, clear documentation use evaluation, as well as formulary management.
of processes and outcomes should be maintained, All are important components for devising cost
and these outcomes measured against a reasonable containment and utilization management strategies.
benchmark. These activities are also used to support an evidenced-
Pharmacists are positioned well to take a sig- based approach to DSM for developing population-
nificant role in DSM because effective drug therapy based treatment plans and protocols. Further,
is integral to managing most conditions targeted in pharmacists conduct physician and allied health
these programs. Many examples exist that support professional education to offer a balanced assessment
the role of the DSM pharmacist in the commu- of supporting literature and facilitate the team’s
nity pharmacy, hospital, managed care, and other buy-in of the treatment plans.
non-traditional practice settings.31 The DSM services Pharmacists may serve as care managers in a DSM
that pharmacists may provide vary and can include program. This is particularly advantageous when the
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552 | An Introduction to Pharmacy

drug therapy regimen used to treat the disease is sus- these skills and prepares pharmacists for independent
ceptible to drug–drug, drug–food, or drug–disease research.
complications. As detailed in the literature refer-
enced in Table 13.4, DSM programs that incorporate Components of a successful DSM
pharmacists as care managers have been success- program
fully deployed to patients with various conditons
There are certain characteristics that successful DSM
and concerns, including treating diabetes mellitus,
programs share. A reliable and extensive medical
depression, smoking cessation, cardiovascular risk
informatics infrastructure allows for easy access to
reduction, anticoagulation, and hypertension.
patients and their medical records. This includes
Careers in health informatics, pharmacoeco-
telecommunications, computer networking, and data
nomics and outcomes research provide other storage. Care managers working within a DSM pro-
expanded opportunities for pharmacists in DSM. gram may monitor patients’ progress using telephone
Pharmacists in these roles use their enhanced surveillance and/or web-based telephone data collec-
analytical and research skills to determine the value tion devices. Integrated data collection and storage
of medications for the treatment and prevention across the continuum of care, though not required,
of disease, and the research may involve either a best serves the practitioners of DSM for patient
drug-specific focus or population-based healthcare follow-up and for reporting cost and quality out-
delivery. Most pharmacy schools provide a solid comes. Complete data that are accurate and timely
background in science, therapeutics, and economics are essential to the success of a DSM program.
necessary for this enhanced role. Postgraduate train- Data collected should be analyzed and compared to
ing (e.g., graduate study and fellowships) enhances benchmarked data points when available [as, for

Table 13.4 Published reports of pharmacist involved in disease state management (DSM) programs

Disease State Findings Reference

Asthma Significant reduction in ER visits, hospital admissions, total asthma-related costs, Bunting and Cranor13
disease severity classification, FEV1

Anticoagulation Significant reduction in length of hospitalization Dager et al.14

Significant reduction in total hospital costs Mamdani et al.15

Heart failure Significantly lower all-cause mortality Gattis et al.16

Significant decrease in hospital readmissions Riegel et al.17

ICU patients Decreased bleeding, mortality and ICU LOS MacLaren and Bond.18

Significant reduction in preventable ADEs Leape et al.19

H. pylori Cost-avoidance of $95 per patient Segarra-Newnham and Siebert20

Hyperlipidemia Improved attainment of LDL-C goal Palmieri et al.21 , Ito et al.22

Diabetes mellitus Reduction in mean HbA1c , total healthcare costs, increase in patient self-care Garrett and Bluml23

Hypertension Significant improvement in systolic and diastolic BP Santschi et al.24

General DSM Decrease total monthly medical costs Munroe et al.25

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Patient care | 553

example, from the National Committee for Qual- time and patient discomfort) should be reduced.
ity Assurance’s (NCQA) Health Plan Employer Data In contrast, a DSM program that increases total
and Information Set (HEDIS)] to demonstrate qual- healthcare costs with improvement in outcomes may
ity outcomes. Medical claims, clinical, and human- be at odds with the goal of the healthcare system.
istic (satisfaction) data are all useful data points Patient and physician education helps ensure that
to benchmark. a DSM program is successful. Patients are empowered
As mentioned previously, one of the basic princi- through learning about their disease. Signs of proper
ples of DSM is identifying and offering a patient the therapeutic management, as well as therapeutic mis-
best care for their disease. Successful DSM programs adventure, enable the patient to stay out of trouble if
base goals on evidence-based outcomes. They incor- they are taught how to identify these. Likewise, physi-
porate treatment guidelines to reduce the amount of cians are more apt to incorporate proven therapeutic
variability in practice that can lead to cost and qual- modalities into patient care if they are informed of
ity inefficiencies. Development of treatment guidelines evidence-based best practices.34
should be a cooperative consensus of all disciplines Finally, continuous quality improvement (CQI)
involved, as well as expert opinion and evidence processes should be incorporated into the practice
from the scientific literature (e.g., using published model to monitor and enhance care practices. Com-
evidence grading). pliance with guidelines and assessment outcomes
Care in a DSM program should be physician- (humanistic, clinical, and economic) should be eval-
directed, yet take advantage of the expertise of a multi- uated periodically and new evidenced-based infor-
disciplinary healthcare team (mid-level providers and mation needs to be incorporated into the treatment
pharmacists) to improve care and cost efficiency. guidelines as well.
Proper use of ancillary care for patient monitor-
ing and management can improve quality, reduce Development of a DSM protocol
care costs, and have a positive effect on physicians
workload, making room for patient visits requiring The Protocol
diagnosis-related activities. One of the first tasks for the pharmacist planning
Acceptance of the program by the primary care to provide DSM is a detailed and specific protocol.
physician and/or health plan is of paramount impor- Generally, this would be specific to a particular disease
tance to the success of a DSM program. Autho- condition or area. The protocol should spell out in
rization from one or both entities is required for detail the responsibility of the pharmacist and specific
patients to have access to the DSM program. A key endpoints for drug therapy.
to acceptance may include shared risk, which also The pharmacist wishing to develop such a pro-
includes shared cost savings. Changing prescribing tocol need not start from ‘‘ground zero.’’ Numer-
patterns and adherence to treatment guidelines might ous examples of DSM services and protocols have
be enhanced by reasonable financial incentive. In addi- been published or are readily available from national
tion, the practitioners affected by DSM programs need organizations (see Table 13.4).
to be included early in development of the program The protocol should clearly define pharmacist
to gain their support. responsibility, including prescriptive privileges, au-
DSM programs should be financially viable. As thority to order and monitor selected laboratory
such, demonstrable outcomes are only part of the indices, and consultation privileges. In addition,
story. They must be couched within a reimbursement patient follow-up intervals and outcomes expected
system that acknowledges benefit of integrated care of pharmaceutical care should be included. Quality
delivery. For example, payers should recognize that improvement measures may also be included as part
the costs for pharmaceuticals (e.g., beta-blockers of the protocol and are highly recommended, as
and angiotensin converting enzyme inhibitors) discussed above.
may increase in a DSM program targeting chronic Documentation of the DSM activities in the
heart failure, but that other, offsetting costs (e.g., patient care record is also a key element. Without
hospitalizations, surgical procedures, lost productive proper documentation the pharmacist will be unable
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554 | An Introduction to Pharmacy

to manage accurately and safely the patient’s prior to being dropped from the service need to
disease condition. In addition, without adequate be established.
documentation the pharmacist will be unable to Periodic review and update of the protocol is
obtain compensation for services as well as determine also essential. The ultimate goal is a DSM protocol
the economics of the program. Finally, programs that is dynamic, current with evidence-based medical
with poor or absent documentation of patient care care, and designed to be easily applied to the care
activities may run afoul of various regulatory bodies of patients.
such as the Centers for Medicare and Medicaid
Services (CMS, formerly the Healthcare Financing
Collaborative Agreement with Health Providers
Administration, or HCFA), the Department of Health Pharmacists who desire to establish DSM programs
and Human Services (DHHS), and the Joint Commis- must be willing to invest time and energy to estab-
sion on Accreditation of Healthcare Organizations lish strong, professional working relationships with
(JCAHO). Documentation of the complexity of the other healthcare providers and staff members. DSM
interventions should be included, such as details programs may also include additional service pro-
about the amount of time spent with a patient and visions (e.g., behavioral health, nutrition screening,
the extent of the examination. or other patient monitoring services) to fulfil more
Objectives within DSM protocols should be real- patient specific needs, so collaboration with those
istic. Unrealistic objectives that have a low likelihood having expertise in select specialties is also key.35
of being attained will serve to frustrate the pharma- Typically one individual caregiver does not have com-
plete patient information. Coordinating services with
cist and disappoint the patient. Of equal importance,
other providers helps assure the DSM program is
failure to meet one’s objectives while increasing the
comprehensive and the care of the patient is seamless.
utilization of resources will be a conflict for one’s
Several keys to building working relationships are
healthcare system.
being responsive, doing more than what is expected
As mentioned in the previous section, when devel-
of the pharmacist, and being willing to spend time
oping DSM protocols and determining objectives
with patients. Most often, examples of pharmacists
for such services, pharmacists should consult clin-
providing DSM involve the pharmacist having iden-
ical practice guidelines established by government
tified a physician ‘‘champion’’ or advocate for his
agencies, professional organizations, or international
or her activity. Often this individual is a general
bodies. Historically, such guidelines are evidence-
practitioner in primary practice or a specialist in a
based and comprise a consensus of experts in a
particular disease area (e.g., cardiologist or endocri-
disease area or diagnosis group. A comprehensive
nologist). In addition, support from physicians higher
database of evidence-based clinical practice guidelines up the administrative hierarchy can be invaluable
and related documents is available online through in allowing the pharmacist to establish and man-
the National Guideline Clearinghouse at http://www age disease-specific clinic activities and/or clinics.
.guidelines.gov, supported by the Agency for Health- Physician support is now trending towards collab-
care Research and Quality. orative practice. Data presented by the American
The protocol should make some effort to define College of Physicians – American Society of Internal
the organizational structure of the DSM program Medicine shows that physicians support pharmaceu-
or clinic. The schedule of the clinic (days meeting, tical care services and pharmacists’ involvement in
hours of clinic), how patients are checked in or collaborative care.35
out and screened, and the time periods allotted for If pharmacist services are contracted, a collabo-
appointments should be included. Consideration rative practice agreement with a provider should be
must be given for the amount of time necessary established as part of the DSM protocol. When estab-
to consult new patients versus returning patients. lishing collaborative practice agreements, pharmacists
Policies for handling patients who do not keep and physicians must evaluate their needs to determine
appointments, for the rescheduling of patients, and the types of services the pharmacist will provide. The
for the number of times a patient can be rescheduled majority of states have passed legislation that allows
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Patient care | 555

pharmacists to practice collaborative drug therapy the pharmacist. There are numerous Windows-based
management with physicians. However, even without software programs available to support pharmacist
legislation most medicine and pharmacy practice acts DSM documentation efforts in the acute, subacute,
are broadly worded to allow collaborative practice and ambulatory care areas. There is little reason,
arrangements (including drug therapy management) in this era, to utilize paper forms for processing
to exist between pharmacists and physicians. As previ- this information. Every effort should be made to
ously discussed, some states may require pharmacists computerize all documentation and interventions of
credentialing in DSM to practice under a collabo- the pharmacist. Online documentation submission
rative agreement with a physician. The pharmacist and systems integration is also becoming easier with
will need to evaluate his or her own individual the continued progression of many institutions and
state requirements. physician clinics towards ‘‘electronic’’ medical record-
keeping. The Veterans Affairs Medical Centers, for
Promoting/Influencing Stakeholders example, have been utilizing electronic medical notes
Once the DSM protocol has been developed, the and medical record for several years.
pharmacist must consider promoting their services If paper documentation is necessary, the phar-
and influencing stakeholders (e.g., patients, physi- macists should be certain to develop forms or use
cians, and the MCO). This may require tremendous a documentation style which reflects the complexity
educational efforts in some cases. As mentioned in of the intervention. Use of a SOAP format (subjec-
the previous section, a physician ‘‘champion’’ will tive, objective, assessment, plan) remains a common
be essential to develop a favorable partnership with format for payer reimbursement consideration.36 All
the stakeholders. The pharmacist must be prepared documentation should be clear and concise, pre-
and flexible enough to meet the concerns of all serve patient confidentiality, and include standardized
stakeholders. The collection of member and provider detail (e.g., the amount of time spent with a patient,
satisfaction data will help to ensure the longevity of the extent of an examination, or the medical deci-
the program. sion making involved). This allows for good patient
management and appropriate billing consideration.
Requisite Equipment and Set-Up
The minimum equipment and space required to prac- Billing and Reimbursement
tice DSM is a private area to interview and examine Pharmacists have faced challenges when attempting to
the patient. An examination room in a clinic or physi- seek reimbursement for DSM services, although recent
cian’s office may be available for this purpose. In the improvements in this process are noted. Traditionally,
case of a clinic that is telephone surveillance-based, a pharmacists have been restricted in their ability to bill
private desk area that includes a telephone and per- for DSM, and there have been discrepancies in com-
sonal computer is necessary. If not already available pensation for their services.37 Despite these problems,
in the examination area, a small desk, several chairs, some pharmacists have been successful in submitting
and electrical power access will be required. This addi- claims for reimbursement to insurance companies for
tional space would be required for equipment, such as DSM while others have found patients willing to pay
computers, and to allow for processing of paperwork. directly for these services. Still others use DSM as a
In addition, a combination television/DVD player is a way to differentiate their pharmacy from the compe-
very helpful option in case instructional videos need tition, increasing the loyalty of their patients and, in
to be viewed by the patient. The ideal situation would turn, their prescription and over-the-counter sales.
be a separate interview/counselling room that would Pharmacists can use a variety of mechanisms
also double as the pharmacist’s office. to obtain reimbursement through the Centers for
Medicare and Medicaid Services (CMS) that over-
Documentation and Forms sees Medicare and Medicaid financing. These include
Documentation is a key element of DSM. Before new Current Procedural Terminology (CPT) codes
initiating the service forms should be available that for pharmacists, ‘‘incident to’’ billing, under an out-
document accurately and adequately all activities of patient technical component using ambulatory patient
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556 | An Introduction to Pharmacy

classification (APC) codes, or for outpatient diabetes to 99215 is controversial and may be determined by
self-management training as part of a multidisci- regional payers. Pharmacists in some states providing
plinary team. pharmacy DSM services are billing at the higher CPT
CPT codes for pharmacists were initially approved codes and getting reimbursement from payers (e.g.,
for the provision of medication therapy management Medicare).
(MTM) services through the Medicare Part D drug Medicare initiated a prospective payment system
benefit. Initially established as a five-year pilot on Jan- for reimbursement of the technical component (i.e.,
uary 1, 2006, this became permanent as of January 1, facility fees) of outpatient visits in July 2000. Reim-
2008.38 These codes enable the billing of government bursement for outpatient services is procedure-based,
healthcare programs, managed care organizations, whereas inpatient is diagnosis-related reimbursement.
and other payers for pharmacists’ clinical services, Medicare-approved providers continue to bill profes-
including MTM and DSM. CPT codes are published sional services retrospectively. This new system sets
by the American Medical Association with the intent consistent reimbursement rates for outpatient services
to be used for the listing and coding of medical, and charts nonprofessional procedures performed to
surgical, and diagnostic services.39 known patient-care level APC codes. APC stands for
These new CPT codes are to be used to bill Medicare’s Ambulatory Payment Classification. Since
only for services performed face-to-face between a pharmacists cannot bill as a provider, their services
pharmacist and a patient. Code 99605 is used for a become part of the overall facility reimbursement. The
first-encounter performed face-to-face with a patient, pharmacist’s time to provide care increases the tech-
in time increments of up to 15 minutes, while Code nical level, allowing reimbursement which is often
99606 is for services provided to the same patient for several times higher than the lowest ‘‘incident to’’
time up to 15 minutes for a subsequent or follow-up physician fee. In January 2001 CMS (then HCFA)
encounter. Code 99607 is an additional code used finalized rules on Medicare coverage of outpatient
to bill for additional increments of 15 minutes of diabetes self-management training, which allows pay-
time following use of the other two codes. MTM ment of the pharmacist for diabetes training as part
services provided can include a review of the patient’s of a multidisciplinary team.
medical history and medication profile, development Payment for professional services for community
of an action plan, interventions, recommendations pharmacists is more challenging, but opportunities
for medication therapy optimization, referrals, and continue to improve. Pharmacists approved by CMS
compliance assessment, as well as provider and other as immunization providers may bill for immuniza-
communications pertinent to the patient’s care. The tions. The first step in billing for services is to
codes are not to be used for standard patient coun- obtain a Medicare provider number to allow for
selling during prescription dispensing.39 billing. Provider status can be obtained through local
In institutions and physicians’ offices, the phar- Medicare offices, which also process CMS claims for
macist can continue use of the physician provider reimbursement (CMS-1500 claims) or electronically
number (‘‘incident to’’ billing) to seek payment for submitting through the CMS website at http://
professional services. Pharmacists under collabora- www.cms.hhs.gov. Pharmacists should review each
tive practice agreements would bill under the CPT third party plan’s coverage and reimbursement poli-
counselling code series 99211 to 99215 (levels I–IV) cies for immunizations as a cost-effective preventative
for the assessment and management of patients ‘‘inci- measure for patient care. Other options are to charge
dent to’’ the physician visit, most often using the CPT a professional fee. Some pharmacists, particularly in
code 99211 (reflecting a 5 to 15 minute consulta- community pharmacy, have found success billing a
tion). Specific requirements must be met in order to professional fee directly to the patient.
support a pharmacist’s use of these billing codes, for
example, only if the encounter occurred in a clinic
Potential barriers
with the physician present. The rules for billing vary
from state to state and by regional Medicare payers. Potential barriers to DSM practices have been alluded
Billing at a higher CPT code for services such as 99212 to or discussed in some detail in previous sections.
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Patient care | 557

The main barriers are acceptance by other providers of provider satisfaction, program profitability, and goal
the services of the pharmacist and the reimbursement attainment. Some DSM programs may increase drug
issues covered above. utilization but lower total healthcare costs by reducing
Each discipline that participates in the DSM pro- hospitalizations and emergency room visits. Thus, a
gram will have different interests, goals, and views. It means for measuring DSM program outcomes should
is not critical that there is total agreement on every be incorporated into the plan.
issue. However, trust is one of the most important
elements to be established and confirmed in order to
Quality assurance
overcome obstacles.
Pharmacists earn the acceptance of other pro- Evaluation of Outcomes
viders by investing the time and energy to create strong Evaluation of health outcomes is the ultimate mea-
professional relationships. The pharmacist must be sure of success of DSM. Measures of health outcomes
engaged and willing to spend time providing direct should be an essential part of the management pro-
patient care. tocol. Usually, the initial step is a baseline evaluation
Successful reimbursement strategies must include of current indicators of performance for disease con-
thorough documentation of the care provided and trol and outcome. Measured outcomes of the DSM
adherence to proper and legal billing requirements. program may include well-known indicators of dis-
Specific reimbursement strategies may include ease control such as glycosylated hemoglobin, blood
‘‘incident-to’’ billing to CMS and other third-party pressure, or lipid concentrations, as well as sec-
payers, direct third-party pharmacy contracting for ondary complications, hospitalizations, quality of life
services, MTM, and direct fee for service. (QOL), patient and physician satisfaction, mortality,
or healthcare costs. As mentioned previously, these
outcomes should be benchmarked to measures such
Business plans
as those from NCQA HEDIS or TJC.
It is common for pharmacists in managed care and In addition, measuring process-oriented out-
at private healthcare facilities to create a business comes, such as percentage of patients treated to
plan when considering the incorporation of DSM ser- established guidelines which are a component of the
vices into their current practice. The business plan DSM protocol may be another useful measure of
may contain some background and description of service quality. After implementation of the program,
the service, market analysis and strategy, operational outcomes assessment leads to continuous modifica-
structure and process, financial projections, mile- tion of the program from feedback and constantly
stones, schedule, action plan, risks, opportunities, updated practice standards.
conclusions, and any supporting documentation. The One of the dichotomies of pharmacists’ activ-
plan should emphasize total care (and costs of care) ities in DSM is that, to improve overall patient
for the patient while de-emphasizing the traditional health and outcomes, increasing the overall quality
product-oriented ‘‘distribution’’ role of the pharma- of care may require the need for increased prescrip-
cist. Key to the plan is correctly identifying the viable tion costs through increased utilization. Success is
patient market (disease state) that matches the needs demonstrated when overall healthcare savings, recog-
of the providers and healthcare organizations in the nized by maximizing medication efficacy, offset the
area that may serve as a DSM provider. This niche overall costs.23,24
should also be within the pharmacist’s area of interest More difficult measures of quality of care asso-
or at least not fall too far outside the ‘‘trainable’’ area ciated with DSM include reduction of disease events
of expertise. and mortality. Because long-term outcomes require
A continuous evaluation of the impact on current longer-term data collection and a concurrent con-
practice is important. There should be a plan of action trol group (using historical controls have their own
for continuously monitoring the program’s impact on inherent problems), which are not always practi-
other aspects of the pharmacy business, including cal, intermediate outcomes (i.e., LDL cholesterol) are
but not limited to impact on staffing, patient and often substituted.
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558 | An Introduction to Pharmacy

Final measures of quality of DSM services are practitioners. Examples include introductory phar-
humanistic (patient-specific) outcome measures such macy practice experiences, emphasis on medication
as patient satisfaction, QOL measures, and func- therapy management, and training for immunization
tional status. Patient satisfaction may assess numerous delivery. Students must identify their current roles,
aspects of a DSM services, including satisfaction with as well as anticipate future opportunities in the ever-
clinic process and waiting times, pharmaceutical care, changing healthcare system. Further, students’ didac-
disease control and endpoint attainment, and provider tic experience should include elements that develop
communication. and nurture their knowledge, skills, attitudes, and
values. One central concept that often forms the
framework for this approach to learning is that of
Summary pharmaceutical care.
Many diseases go untreated or are not managed opti- On the surface, pharmaceutical care appears to be
mally in the United States and other countries. DSM a straightforward concept. It involves the pharmacist
programs can be used as an effective strategy for working in concert with his or her patients and other
enhancing patient outcomes and reducing manage- healthcare providers to identify, monitor, and achieve
ment cost of diseases by ensuring consistent care desirable health-related outcomes through the appro-
using evidence-based treatment algorithms or proto- priate use of medications. While many consider the
cols. Multidisciplinary care is a hallmark of DSM, first reference to modern-day pharmaceutical care to
and pharmacists are a valuable asset to the care be in 1989,40 the theoretical construct was described
team. The type and depth of training pharmacists several years before.41 This expanded approach to
receive during their formal pharmacy education and care has been the subject of much discussion ever
postgraduate training programs, as well as enhanced since, as well as recognized and supported in recent
recognition through board certification, has opened years by other healthcare providers.42,43 And, while
up opportunities for collaborative care and other cog- this advance appears to be logical and sensible, phar-
nitive services within DSM programs. DSM programs maceutical care remains very difficult to define. At
are becoming more popular with healthcare systems, times pharmaceutical care is perceived to include only
and MCO and many programs now showcase the a specific set of practitioners or practice settings. Fur-
unique expertise of the pharmacist toward making ther, in spite of a variety of excellent models for
them effective. As such, pharmacist reimbursement the provision of this care, i.e., inpatient and outpa-
for such services is becoming more common. Taking tient, the delivery of pharmaceutical care is far from
all of this into account, the opportunity is upon us for uniform within the profession.
pharmacists to enhance their role in disease-oriented In spite of our advancing knowledge and technol-
approaches to patient care. ogy, drug-related problems and adverse drug events
are a major source of morbidity and mortality in the
United States. In one study the incidence of serious
adverse events reported to the FDA increased 2.6-fold
Development of a pharmacy care for the years studied.44 In a recent study, 4.4 adverse
plan and patient problem solving drug events were found to have occurred per 100
patient days in an inpatient setting, with 58% deemed
Introduction to pharmaceutical care
to be preventable.45 These findings support other
The practice of pharmacy continues to undergo signif- studies.46,47 Further, medication-related errors have
icant growth in response to its evolving role. Emphasis been identified as a significant cause of emergency
on the creation, preparation, and dispensing of phar- room visits and subsequent hospitalizations.48 – 52
maceuticals has given way to pharmacotherapeutic Thus, new approaches to the safe and effective use of
decision making and measurable patient outcomes, medicinal products should be considered. One way
with increasing focus on patient safety. As this empha- this may be accomplished is through the enhanced
sis has shifted, academic pharmacy has adopted new utilization of the pharmacist in the drug delivery and
paradigms and approaches in its preparation of future utilization process.
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Patient care | 559

Comparison to Clinical Pharmacy A central feature of pharmaceutical care is to

identify, prevent, and resolve drug-related pro-
Recently, the American College of Clinical Phar-
blems (DRPs). Pharmaceutical care and pharmacist-
macy (ACCP) has defined clinical pharmacy as ‘‘a
managed drug-related problems may differ among
health science discipline that embodies the applica-
practice settings and from patient to patient. Examples
tion and development, by pharmacists, of scientific
of pharmaceutical care services offered include generic
principles of pharmacology, toxicology, therapeutics,
and therapeutic interchange, pharmacokinetic and
clinical pharmacokinetics, pharmacoeconomics, and
therapeutic consultation, patient interviewing, patient
other life sciences for the care of patients.’’53 The
counseling, team rounding, drug information, labora-
origin of the phrase appears to be related closely to
tory monitoring, and monitoring drugs with high costs
the development of cognitive services in the inpa-
or narrow therapeutic windows or potential adverse
tient setting54 as well as to a focus on patients and
effects if used indiscriminately, to list just a few.
their needs. As these services are intended to opti-
mize the care provided to patients by pharmacists,
there appears to be a significant amount of overlap Role of a Pharmacist
with the provision of pharmaceutical care.55 In fact,
The profession and the roles of pharmacists are
all providers of pharmaceutical care should be consid-
continuously evolving, but at the foundation of all
ered to be practicing as clinical pharmacists, regardless
pharmacist roles is the same provision to provide
of practice setting. However, the explicit definition of
quality pharmaceutical care to patients. In fact, there
pharmaceutical care requires the provider to assume a
is a consensus among all major pharmacy organiza-
shared responsibility for therapeutic outcomes, as well
tions since the 1990s that the mission of the profession
as for the communication of their efforts with other
is to provide pharmaceutical care and, as such, all
healthcare professionals. This requires an expanded
students of pharmacy should be trained to provide
view of pharmaceutical care as a strategy rather than
it.56 Pharmaceutical care is defined by Hepler and
a discipline. Further, while clinical pharmacy is by
definition provided by pharmacists, it has been pro- Strand40 as the responsible provision for providing
posed that pharmaceutical care may be provided by a drug therapy for the purposes of achieving definite
variety of healthcare professionals.40 outcomes. Pharmaceutical care focuses on activities
This section is intended to contribute toward the that are patient centered and lead to positive med-
pharmacy student’s and the practitioner’s ability to ication therapy outcomes. According to Penna,57 to
provide pharmaceutical care. The care provided must practice pharmaceutical care, a pharmacist must be
be based upon a logical, effective, and patient-specific a scientific problem solver, a good communicator,
pharmaceutical care plan. educator, and learner. Primary activities involved in
the provision of pharmaceutical care include obtain-
ing a thorough medication history; identifying real
Who Provides Pharmaceutical Care? and potential drug-related problems; developing and
Pharmaceutical care is an equally appropriate implementing a pharmacy care plan, which includes
practice model for independent community practice, monitoring parameters to prevent drug-related prob-
chain community practice, and institutional practice, lems, periodically evaluating the plan for achievement
among other settings. While the specific services pro- of predefined clinical outcomes; and consulting with
vided may differ among these practice environments, patients to ensure successful plan implementation.
the underpinning philosophy of pharmaceutical care Encompassing all these components in a patient care
remains the same, i.e., achieving definitive outcomes plan is essential to achievement of positive patient
for patients. Some examples of the various care outcomes but requires a pharmacist that is compe-
settings include outpatient clinics, emergency patient tent and knowledgeable in providing cognitive ser-
care centers, and specific inpatient units such as vices or value-added services (e.g., patient drug or
medical/surgical intensive care, infectious disease, disease counseling).58
transplant, pediatrics, trauma, internal medicine, and Cognitive services are closely linked with the
cardiac, among others. concepts of clinical pharmacy and pharmaceutical
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560 | An Introduction to Pharmacy

care. Key components of both include application In carrying out daily responsibilities, identifying
of one’s judgment, knowledge, and abilities to DRPs, or developing a pharmacy care plan, phar-
solve DRPs. To practice effectively, pharmaceutical macists must also address societal needs. Societal
care focus must be placed on patient satisfaction. needs may be identified by providing value-added ser-
It is important to conduct a one-on-one patient vices for patients and performing these activities with
session to review past disease and medical histories, ethical and professional prerogatives in mind. On a
current drug, herbal, dietary supplement and non- daily basis, pharmacists may be confronted with pro-
drug therapies, related signs and symptoms, and fessional dilemmas that are legally, ethically and/or
desired outcomes. Collection of this information morally challenging (e.g., patient confidentiality issues
allows the pharmacist to identify patient drug-related and pro-life issues). One must learn to balance these
problems and develop a pharmacy care plan to help challenges while maintaining a level of personal com-
fort to practice successfully and deliver optimal care
resolve these problems.59,60 Box 13.1 demonstrates
on behalf of the patient.61
the proposed nine steps to pharmaceutical care
for pharmacists.
Student Responsibilities
Education
Box 13.1 Nine steps to pharmaceutical care According to the AACP Commission, the goal of phar-
1. Develop a covenantal relationship between maceutical education is to ‘‘inculcate students with
the pharmacist and the patient values necessary to serve society as caring, ethical,
2. Collect relevant drug, disease, and patient learning, professional, and enlightened citizens.’’61
information This is accomplished by providing a curriculum which
3. Interpret this information to identify all enables students to learn and develop knowledge,
the patient’s drug-related problems skills, attitudes, and values necessary to meet the
4. Prioritize the patient’s drug-related prob- needs of patients and society both today and tomor-
lems row. This knowledge and skill should be developed in
5. Identify those drug-related problems for three core areas according to the CAPE educational
which the pharmacist will assume respon- outcome of 2004: pharmaceutical care, systems man-
sibility agement, and public health.56 It is also imperative for
6. Identify patient-specific outcomes for each students to acquire appropriate attitudes and good
drug-related problem for which the phar- values in the areas of professionalism, self-directed
macist has assumed responsibility. learning, leadership and advocacy, interprofessional
7. Develop a therapeutic plan to attain the collaboration, and cultural competency.62 Education
desired patient-specific outcomes for each that encompasses all these components lays the foun-
drug-related problem dation for students to acquire the knowledge and
8. Develop a monitoring plan to assess abilities required to be successful pharmacists in the
whether predetermined outcomes have future. Students are responsible for becoming active
been attained participants in this process, incorporating knowledge
9. Implement and follow the pharmacy care and developing skills in their careers, and embracing
plan, which consists of desired outcomes, life-long learning.61
therapeutic plan, and monitoring plan.
Importance of Skills
(Adapted from Winslade NE, Bajcar JM, et Skills necessary for the delivery of pharmaceutical
al. Pharmacist’s management of drug-related care include patient care skills, clinical skills, applica-
problems: a tool for teaching and providing tion of drug knowledge and drug information skills,
pharmaceutical care. Pharmacotherapy 1997; and professional skills (e.g., interpersonal skills with
17 (4): 805; with permission.) a service orientation). Collecting, collating, and orga-
nizing patient information from medical charts and
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Patient care | 561

computer databases is necessary. Equally important to problem solving and assist students in identifying
is the personal time a pharmacist invests in obtaining DRPs, learning to ask appropriate questions, and
information directly from the patient. The concept becoming capable of formulating recommendations
of patient-centered practice or patient care skills for monitoring and follow-up planning.63
becomes evident when the pharmacist attempts to Experiential practice and the work environment
build a relationship of trust with the patient. This also help students gain experience toward identifying
interaction will help identify and determine patients’ and resolving DRPs, not all of which will be clear-cut
preferences for their healthcare outcomes. Patient textbook scenarios. Awareness of such ambiguities
encounters for students are planned to occur during exists throughout pharmacy practice and in other
internship and/or the experiential component (e.g., healthcare arenas. Professional prerogatives, ethical
fourth professional year clerkship rotations) of their dilemmas, and the balance of both may be quite
curriculum. Routinely, students on rotation provide challenging. The American Pharmacists Association
clinical pharmacy services under the direct supervi- (APhA) Code of Ethics states, ‘‘A pharmacist should
sion of a clinical pharmacy preceptor. The goal of hold the health and safety of patients to be of first
the preceptor is to bridge classroom learning and consideration and should render to each patient the
real-life clinical experiences, enhance the students’ full measure of professional ability as an essential
drug knowledge, and help develop the students’ pro- health practitioner.’’61 In some instances, a pharma-
fessional judgment and values. Clinical skills (e.g., cist’s moral and ethical beliefs may conflict with his
being capable of interpreting blood levels and lab- or her professional duty. For this reason, as a future
oratory data, assess the patient’s needs, and apply pharmacist it is important to be comfortable making
therapeutic data to drug-related problems) are key decisions in the face of these uncertainties.64
factors for an optimal drug regimen. Furthermore,
drug knowledge and information skills, as well as the Identifying Patients to Follow
ability to rationalize therapeutic decisions, are equally To develop a pharmacy care plan and problem-solve,
important in achieving optimal patient care. Finally, the student will need to identify patients with DRPs to
professional skills remain essential for a successful, follow. Numerous studies have indicated that elderly
future practicing pharmacist. Professional respon- patients (e.g., over 65 years of age) are at an increased
sibilities, whether learned through school courses risk for DRPs because, typically, they have multiple
or heightened during clerkship rotations, distinguish medical problems, have multiple drug therapies, and
all healthcare professionals.61 Examples of profes- suffer the physiological effects of aging, which war-
sional responsibilities for pharmacists may include rants close monitoring on the disposition of drugs.
holding high professional aspirations for the prac- Greater than three concomitant diseases, five or more
tice of pharmacy, upholding a commitment to serve medication regimens, twelve or more doses of drugs
the community and humanity, serving as mentors a day, and frequent medication regimen changes in
for future pharmacists, and maintaining personal the past year can lead to non-adherence and demand
standards of integrity, competency, reasoning, and further investigation. Students may also learn, by
life-long learning. monitoring patients with compromised renal or hep-
For one to be proficient in skills gained or atic function, to identify abnormal clinical laboratory
acquired, one must demonstrate competency or mas- values, and to monitor for potential drug–drug and
tery of skills learned. In pharmacy school competency drug–disease state. Sometimes regulatory or reim-
may be ascertained through successful outcomes bursement issues dictate or necessitate tracking the
on examinations, quizzes, and simulated patient care of certain patients (e.g., high cost drugs and
exercises, among others. To test student competency therapies). By this selective process, the student can
and skill sets in a clinical setting, the use of algorithms concentrate his or her activity effectively on those
and flow charts may be used on clerkship rotations. patients who have the greatest potential for benefit
Flow charts (Fig. 13.2) encourage a uniform approach from clinical services.65
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562 | An Introduction to Pharmacy

ID patients Refer to
to follow text

Collect information –
chart, records, lab results, the patient, etc.

Create a patient-specific information base

Identify medication
problems & prioritize List

Specify pharmacotherapeutic goals/outcomes

Develop a therapeutic plan

Refer to
box 101-2,
Devise a monitoring plan
check levels &
labs

Follow-up

Figure 13.2 Example of a flow chart.

Specialization in pharmacy practice and power to heal. Therefore, he differed from other
members of the tribe and was so recognized.66
Introduction
Compared with many other professions, only recently
History of Specialization in Medicine
has the profession of pharmacy entered the arena of
advanced level credentialing. The medical profession Specialization in medicine enjoys a long history.
has formally recognized specialty practice for nearly Medicine’s evolution to its current highly credentialed
100 years. Several other health professions, e.g., nurs- state provides an interesting study in the professional,
ing, optometry, and dentistry, also demonstrate a economic, and political forces that influence such
long history of advanced level credentialing of quali- a transformation. While there are major differences
fied members. In fact, specialization in the healing arts between medicine and many other health professions,
is probably as old as the first declaration by a priest or medicine can serve as a model for other professions
shaman that he possessed special knowledge, insight, seeking to have credentialed specialists.
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Patient care | 563

In medicine, the growth of specialization began standard by which the profession and the public rec-
in the 1920s and 1930s and is directly connected to ognize physician specialists in the United States.68 In
the development of medical science and the result- addition to the 24 ABMS member boards, approxi-
ing improvements made in medical care delivery. In mately 180 non-ABMS boards issue specialty certifi-
the United States, the growth of medical specializa- cation.
tion is largely due to the physician’s need to master The establishment of board certification for physi-
the special tools and skills needed to deliver quality cian specialists was based on the concept that a
healthcare and the intricacies of social, political, and physician, who successfully met certain predeter-
economic forces. mined qualifications and attained the requisite level
Most specialty areas developed around organ of knowledge, skill, and experience in a well-defined
systems, e.g., ophthalmology, otolaryngology, urol- specialized area of medicine, would be a better practi-
ogy, neurosurgery, gastroenterology, and cardiology. tioner than one who did not meet these qualifications.
However, physicians were the only assessors of their The implication was that a specialist would produce
own qualifications to practice a given specialty. There better healthcare outcomes, less morbidity, and/or
was no formal system to assure the public that the greater efficiency in providing healthcare. However,
heart specialist was different from the general practi- while intuitively logical, this concept has not been
tioner or that a physician claiming to be a specialist validated by any studies.69 One may argue that
was indeed qualified. Consequently, specialty soci- physicians with specialties provide state-of-the-art
eties and medical education institutions collaborated knowledge and that the patients ultimately benefit
on developing boards to define specialty qualifica- from specialist-dominated care. On the other hand,
tions and to issue credentials that would assure the there may be instances where the sophisticated, expen-
public of the specialist’s qualifications. The American sive, specialist-dominated care may not produce any
Board of Ophthalmology, established in 1917, was the better health outcomes than did other, simpler, less-
first specialty board in the United States.67 It estab- expensive healthcare delivery systems.
lished the guidelines for the education, training, and
evaluation of candidates desiring certification to prac- Value of Specialization in Medicine
tice ophthalmology. The second specialty board, the
Although board certification is not required for an
American Board of Otolaryngology, was established individual physician to practice medicine, the value of
in 1924. The third and fourth boards, the American specialty certification in medicine, at least in medically
Board of Obstetrics and Gynecology and the Amer- sophisticated societies, is quite clear. Most hospitals
ican Board of Dermatology and Syphilology, were and managed care organizations require that at least a
established in 1930 and 1932, respectively. These certain percentage of their staff be board certified. Spe-
were followed by several other specialties, such as the cialty board certification status for a physician is often
American Board of Internal Medicine in 1936 and the used as a standard of excellence. Most hospitals, man-
American Board of Surgery in 1937. aged care organizations, and health insurance plans
The objectives of each specialty board were to ele- require board certification for physicians for them to
vate the standards of a specialty area, to familiarize obtain clinical privileges and hospital appointments.
the public with its aims and ideals, to protect the pub- Furthermore, The Joint Commission and the National
lic against irresponsible and unqualified practitioners, Committee for Quality Assurance embrace medical
to receive applications for examinations in a specialty specialty board certification by incorporating it into
area, to conduct examinations of such applicants, and their accreditation standards.70 Commonly, the pub-
to issue certificates of qualification in a specialty area. lic also views medical specialty board certification as
Since 1934, official recognition of specialty boards a measure of a physician’s clinical expertise.
in medicine has been achieved by the collaborative
efforts of the American Board of Medical Special- History of specialization in pharmacy
ties and the American Medical Association (AMA)
Council on Medical Education. The American Board The Basis of Specialization
of Medical Specialties (ABMS) approves 24 med- For most of its history as a profession, phar-
ical specialties. This organization has become the macy was relatively undifferentiated. Prior to the
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564 | An Introduction to Pharmacy

mid-1900s, most pharmacists concentrated on pro- specialties could be identified, and (3) develop the
viding drug products to patients in response to an means by which individuals could become recognized
order of a physician or other credentialed prescriber. as specialists, as well as make recommendations
The emergence of practice differentiation really began for recertification.
to be recognized in the late 1960s and early 1970s. The Task Force published its report in 1974.73
In a 1968 editorial, Paul Parker described hospital While not concluding whether specialties existed at
pharmacists who had developed unique roles that that time, it did determine that one or more specialties
were distinct from the traditional dispensing roles of would develop in the near future and that there was
the pharmacist.71 These pioneering ‘‘clinical phar- need for an independent agency to recognize these spe-
macists’’ participated with physicians in therapeutic cialists. It made several recommendations concerning
decision-making, and Parker suggested that their the recognition process and proposed the establish-
level of knowledge and practice skills required special ment of a Board of Pharmaceutical Specialties, now
educational and experiential preparation. Further, he the Board of Pharmacy Specialties (BPS), to develop
encouraged hospital pharmacists to organize their a mechanism to identify specialty practice areas and
departments to recognize and utilize these emerging recognize individual specialists.
‘‘specialists’’ and proposed that the medical model
of specialty organization might be applicable to Development of the Board of Pharmacy
pharmacy.71 Shortly thereafter, the Study Commis- Specialties (BPS)
sion on Pharmacy, known synonymously as the The Board of Pharmacy Specialties was officially
Millis Commission, was chartered by the American established on January 5, 1976, when APhA members
Association of Colleges of Pharmacy (AACP). Its approved the BPS bylaws within the APhA structure.
report, published in 1975, acknowledged that The initial mission of BPS was based on respon-
differentiation in pharmacy practice was occurring sibilities outlined in its bylaws. (1) BPS recognizes
and that this was, in general, expected and desirable. appropriate specialties in pharmacy practice, using
While not specifying specialty practice areas, the specific criteria developed for this purpose. These cri-
commission suggested that a structure be established teria are discussed below in the Petition Process. (2)
to oversee all pharmacist credentialing. BPS sets standards for certification and recertifica-
In a series of editorials between 1974 and 1976, tion of pharmacists in designated areas of specialty
Donald Francke outlined his concept of a structure practice. This is achieved primarily by individual
for the practice of pharmacy.72 Specialization was specialty councils, within the BPS structure, which
addressed as part of the continuum of education, make recommendations to the full Board. (3) BPS
and he identified the pharmacotherapeutic special- administers the examination and evaluation of indi-
ist, the clinical radiopharmacist specialist, the drug viduals who seek certification and recertification as
information specialist, the pediatric clinical phar- specialists. (4) BPS serves as an information clear-
macy specialist, and the pharmacy practice specialist, inghouse and coordinating agency for organizations
among others.72 and pharmacists with regard to the specialty practice
of pharmacy.
Task Force on Specialization in The organizational relationship of the BPS to
Pharmacy – Role of APHA the APhA was intended to provide financial and
Perceiving the evolving interest in differentiated prac- administrative support for the young organization
tice within the pharmacy profession, the Board of while ensuring that decisions regarding recognition of
Trustees of the American Pharmaceutical Association specialties and credentialing of specialists would be
(APhA, now the American Pharmacists Association) independent. Today BPS operates as an autonomous
appointed a Task Force on Specialties in Pharmacy division of APhA. BPS Governing Policies adopted in
in early 1973. This group was charged to (1) identify July 2008 provide for an eleven-member Board, com-
existing or potential areas of specialization (or, alter- prising eight pharmacists and three non-pharmacists
natively, to determine that there were no specialties (i.e., two other health professions members and one
and that the practice of pharmacy was not likely to public/consumer member.) This Board is advised
become specialized), (2) propose a means by which by Specialty Councils, representing each recognized
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Patient care | 565

specialty. The Specialty Councils are composed of six 5. Pharmacists in the specialty practice area perform
pharmacists who hold BPS certification in a specialty specialized functions, acquired through education
practice area and three pharmacists representing the and training beyond the basic level attained by
profession in general. The Specialty Council Chairs licensed pharmacy generalists.
(i.e., currently numbering six and representing the 6. Pharmacy schools and other organizations offer
specialties of Nuclear Pharmacy, Nutrition Support education and training in the specialty practice
Pharmacy, Oncology Pharmacy, Pharmacotherapy, area.
Psychiatric Pharmacy, and Ambulatory Care Phar- 7. Transmission of knowledge in the specialty prac-
macy), as well as the Executive Director of BPS tice area occurs through books, journals, sym-
(an administrative staff position), serve as ex-officio posia, professional meetings, and other formal
members of the Board of Pharmacy Specialties. media or mechanisms.

BPS New Specialty Petition Process Petition Review and Approval

A key role of the Board of Pharmacy Specialties is the
The formal review process begins when the BPS
recognition of new specialties within the profession.
receives a petition proposing a new specialty. The
To their credit, the founders of BPS sought to make
petition is released for comment by the profession
this a very formal and participative process for the
and the public if an initial review by BPS staff and
pharmacy profession. Seven criteria for recognition of
the Board of Directors indicate that the petition is
a new specialty were established and remain in effect
complete and reasonably meets criteria. At least two
today.74 These criteria must be addressed in detail in
open hearings are usually held at major pharmacy
the petition which is submitted to BPS by an organi-
meetings to solicit input from the pharmacy pro-
zation or group seeking new specialty recognition in
fession, other health professions, third-party payers,
pharmacy. A more detailed description of the petition
and the public. Finally, the Board will consider the
process is available from BPS and detailed on its web
detailed information in the petition and any com-
site, which provides additional guidelines for needed
ments provided during the petition review period to
supporting information under each criterion. The BPS
determine whether the criteria for new specialty estab-
criteria, which must be met for any new specialty to
lishment are met. The Board’s decision is appealable
be recognized, are as follows:
in accordance with established BPS appeals policy.
1. The profession of pharmacy needs specifically Once a new specialty has been approved, the ini-
trained practitioners in the specialty practice area tial Specialty Council is appointed. The organization
to fulfill the responsibilities of the profession in or group which submitted the petition appoints the
improving the health and welfare of the public. six, non-certified specialist members to the Council,
Licensed pharmacy generalists or other healthcare and BPS appoints the three non-specialist pharmacist
professionals cannot provide the level of services members. After the first certification examination is
that pharmacist specialists can, and pharmacies’ administered, and the first group of specialists is cer-
responsibilities may not be fulfilled effectively tified, there will be three new appointees each year to
without their contributions. replace the original Specialty Council. Two appointees
2. A clear, significant demand for the specialty is will be Board Certified in that specialty, and one will
made by the public and healthcare systems. be a pharmacy generalist appointee.
3. A reasonable number of pharmacist specialists The major charge of the Specialty Council is to
practice in and devote significant time to provision work with the BPS testing consultant to develop and
of services in the specialty area. maintain the examination process itself.
4. Practice in a specialty area requires specialized
knowledge of pharmaceutical sciences based upon Establishment of a Specialty Certification
the biological, physical, and behavioral sciences. Process
The specialty may not be based solely on the prac- Across all professional fields, there are relatively con-
tice environment or managerial, procedural, or sistent procedures that need to be followed for the
technical services. development and implementation of an advanced
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566 | An Introduction to Pharmacy

practice certification process. To be respected and examinations consisting of 100 multiple choice ques-
successful, a certification examination must be psy- tions in the same format as the original certification
chometrically sound and legally defensible. This pro- examination. When available, a BPS-approved pro-
cess begins when the BPS determines that legitimate fessional development program may be substituted
criteria for the establishment of the specialty have for the written recertification examination.
been met. An early part of the specialty recognition
process is to conduct a role delineation study, also Evolution of Specialties
known as a job analysis. This is a very comprehensive In the pre-BPS discussions across the pharmacy pro-
survey designed to identify what specific knowledge, fession, several potential specialties were identified. It
skills, and tasks characterize the specialty and can be was not surprising that Nuclear Pharmacy emerged as
used to differentiate between practitioners who are, the first petition to be submitted to the BPS. A section
and are not, at the specialist level. This is administered on Nuclear Pharmacy had been established within the
to a large group of pharmacists, generally believed to APhA structure in 1975, and there was little debate
be practicing at the specialist level. that specialized knowledge and skill was required to
When appropriately analyzed, the results of this practice nuclear pharmacy safely and competently.
study serve two purposes: (1) to determine if there The community of nuclear pharmacy practitioners
is both the presence of specialized knowledge and was relatively small and close-knit, and the APhA
functions within the proposed specialty and (2) if was in an excellent position to assist BPS to develop
the petition is approved by BPS, the study forms the the specialty.75 It was nearly 12 years, however,
Content Outline or Examination Specifications for before any other specialties were proposed. Since
the specialty’s certification examination. This deter- that time, five additional specialties have been rec-
mines the types of questions that should comprise the ognized. Those petitions were submitted by three
examination. Once a specialty has been approved by other major professional organizations, marking the
BPS, the Council is established and convenes groups profession’s recognition that the BPS could ideally
of knowledgeable individuals to draft questions (also serve the entire pharmacy profession as its specialty
known as test items) which meet established test spec- certification body. Although other certifications have
ifications. When appropriate, test items are based emerged in recent years under other auspices, BPS
on evidence-based clinical practice guidelines and remains the largest organization and most rigorous in
randomized clinical trial data, and each item is refer- offering specialty level certification.
enced for validation purposes. Following an extensive The bar graph (Fig. 13.3) illustrates the devel-
review, these questions are used to create the spe- opment and growth of specialties in pharmacy since
cialty examination itself. All BPS specialty certification 2002. Note that numbers represent individuals cur-
examinations consist of 200 multiple-choice ques- rently certified by BPS as of the year indicated.
tions. Each has four possible answers, only one of Individuals who failed to recertify when required are
which is correct. After the first examination has been removed from these totals. It should also be noted that
drafted, the Council and other experts conduct a pass- the number of BPS certified pharmacists has doubled
ing point study, which results in a psychometrically between 2005 and 2010.
valid passing score. A passing point study involves
determining what fraction of competent specialists
would likely select the correct answer for each item.
Current specialties in pharmacy
BPS and most similar advanced practice certifications Nuclear Pharmacy
utilize a criterion referenced scoring system, rather
than the more familiar norm referenced system more 1. Supporting Organization(s): American Pharma-
common in academic institutions. Detailed discus- cists Association
sion of these systems in included on the BPS web- 2. Year of Specialty Recognition: 1978
site (http://www.bpsweb.org) and educational test- 3. Description of the Specialty:
ing references. Recertification in all six BPS special- Nuclear Pharmacy seeks to improve and promote
ties is required every 7 years, with recertification the public health through the safe and effective use
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Patient care | 567

12,900
12,750 518
12,500
12,250
12,000
11,750 1247
11,500
11,250
11,000 684
10,750
10,500
10,250 482
10,000 1083
9,750
9,500
9,250 627
9,000
8,750 956 457
8,500
8,250
8,000 582
7,750
860
7,500 423
7,250
7,000 548
6,750
6,500 757 410
6,250
6,000
5,750 509
5,500 655
5,250 382 9445
5,000 557 490
4,750
4,500 463 358 7766
4,250
473
4,000 348 6657
409 493
3,750
3,500 461 339 5567
3,250 4523
3,000 360
2,750
2,500 3688
2,250 3191
2,000 2637
1,750 2228
1,500
1,250
1,000
750
500 468 463 495 501 507 515 496 513 524
250
0
2003* 2004* 2005* 2006* 2007* 2008* 2009* 2010* 2011*
Nuclear Pharmacotherapy Nutrition support Psychiatric Oncology Ambulatory care**

* Individuals who failed to certify have been excluded from these statistics.
** 2011 is the first year for Ambulatory Care Certification.

Figure 13.3 Pharmacists certified by the Board of Pharmacy Specialties.

of radioactive drugs for diagnosis and therapy. 4. Eligibility Requirements

A nuclear pharmacist, as a member of the nuclear The minimum requirements for certification in
medicine team, specializes in the procurement, nuclear pharmacy are
compounding, quality control testing, dispens- • Graduation from a pharmacy program accred-
ing, distribution, and monitoring of radiophar- ited by the Accreditation Council for Pharmacy
maceuticals. In addition, the nuclear pharmacist Education (ACPE) or program outside the US
provides consultation regarding health and safety that qualifies the individual to practice in the
issues, as well as the use of non-radioactive drugs jurisdiction. Foreign trained pharmacists must
and patient care. Those who are granted certifi- pass the Foreign Pharmacy Graduate Examina-
cation in this specialty may use the designation, tion Committee (FPGEC) examination.
Board Certified Nuclear Pharmacist and the ini- • Current, active license to practice pharmacy in
tials BCNP, as long as their certification is valid. the US or another jurisdiction
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568 | An Introduction to Pharmacy

• 4000 hours of training/experience in nuclear • Subdomain C: Quality Assurance (9% of

pharmacy practice the examination)
• Achieving a passing score on the Nuclear Phar- • Subdomain D: Dispensing (23% of the
macy Specialty Certification Examination. examination)
The required 4000 hours of experience may be Domain 2: Health and Safety (24% of the exami-
earned in a variety of settings. nation)
Academic – up to 2000 hours: Domain 3: Drug Information Provision (10% of
• Undergraduate courses in nuclear pharmacy: the examination).
up to 100 hours experience for every quar- 6. Recertification
ter credit hour or 150 hours experience for Recertification for Board Certified Nuclear
every semester credit hour, to a maximum of Pharmacists (BCNP) is a three-step process:
1500 hours • Self-evaluation: Review of the nuclear phar-
• Postgraduate courses in nuclear pharmacy: macy practice activities/functions that have
up to 100 hours experience for every quarter changed since initial certification or last
credit hour or 150 hours experience for every recertification.
semester credit hour, to a maximum of 1500 • Peer review: Documentation of nuclear
hours pharmacy practice over the seven year
• MS or PhD degree in nuclear pharmacy: certification period.
2000 hours • Formal Assessment: This assessment of a
• Successful completion of the Nuclear Pharmacy practitioner’s knowledge and skills
Certificate Program offered by Purdue Univer- will be accomplished through one of
sity (217 hours) or The Ohio State University two methods:
(214 hours), or the Nuclear Education Online • Option One: Examination
(NEO) Program offered by the Universities Achieve a passing score on the 100-item,
of New Mexico and Arkansas (250 hours). multiple choice objective recertification
Credit for other courses will be assessed on a examination based on the content outline.
case-by-case basis. (Refer to the Nuclear Pharmacy Content
Training/practice – up to 4000 hours: Outline for details.)
• Residency in nuclear pharmacy: hour-for-hour • Option Two: Continuing Education
credit to a maximum of 2000 hours The continuing education option for
• Internship to satisfy requirements of state recertification was implemented in 1976
boards of pharmacy: hour-for-hour credit with BPS designation of the University
in a licensed nuclear pharmacy or facility of New Mexico College of Pharmacy’s
authorized to handle radioactive materials, to a Correspondence Continuing Educa-
maximum of 2000 hours tion Courses for Nuclear Pharmacists,
• Nuclear pharmacy practice: hour-for-hour beginning with Volume V, as an
credit in a licensed nuclear pharmacy or acceptable professional development
healthcare facility approved by state or federal program.
agencies to handle radioactive materials, to a
maximum of 4000 hours. A BCNP recertifying is required to earn 70 hours
5. Examination Content over the 7 year certification period. At least 30 of these
Domain 1: Drug Order Provision (66% of the hours MUST be earned within the last 3 years of the
examination) certification period. There are no other restrictions as
• Subdomain A: Procurement (8% of the to which lessons in which years may be used to obtain
examination) the required number of hours, other than the lesson
• Subdomain B: Compounding (26% of the must have been issued in 1996 or thereafter (Volume
examination) V or later volumes).
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Patient care | 569

A current, active license to practice pharmacy is • Completion of a (PGY2) residency* in nutri-

required for recertification. As part of the recertifi- tion support pharmacy.
cation process, every BCNP is asked to complete an • *Effective January 1, 2013, only residencies
annual practice report form provided by BPS. The accredited by the American Health-System
information is compiled by BPS at the beginning of Pharmacists or other recognized bodies are
the recertification process and sent to the BCNP for creditable for this purpose.
verification and updating. At the time of recertifica- • Achieving a passing score on the Nutrition Sup-
tion, the BCNP is also required to certify that he or port Pharmacy Specialty Certification Exami-
she is not currently under suspension by either the US nation.
Nuclear Regulatory Commission or a state Radiation 5. Examination Content
Control Organization. Domain 1: Clinical Practice/Provision of Individ-
ualized Nutrition Support to Patients (68% of
Nutrition Support Pharmacy the examination)
1. Supporting Organization(s): American Society of • Subdomain A: Assessment (21% of the
Health-System Pharmacists and American Society examination)
for Parenteral and Enteral Nutrition • Subdomain B: Develop and Implement a
2. Year of Recognition: 1988 Therapeutic Plan of Care (21% of the exam-
3. Description of the Specialty ination)
Nutrition Support Pharmacy addresses the care of • Subdomain C: Monitoring and Clinical
patients who receive specialized nutrition support, Management (26% of the examination)
including parenteral and enteral nutrition. The Domain 2: Management of Nutrition Support
nutrition support pharmacist has responsibility Operations (20% of the examination)
for promoting maintenance and/or restoration • Subdomain A: Patient Care Management
of optimal nutritional status and designing and (12% of the examination)
modifying treatment according to patient needs. • Subdomain B: Compounding Operations
The nutrition support pharmacist has responsi- (8% of the examination)
bility for direct patient care and often functions Domain 3: Advancement of Nutrition Support
as a member of a multidisciplinary nutrition Practice (12% of the examination).
support team. Those who are granted certification 6. Recertification
in this specialty may use the designation Board Recertification for Board Certified Nutrition Sup-
Certified Nutrition Support Pharmacist and port Pharmacists (BCNSP) is based on the follow-
the initials BCNSP, as long as their certification ing activities:
is valid. • Earning a minimum of 30 hours of continu-
4. Eligibility Requirements ing education in nutrition support with no less
The minimum requirements for this specialty than 10 hours earned every two years. These
certification are hours must be from providers approved by the
• Graduation from a pharmacy program accred- Accreditation Council for Pharmacy Education
ited by the Accreditation Council for Pharmacy (ACPE).
Education (ACPE) or program outside the US • Achieving a passing score on the 100-item,
that qualifies the individual to practice in the multiple-choice recertification examination,
jurisdiction. which is based on the content outline of the
• Current, active license to practice pharmacy in certification examination
the US or another jurisdiction. • A current, active license to practice pharmacy
• Completion of 3 years practice experience with is required for recertification.
at least 50% of time spent in nutrition sup-
port pharmacy activities (as defined by the BPS Pharmacotherapy
Nutrition Support Content Outline) 1. Supporting Organization(s): American College of
OR Clinical Pharmacy
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570 | An Introduction to Pharmacy

2. Year of Recognition: 1988 practitioner’s knowledge and skills through one of

3. Description of the Specialty two methods:
Pharmacotherapy is that area of pharmacy • Achieving a passing score on the 100-item,
practice that is responsible for ensuring the safe, multiple-choice objective recertification exam-
appropriate, and economical use of drugs in ination, based on the content outline of the
patient care. The pharmacotherapy specialist certification examination
has responsibility for direct patient care, often OR
functions as a member of a multidisciplinary • Earning 120 hours of continuing education
team, and is frequently the primary source of credit provided by a professional development
drug information for other healthcare profes- program approved by BPS. The approved pro-
sionals. Those who are granted certification in fessional development program provider for
this specialty may use the designation Board the pharmacotherapy specialty is the American
Certified Pharmacotherapy Specialist and the College of Clinical Pharmacy.
initials BCPS, as long as their certification • A current, active license to practice pharmacy
is valid. is required for recertification.
4. Eligibility Requirements
The minimum requirements for this specialty cer- Psychiatric Pharmacy
tification are 1. Supporting Organization(s): American Society of
• Graduation from a pharmacy program accred- Health-System Pharmacists
ited by the Accreditation Council for Pharmacy 2. Year of Recognition: 1994
Education (ACPE) or a program outside the US 3. Description of the Specialty
that qualifies the individual to practice in the Psychiatric Pharmacy addresses the pharmaceu-
jurisdiction. tical care of patients with psychiatric-related ill-
• Current, active license to practice pharmacy in nesses. As a member of a multidisciplinary treat-
the US or another jurisdiction. ment team, the psychiatric pharmacy specialist is
• Completion of 3 years of practice experience often responsible for optimizing drug treatment
with at least 50% of time spent in pharma- and patient care by conducting such activities as
cotherapy activities (as defined by the BPS monitoring patient response, patient assessment,
Pharmacotherapy Content Outline) recognizing drug-induced problems, and recom-
OR mending appropriate treatment plans. Those who
• Completion of a PGY1 residency. are granted certification in this specialty may use
*Effective January 1, 2013, only residencies the designation Board Certified Psychiatric Phar-
accredited by the American Society of Health- macist and the initials BCPP, as long as their certi-
System Pharmacists or other recognized bodies fication is valid.
are creditable for this purpose. 4. Eligibility Requirements
• Achieving a passing score on the Pharma- The minimum requirements for this specialty cer-
cotherapy Specialty Certification Examination. tification are:
5. Examination Content.
• Graduation from a pharmacy program accred-
Domain 1: Patient-specific Pharmacotherapy ited by the Accreditation Council for Pharmacy
(60% of the examination) Education (ACPE) or a program outside the US
Domain 2: Retrieval, generation, interpretation, that qualifies the individual to practice in the
and dissemination of knowledge in pharma- jurisdiction.
cotherapy (25% of the examination) • Current, active license to practice pharmacy in
Domain 3: Systems and Population-based Phar- the US or another jurisdiction.
macotherapy (15% of the examination) • Completion of 4 years of practice with at least
6. Recertification 50% of time spent in psychiatric pharmacy
Recertification for Board Certified Pharma- activities (as defined by the BPS Psychiatric
cotherapy Specialists (BCPS) is an assessment of a Pharmacy Content Outline)
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Patient care | 571

OR pharmacotherapeutic plans to optimize outcomes

Completion of a specialty (PGY2) residency* in patients with malignant diseases. Those who
in psychiatric pharmacy plus one (1) additional are granted certification in this specialty may
year of practice with at least 50% of time spent use the designation Board Certified Oncology
in psychiatric pharmacy activities (as defined Pharmacist and the initials BCOP, as long as their
by the BPS Psychiatric Pharmacy Content Out- certification is valid.
line) 4. Eligibility Requirements
*Effective January 1, 2013, only residencies The minimum requirements for this specialty
accredited by the American Society of Health- certification are
System Pharmacists or other recognized bodies
• Graduation from a pharmacy program accred-
are creditable for this purpose. ited by the Accreditation Council for Pharmacy
• Achieving a passing score on the Psychiatric Education (ACPE) or a program outside the US
Pharmacy Specialty Certification Examination. that qualifies the individual to practice in the
5. Examination Content jurisdiction.
Domain 1: Clinical Skills and Therapeutic • Current, active license to practice pharmacy in
Management (65% of the examination) the US or another jurisdiction.
Domain 2: Education and Dissemination
• Completion of 4 years of practice experience
of Information (25% of the examination) with at least 50% of time spent in oncology
Domain 3: Clinical Administration (10% of the pharmacy activities (as defined by the BPS
examination). Oncology Pharmacy Content Outline)
Check the BPS website at http://www.bpsweb.org OR
for updates. Completion of a specialty (PGY2) residency*
6. Recertification in oncology pharmacy plus one (1) additional
Recertification of Board Certified Psychiatric year of practice with at least 50% of time spent
Pharmacists (BCPP) requires an assessment of a in oncology pharmacy activities (as defined
practitioner’s knowledge and skills through one of by the BPS Oncology Pharmacy Content
two methods: Outline)
• Achieving a passing score on the 100-item *Effective January 1, 2013, only residencies
multiple choice recertification examination, accredited by the American Society of Health-
based on the content outline of the certification System Pharmacists or other recognized bodies
examination
are creditable for this purpose.
OR
• Achieving a passing score on the Oncol-
• Earning 100 hours of continuing education ogy Pharmacy Specialty Certification
credit provided by a professional development
Examination.
program approved by BPS. The approved
5. Examination Content
professional development program provider
for psychiatric pharmacy is the College of Domain 1: Clinical Skills and Therapeutic Man-
Psychiatric and Neurologic Pharmacists. agement (60% of the examination)
Domain 2: Generation, Interpretation, and Dis-
• A current, active license to practice pharmacy
is required for recertification. semination of Information (20% of the exami-
nation)
Oncology Pharmacy Domain 3: Guidelines, Policies, and Standards
1. Supporting Organization(s): American Society of (15% of the examination)
Health-System Pharmacists Domain 4: Public Health and Advocacy (5% of
2. Year of Recognition: 1996 the examination).
3. Description of the Specialty 6. Recertification
Oncology Pharmacy specialists recommend, Recertification for Board Certified Oncology
design, implement, monitor and modify Pharmacists (BCOP) requires assessment of a
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572 | An Introduction to Pharmacy

practitioner’s knowledge and skills through one of 4. Eligibility Requirements

two methods: The minimum requirements for this specialty
• Achieving a passing score on the 100-item, certification are
multiple-choice objective recertification exam- • Graduation from a pharmacy program accred-
ination, based on the content outline of the ited by the Accreditation Council for Pharmacy
certification examination Education (ACPE) or a program outside the US
OR that qualifies the individual to practice in the
• Earning 100 hours of continuing education jurisdiction.
credit provided by a professional development • Current, active license to practice pharmacy in
program approved by BPS. In 2005, BPS the US or another jurisdiction.
approved a professional development program • Completion of 4 years of practice experience
which is offered by the American College of with at least 50% of time spent in ambulatory
Clinical Pharmacy (ACCP) in conjunction care pharmacy activities (as defined by the BPS
with the American Society of Health-System Ambulatory Care Content Outline)
Pharmacists (ASHP), and the Hematol- OR
ogy/Oncology Pharmacy Association (HOPA)
• Completion of a PGY1 residency * plus one
that can be used by BCOP for recertification. (1) additional year of practice with at least
Contact one of the organizations listed above 50% of time spent in ambulatory care phar-
for specific information about the program. macy activities (as defined by the BPS Ambula-
• A current, active license to practice pharmacy tory Care Content Outline)
is required for recertification.
OR

Ambulatory Care Pharmacy • Completion of a specialty (PGY2) residency *

in ambulatory care pharmacy.
1. Supporting Organization(s): American College of *Effective January 1, 2013, only residencies
Clinical Pharmacy, American Pharmacists Asso- accredited by the American Society of Health-
ciation, American Society of Health-System Phar- System Pharmacists or other BPS-recognized
macists bodies are creditable for this purpose.
2. Year of Recognition: 2009
• Achieving a passing score on the Ambulatory
3. Description of the Specialty: Care Specialty Certification Examination.
Ambulatory Care Pharmacy practice is the pro- 5. Examination Content
vision of integrated, accessible healthcare ser-
Domain 1: Direct Patient Care (50% of the exam-
vices by pharmacists who are accountable for
ination)
addressing medication needs, developing sus-
Domain 2: Practice Management (20% of the
tained partnerships with patients, and practicing
examination)
in the context of family and community. This
Domain 3: Public Health (5% of the examination)
is accomplished through direct patient care and
Domain 4: Retrieval, generation, interpretation
medication management for ambulatory patients,
long-term relationships, coordination of care, and dissemination of knowledge (15% of the
patient advocacy, wellness and health promotion, examination)
triage and referral, and patient education and self- Domain 5: Patient Advocacy (10% of the exami-
management. The ambulatory care pharmacists nation).
may work in both an institutional or community- 6. Recertification
based clinic involved in direct care of a diverse Recertification for Board Certified Ambulatory
patient population. Those who are granted certi- Care Pharmacists (BCACP) requires:
fication in this specialty may use the designation • Achieving a passing score on the 100-item,
Board Certified Ambulatory Care Pharmacist and multiple-choice recertification examination,
the initials BCACP, as long as their certification which is based on the same content outline as
is valid. the certification examination
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Patient care | 573

• Earning 100 hours of continuing education information, including a Candidate’s Guide, Spe-
credit provided by a professional development cialty Content Outlines, current fees, and application
program approved by BPS (to be developed). materials are available upon request from BPS or
at the website, http://www.bpsweb.org. First-time
applicants are encouraged to apply online.
Added qualifications process and As previously described, each BPS specialty certi-
currently recognized areas fication examination consists of 200 multiple choice
In 1997, BPS approved a process for the recogni- questions, each having only one correct answer. Writ-
tion of Added Qualifications in an existing specialty. ten recertification examinations consist of 100 ques-
Added Qualifications provides a method to docu- tions. Short practice tests for each specialty are posted
ment further differentiation of practitioners within on the BPS website to illustrate the construction of
BPS-recognized specialties.76 BPS issued its Petitioner the questions and their content.
Information for Added Qualifications in Infectious Candidates are informed in writing of their per-
Diseases document in August, 1997. Conferral of the formance on each domain of the examination, and
Added Qualifications credential requires submission successful candidates are awarded a BPS certificate.
of a $100 fee and a structured portfolio, which is A BPS certification or recertification examination may
reviewed by the pertinent BPS Specialty Council and be retaken, if necessary, at a reduced fee.
scored in accordance with published criteria. Added
Qualifications must be reaffirmed every 7 years, just
The value of specialty certification
as BPS certification in a primary recognized specialty.
in pharmacy
In May 1998, the Society of Infectious Diseases
Pharmacists submitted a petition for Added Qualifi- As in other professions where specialty certification
cations in Infectious Diseases Pharmacotherapy. The has become established, this rigorous process pro-
petition, including the portfolio review process, was vides value and benefit to society, to the pharmacy
approved by BPS in March 1999. In March 2000, profession, and to the certified individuals.
the American College of Clinical Pharmacy (ACCP)
submitted a petition to BPS, requesting designation of A. Society. The existence of pharmacists who have
cardiology as a second area of Added Qualifications demonstrated an advanced level of practice
within Pharmacotherapy. The petition, which incor- knowledge and skill has clearly resulted in
porates the portfolio review process, was approved improved pharmaceutical care for patients.
by BPS in October 2000. Numerous studies have investigated the positive
As of 2012, 147 Board Certified Pharmacother- impact of clinically trained pharmacists in
apy Specialists held Added Qualifications in Infectious inpatient and ambulatory care settings.77 – 80
Diseases, and 92 held Added Qualifications in Car- Pharmacists who are able to interact with other
diology. More than 10,500 pharmacist specialists are health professionals in planning and implement-
currently certified by BPS. ing therapy contribute special expertise in areas
that complement the skills of their colleagues. As
recognized ‘‘drug experts,’’ they can also help to
The BPS specialty certification process
ensure that patients maximize the potential bene-
Currently, BPS specialty certification and recertifica- fits of therapy. While there have been few direct
tion examinations are administered once annually, on studies of the impact of specialty certification in
the first Saturday in October. The application deadline pharmacy (or in medicine, for that matter) on
is the preceding August 1. BPS administers specialty patient outcomes, available evidence suggests that
certification examinations at approximately 45 sites training and experience are important determin-
each year worldwide. ants of the quality of care. Specialty certification
Additional, ‘‘alternate sites’’ may be established provides an objective, independent measure of
in other US and foreign cities, at the request of knowledge and experience against established
ten or more candidates. Complete examination criteria. High quality certification programs in
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574 | An Introduction to Pharmacy

all areas of specialization maintain that their first after their initial entry into practice. Other credentials
obligation is to society, and ensure that these available include
programs meet that goal.
B. The Pharmacy Profession. As the numbers of • Formal post-graduate degree programs
BPS-certified pharmacists have grown within the • Residency or Fellowship training
pharmacy profession, the value of this credential • Certificate training programs
has been increasingly recognized just as in other • Multi-disciplinary certification programs (e.g.,
health professions; increasingly, specialty board Certified Diabetes Educator)
certification is viewed as an important qualifica- • Non-specialty certification programs (e.g., Certi-
tion for clinical faculty in pharmacy schools.81,82 fied Disease Manager).
BPS certification has also been accepted by Idaho
State University as a measure of the clinical exper- Detailed discussion of these opportunities is beyond
tise of applicants to their non-traditional PharmD the scope of this chapter. Attainment of some of these
program. In the Idaho State University program, credentials may help prepare or qualify a pharmacist
candidates may obtain academic credit via cur- for BPS specialty certification.
rent Board Certification in Pharmacotherapy and
shorten the didactic requirements for the degree.
Specialty board certification is a respected model Council on Credentialing in Pharmacy
of clinical expertise in institutional settings where Because of the multiplicity of credentials available to
clinical privileges are required to perform some pharmacists, several of the major membership organi-
patient-care services. zations in pharmacy joined to establish the Council
C. The Individual. Specialty certification confers on Credentialing in Pharmacy in 1997. The Council
many potential benefits for the pharmacist. on Credentialing in Pharmacy provides leadership,
Positive recognition by patients, colleagues, guidance, public information, and coordination for
and employers often brings psychological the profession, of pharmacy’s credentialing programs.
‘‘enrichment’’ and reward to pharmacists The vision of the Council on Credentialing in
who have worked hard to develop, maintain, Pharmacy is that all credentialing programs in phar-
and document their expertise. There are also macy will meet established standards of quality and
increasing instances of monetary reward for contribute to improvement in patient care and the
specialty certification. Some examples include overall public health.
bonus pay for members of the uniformed services The Council has published resource papers on the
and pharmacists in many institutional systems; following topics: credentialing in pharmacy, the scope
hiring or promotion preference, particularly of practice of pharmacists and pharmacy technicians,
for professionally challenging clinical specialist and guiding principles for certification of individuals
positions; reimbursement of costs for successful and accreditation organizations, sites, or programs.83
certification and/or recertification; and eligibility In an era where there is greater emphasis not only
for participation in collaborative practice or other on cost, but on healthcare quality and accountability,
arrangements where payment for pharmaceutical healthcare systems, payers, and patients will continue
services is possible. As specialty certification to demand greater knowledge and skill and docu-
becomes more common in pharmacy, recognition mentation of that knowledge and skill from those
of its value to the individual pharmacist will also professionals responsible for drug therapy manage-
increase, just as it has for medicine and other ment. In their document titled, Guiding Principles
health profession specialists. for Post-licensure Credentialing of Pharmacists, the
Council on Credentialing in Pharmacy calls for
Other credentials in pharmacy
a planned, coordinated effort by the phar-
Specialty certification is but one of several options macy profession to educate pharmacists, other
open to pharmacists seeking to advance professionally health professionals, employers, payers, and
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Patient care | 575

the public about all credentials held by phar- While it is uncertain which areas of pharmacy
macists and their value to patients and the practice will be recognized as specialties in the future,
health care system. This effort should also BPS is currently conducting role delineation studies
advocate for the effective integration of phar- in critical care, pain management, palliative care, and
macists with post-licensure credentials into pediatrics. Each new specialty must satisfy all seven
current and evolving health care delivery sys- criteria for recognition by BPS, and this process main-
tems. Credentials should enable pharmacists tains the high standards set forth by the visionaries
to obtain specific patient care privileges and who began this process nearly three decades ago.
should not create barriers to the provision
of any services pharmacists provide to their
patients.84 Ambulatory care pharmacy
From 1995 to 2010 the number of board cer- practice
tified specialists in pharmacy has grown by over
600% (i.e., from 1649 to 10,337); this number rep- Ambulatory care pharmacy practice encompasses a
resents just 5% of practicing pharmacists. For those broad range of patient care and public health activities
pharmacists that have sought BPS certification, the conducted in settings where patients are responsible
recognition and acceptance of specialization have for administering their own medications and engag-
increased. The future of specialty certification will ing in self-care behaviors.88 According to the Board
ultimately be defined by many factors, including pay- of Pharmacy Specialties, ambulatory care pharmacy
ment for medication therapy management services, practice is:
continued development of collaborative prescriptive
practices (i.e., currently, more than 40 states have such the provision of integrated, accessible health-
legislation), evolution of accountable care organiza- care services by pharmacists who are account-
tions and medical home models, further expansion able for addressing medication needs, develop-
of postgraduate training programs (including new ing sustained partnerships with patients, and
degrees and specialty practice residencies), employer practicing in the context of family and com-
practices, and society’s acceptance of new roles and munity. This is accomplished through direct
practices for pharmacists. Over the past decade, the patient care and medication management for
growth in pharmacy residents has been impressive, ambulatory patients, long-term relationships,
from 896 graduates in 2001 to over 2100 graduates coordination of care, patient advocacy, well-
in 2010.85 As more and more students continue to ness and health promotion, triage and referral,
seek postgraduate training to differentiate themselves and patient education and self-management.89
from the typical graduate, the number of pharmacy
practice residencies and specialty practice residen- Although commonly perceived to be a practice
cies must expand. Unfortunately, the development of setting, ambulatory care pharmacy practice is not
new residency programs is currently lagging behind location-specific.88 Indeed, ambulatory care pharma-
demand for this training. A new cadre of specialty cists practice in community health centers, community
trained practitioners will help drive the process of pharmacies, employee health clinics, family medicine
specialty recognition. practices, physician offices, primary care clinics, spe-
There has been consistent support for board certi- cialty care clinics, and occasionally visit patients in
fication by many of the profession’s professional orga- their homes. Many ambulatory care pharmacists work
nizations, including the American College of Clinical in organized health systems like academic health sci-
Pharmacy,82 the American Society of Health-System ence centers, health maintenance organizations, the
Pharmacists in their document, ASHP Long-range Indian Health Service, military hospitals, ambulatory
Vision for the Pharmacy Work Force in Hospitals care centers, or Veterans Affairs Medical Centers.
and Health Systems86 and through the ASHP’s Com- But a growing number of ambulatory care pharma-
mission on Credentialing accreditation standards for cists are employed by national pharmacy chains and
PGY2 residency program directors.87 independently owned pharmacies. Some ambulatory
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576 | An Introduction to Pharmacy

care pharmacists are self-employed independent prac- medication-management needs.88 Ambulatory care
titioners. Thus, ambulatory care pharmacy practice pharmacist specialists possess specialized knowledge
does not occur in a specific location or specific employ- and skills that enable them to meet the needs of
ment model, but rather is a patient-centered prac- complex ambulatory care patients with chronic dis-
tice where pharmacists interact directly with patients eases and to take responsibility for achieving desired
and their families over sustained periods of time to medication therapy outcomes. As the profession of
address health and medication-related issues. Many pharmacy has evolved and become more specialized,
ambulatory care pharmacists devote a considerable ambulatory care pharmacist specialists have become
amount of their time to wellness and health promo- leaders in chronic and preventive care. They often
tion activities, rather than focusing solely on disease implement patient care programs; educate and train
management tasks.90 other pharmacists to deliver innovative clinical
Chronic illnesses such as cardiovascular disease, services in ambulatory care settings; and participate
diabetes, chronic respiratory diseases, and bone dis- in practice-based research. Moreover, they often serve
eases are the leading causes of death and disability as preceptors for the required advanced pharmacy
in the United States. The incidence of obesity and practice experiences and the growing number of
related complications is rising. By 2009, 145 million postgraduate residency programs.
Americans, nearly half the population, lived with a
least one chronic disease.91 Nearly a quarter of the Self care
population has multiple chronic diseases. Further-
more, 84% of all healthcare expenditures are related Pharmacists and Self-Care with
to chronic care. In October 2007, the Milken Institute Non-prescription Products
released a report indicating that the seven most com- In the matter of self-medication by the public with
mon chronic diseases resulted in a $1.3 trillion annual non-prescription (over-the-counter or OTC) drugs,
cost to the US economy.92 These costs are expected pharmacists are in a unique position to provide assis-
to exceed $6 trillion by 2050. tance because of their education, training, and ready
Medications play a significant role in the pre- accessibility to the public. Experts estimate that the
vention and treatment of most chronic diseases.93 number of non-prescription products is in excess of
Millions of patients are prescribed complex regimens 300,000.108,109 In the United States, non-prescription
with multiple medications taken several times a day product sales exceeded $16.8 billion in 2008.110
and requiring special administration procedures.88 Like other businesses, pharmacies are in a fight
With increasing medication use there comes a greater for survival. Recent years have seen closings of many
potential for medication errors, adverse drug events, small, independent stores. Third-party plans have
and drug misuse. The negative consequences of poor reduced prescription profits so drastically that some
medication use behavior are well documented.94,95 retailers have turned to high volume strategies in an
Poor medication adherence contributes to poor out- attempt to survive. One unfortunate result of high
comes, hospitalizations, and unnecessary costs.96 volume is decreased patient interaction time. Phar-
Numerous scientific publications have docu- macists are forced to spend long hours behind the
mented the significant reductions in morbidity and prescription counter with no scheduled lunch hour
mortality when patients with chronic illnesses have and little patient contact. Pharmacist-generated com-
access to the professional services of an ambulatory ments on websites detail these complaints.111,112 Even
care pharmacist.97 – 100 Clinical, humanistic, and though counseling is required, it can be cursory and
economic benefits have been demonstrated in patients hurried.113 Management demands more work with
with asthma, chronic kidney disease, diabetes, less help, because hiring additional pharmacists and
dyslipidemia, hepatitis C, hypertension, HIV, stroke pharmacy technicians further reduces shrinking prof-
prevention, and venous thromboembolism.98 – 107 By its. This dismal picture is more prevalent in high
virtue of their education, training, and experience, volume chain stores.
ambulatory care pharmacists are better prepared than Fortunately, some pharmacists realize that push-
any other healthcare professionals to meet patients’ ing for high volume is self-defeating in the long run
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Patient care | 577

because it appeals to the patient who wants cheap Those who choose to place non-prescription prod-
products at the expense of services such as delivery. ucts in close proximity to the pharmacy enhance
Some pharmacists have realized that another route to their credibility as experts in self-care.109
survival is to cultivate a specialty or ‘‘niche.’’114,115 • In some community pharmacies, non-prescription
There are several viable and profitable specialties, products are positioned close to the pharmacy, but
such as compounding. Unfortunately, articles in phar- shelving is parallel to the pharmacy, rather than
macy journals and textbooks may advise specializing perpendicular, which also makes it impossible
in products of unknown safety and efficacy, such to see patients who need help. Choosing a store
as herbal supplements and homeopathic products. layout that allows the pharmacist to visualize the
Perhaps pharmacists could focus instead on becom- patients in the self-care aisles allows the pharma-
ing self-care specialists, advising patients on the use cist to render assistance when necessary.109
of a wide range of FDA-reviewed non-prescription
products that are ethical, safe, and effective.116 The pharmacist who wishes to develop this niche
Marketing one’s practice location as a center should obtain current information on the various
for self-care through intense counseling on non- self-treatable conditions, as well as all of the non-
prescription products and devices is a logical and prescription ingredients and the many precautions
profitable specialty. Self-care is especially appealing associated with their use.
because of several factors:

The Movement Toward Self-Care

• Non-prescription products are available in numer-
ous non-pharmacy outlets where personnel lack During the 1960s, the United States experienced
medical training.109 By contrast, most pharmacists a growing distrust of established entities, such as
have had a non-prescription products/self-care the government, organized religion, and legitimate
course as part of the professional pharmacy cur- medicine. One of the consequences was a compelling
riculum. Thus, the pharmacist with expertise and consumer desire to rebel against the traditional
education in self-care of minor medical conditions provider–patient relationship, in which the consumer
can provide competent medical advice that the meekly and unquestioningly followed the direc-
patient will not be able to obtain in non-pharmacy tions of the provider. Patients began to demand a
locations. greater personal involvement and responsibility for
• The typical community pharmacy already stocks healthcare maintenance and treatment, a trend that
a wide range of non-prescription products and continues today.117 Direct-to-consumer advertising
devices, so there is no need to purchase a special of prescription products enhanced this trend by intro-
group of products or invest in costly equipment ducing a medical paradigm in which patients should
and remodeling (e.g., adding a clean room and demand specific prescription products from the
laminar flow hoods).109 physician based on advertisements. Consumers also
• The non-prescription market includes many feel competent to guide their own medical therapy
ingredients and products lacking proof of efficacy based on past personal experience or anecdotal infor-
and/or safety.109 Pharmacist counseling helps mation from friends and relatives in regard to specific
patients choose products whose safety and efficacy non-prescription products. This is partly due to the
is demonstrated. common myth that any non-prescription product or
• Effective counseling in the non-prescription area device advertised in the media is safe and effective for
allows the pharmacist to extend the concept of self-use without medical supervision. Further, some
pharmaceutical care. patients feel that the non-prescription product label
• Many pharmacies locate non-prescription prod- contains all of the important information, denying
ucts away from the immediate location of the phar- the possibility that a pharmacist consultation can
macy. The pharmacist cannot advise patients who add any value to the purchase. Partially as a result
need help with these items, which seriously com- of these various market forces and misconceptions,
promises their ability to offer self-care counseling. non-prescription products cause many episodes
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578 | An Introduction to Pharmacy

of morbidity and mortality that might have been Can Patients Read Non-prescription
prevented with judicious pharmacist counseling.109 Product Labels?
It is an uncomfortable truth that patients who
Another major rationale for pharmacist involvement
enter pharmacies with preconceived notions about
in self-care is the issue of patients’ ability to read
a particular non-prescription product or course of
and/or comprehend non-prescription product labels.
action are often manifestly and profoundly incorrect,
The FDA requires that each OTC label clearly
and it is in the highest tradition of pharmaceutical
communicate to patients all information required for
care that the concerned pharmacist correct those
safe use of that non-prescription product. However,
misconceptions and guide them to more appropriate
pharmacists add value to the purchase of non-
self-care decisions.
prescription products by acting as a ‘‘learned interme-
diary.’’ In this role, the pharmacist points out specific
The Prescription to Non-prescription contraindications to use of certain products, answer-
(Rx-to-OTC) Switch ing questions about dosing, adverse effects, and
appropriate use.
A second factor that greatly increases the validity
Many patients are unable to properly read and/or
of pharmacist counseling in self-care is the dynamic
interpret the label. Some suffer impaired vision (e.g.,
and ongoing switch of prescription products to non-
glaucoma damage, detached retina, macular degen-
prescription status.109,118 – 121 During the past sev-
eration) that does not allow them to read small
eral decades, powerful new therapies have become
print. Some suffer from tremor or other conditions
available for self-care in widely divergent arenas.
that make it difficult to hold the container still for
They include loperamide for diarrhea, ibuprofen and
reading prior to purchase. Other patients cannot
naproxen for pain, hydrocortisone for dermatoses,
understand the terminology used on labels, perhaps
minoxidil for androgenetic alopecia, nicotine patches
because English is not their primary language. Still
and gum for smoking cessation, ophthalmic anti-
other patients have limited reading comprehension
histamines for allergic conjunctivitis, histamine-2-
or may be completely illiterate. In all of these cases,
blockers and proton-pump inhibitors for heartburn
pharmacist counseling can be of immense value.
and gastroesophageal reflux, non-sedating antihis-
tamines for allergic rhinitis, and pyrantel pamoate for
pinworm.122 – 124 Unfortunately, due to widespread
How Patients Choose Non-prescription
opposition, there is no ‘‘third class’’ into which
Products and Devices
switched medications move prior to their unsuper-
vised release to the American public. This leads to Persons do not always seek the advice of a physician
the uncomfortable realization that a particular med- with every illness. Symptoms of the ailment may be
ication awaiting a switch is only available under a deemed minor enough to treat with a non-prescription
physician’s prescription, requiring pharmacist coun- product. In fact, 60% of all medications purchased
seling and refill authorization until midnight the day by Americans are non-prescription products.108 The
before the switch occurs. At 00:01 hours on the day decision of the patient concerning which product
of the switch, the ingredient is suddenly deemed safe to purchase is based on such input as prior expe-
enough to be sold to any consumer in any location at rience with the product, advice received from a
any time, with no professional monitoring or advice neighbor or relatives, or advertisements. However,
being necessary.109 The products can be purchased the pharmacist supersedes all of these, being the only
in any gas station, beauty shop, airport lobby, or expert in self-care with non-prescription products and
hotel vending machine. Since there is no legal require- devices. Pharmacists can develop an enduring self-care
ment for professional counseling prior to purchase of specialty by making defensible patient triage deci-
non-prescription products, the manufacturer assumes sions that are based on scientific principles. Through
the full burden of communicating proper use, pre- this practice, it is often necessary to guide incorrect
cautions, risks, and other information by creating an patient purchase decisions into a more suitable and
appropriate label. appropriate path.
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Patient care | 579

Diagnostic self-care and who is also uniquely positioned to encourage the

patient to seek the professional advice of a physician,
In 2010, the medical device market was worth when necessary
$94.9 billion, 3.65% of the total spent on healthcare
($2.6trillion, about 17.7% of GDP). Diagnostic
devices have revolutionized the self-care industry.
Complementary and alternative
Consumers benefit from their easy accessibility. Some medical healthcare
examples of these devices include blood pressure
monitors, home blood glucose monitors, HIV exams, Nearly 40% of adults in the United States use some
cholesterol exams, and home tests for colorectal form of complementary and alternative medicine
cancer. They help monitor chronic diseases, diminish (CAM) therapy.126 There is a growing interest in
doctor visits and associated costs, decrease hospital- CAM as individuals become more interested in health
izations, and allow consumers to become an active and fitness and disease prevention. CAM therapies
part of their own healthcare.125 With the trend are gaining popularity, in part due to rising pre-
toward pharmaceutical care and preventive medicine, scription drug costs, side effects of conventional
the pharmacist can perform a vital public health role medicine, distrust of and frustration with the health-
by counseling the consumer on newer diagnostic care system, and increased public access to infor-
devices, contributing to a reduction in deaths from mation. Some patients use CAM techniques like
colon cancer, helping patients monitor blood glucose, meditation127 and prayer3 to cope with chronic and
and aiding in the detection of drug abuse. untreatable diseases.
Even though they have become more user friendly, Patients and practitioners are increasingly inter-
patients may still encounter problems with even the ested in integrating CAM therapies with conventional
simplest devices. Consequently, pharmacists are often medical treatments. These therapies include acupunc-
summoned to educate patients on proper use and the ture, chiropractic, herbal medicine, dietary supple-
validity and application of the results. It is essential ments, homeopathy, mind–body techniques, faith
that pharmacists ask questions about the disease or healing, massage, and a number of others. While many
exam and make any appropriate recommendations CAM therapies have not been rigorously tested and
based upon the available information. The pharma- evaluated, knowledge and understanding is growing.
cist should remind the patient that any information Evidence-based resources on CAM128 – 132 compile
attained as a result of counseling shall remain strictly and analyze the available evidence in this field. Open
confidential. The pharmacist should also mention that dialogue should exist between healthcare profession-
these test kits/devices must be used in collaboration als and patients about the use of CAM products and
with healthcare professionals, who can interpret and practices to ensure safety and coordinated care.
discuss the test results and their implications.
Diagnostic aids and tests are complex to use.
Patient comprehension is maximized when a phar- Preventive care
macist is involved in the purchase and use of these
Introduction
products. If these products are purchased in a non-
pharmacy outlet, the consumer does not have the Routine follow up with primary care physicians and
opportunity to ask questions or receive reliable recom- other healthcare professionals can aid in the early
mendations from an educated professional, increasing detection of many medical conditions (e.g., cancer,
the chance of product misuse.125 diabetes, hypertension), and can encourage healthy
Pharmacist-assisted care has direct benefits to the habits that prevent the development of other condi-
patient. The pharmacist is a highly educated drug tions (e.g., lung cancer, obesity). This section seeks
information specialist in OTC products. This, in con- to point out areas of preventive care that are wide-
junction with practical experience, makes the phar- reaching to the general population, and are areas that
macist the only health professional who understands pharmacists of all practices should be aware of when
the limitations of self-treatment with OTC products interacting with patients.
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580 | An Introduction to Pharmacy

To begin with, it is appropriate to provide some regular updates to the Healthy People recommenda-
definitions of prevention. Primary prevention refers tions have been made, the most recent being Healthy
to preventing a disease from occurring (such as child- People 2020, released in 2011. Healthy People 2020,
hood vaccinations). Secondary prevention refers to from the US Department of Health and Human Ser-
trying to reduce morbidity in pre-symptomatic sub- vices, is considered the master plan for improving
jects with established disease by its early detection and the health of the American population over the next
treatment (such as screening of asymptomatic women decade, and covers 42 topics and nearly 600 objec-
and early treatment of detected cervical cancer). Ter- tives. There are 12 key topics, 24 key objectives, and
tiary prevention is implemented on patients with a 24 leading indicators to go with Healthy People 2020
view of cure, palliation, rehabilitation, or prevention (Box 13.2).134 The intent is to increase the quality
of recurrence or complications (such as treatment and years of healthy life, and to eliminate dispari-
of symptomatic cancer). There are numerous inter- ties among the overall health of various communities,
pretations among individual practitioners about these ethnic groups, and classes.
three definitions, and their use is not recommended by Providing cost-effective healthcare throughout the
all.133 Instead, it has been suggested clinical interven- country is a huge challenge, and is being undertaken
tions be defined by their objective, target population, by the US Preventive Service Task Force (USPSTF).
and type (‘‘reduction of mortality by increased use of This task force is an independent panel of experts
statins in patients with a history of myocardial infarc- in primary care and prevention convened by the
tion’’) instead of by level of prevention (‘‘tertiary Agency for Healthcare Research and Quality that
prevention of myocardial infarction’’). systematically reviews the evidence of effectiveness
Health promotion and disease prevention were of, and develops recommendations for clinical pre-
not always priorities of healthcare. It was not until ventive services. The first task force started working
1979 that the Healthy People: The Surgeon General’s in 1984 to 1989 to develop recommendations for pri-
Report on Health Promotion and Disease Prevention mary care clinicians on the content of periodic health
and Promoting Health/Preventing Disease: Objec- exams. It published the Guide to Clinical Preventive
tives for the Nation were published. Since that time, Services based on this work. In 1990, the second

Box 13.2 Healthy People 2020 topic areas

Access to health services Human immunodeficiency virus infection
Adolescent health Immunization and infectious diseases
Arthritis, osteoporosis, and chronic back conditions Injury and violence prevention
Blood disorders and blood safety Lesbian, gay, bisexual, and transgender health
Cancer Maternal, infant, and child health
Chronic kidney disease Medical product safety
Dementias, including Alzheimer’s disease Mental health and mental disorders
Diabetes Nutrition and weight status
Disability and health Occupational safety and health
Early and middle childhood Older adults
Educational and community-based programs Oral health
Environmental health Physical activity
Family planning Preparedness
Food safety Public health infrastructure
Genomics Respiratory diseases
Global health Sexually transmitted diseases
Health communication and health information technology Sleep health
Healthcare-associated infections Social determinants of health
Health-related quality of life and well-being Substance abuse
Hearing and other sensory or communication disorders Tobacco use
Heart disease and stroke Vision
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Patient care | 581

USPSTF updated these recommendations for preven- the patient’s outcome. Effective screening tests should
tive services, and released the second edition of the be highly sensitive (i.e., correctly identifying a high
guidelines in 1996 and the third in 1998. The Guide- proportion of persons with the disease) and highly
lines to Clinical Preventive Services, 2010–2011 Rec- specific (i.e., correctly identifying a high proportion
ommendations of the USPSTF, released in 2010, can of persons without the disease). Effective screening
be found at http://www.ahrq.gov. These recommen- tests should not cause harm from the test itself. These
dations are modified by individual health plans for should also be of an acceptable cost burden to society
their use, endorsed by the American Association of so as to be utilized by the patients who need them.
Health Plans, incorporated into HEDIS (Health Plan
Employer Data and Information Set), and may result Disease Prevention Interventions
in changes in laws regarding health coverage. Part
of the challenge of the USPSTF is to make rec- The first method of prevention for a particular disease
ommendations for care based on cost-effectiveness. is to eliminate the risk factors that a patient possesses.
Accordingly, they have developed ratings for their When one considers risk factors to disease, these
recommendations, based on the levels of evidence, are often broken down into modifiable and non-
which are listed in Table 13.5. modifiable risk factors. Modifiable risk factors are
actions that the individual can make to change his/her
own behaviors, such as smoking cessation, weight
Screening for Disease Prevention
loss and dietary changes. Non-modifiable risk factors
Disease screening is effective when the screening test often include the presence of genetic risk factors,
can detect a disease or its precursor before it becomes concomitant disease states, and abnormal laboratory
symptomatic, and when early treatment can improve values, and cannot typically be changed by the actions

Table 13.5 USPSTF recommendation definition

A Strongly recommends that clinicians routinely provide [the service] to eligible patients. (The USPSTF found good evidence that the
service improves important health outcomes and concludes that benefits substantially outweigh harms.)

B Recommends that clinicians routinely provide [the service] to eligible patients. (The USPSTF found at least fair evidence that the
service improves health outcomes and concludes that benefits outweigh harms.)

C No recommendation for or against routine provision of [the service]. (The USPSTF found at least fair evidence that the service can
improve health outcomes but concludes that the balance of benefits and harms its too close to justify a general recommendation.)

D Recommends against routinely providing [the service] to asymptomatic patients. (The USPSTF found at least fair evidence that the
service is ineffective or that harms outweigh benefits.)

I Evidence is insufficient to recommend for or against routinely providing [the service]. (Evidence that the service is effective is
lacking, of poor quality, or conflicting and the balance of benefits and harms cannot be determined.)

The US Preventive Services Task Force (USPSTF) grades the quality of the overall evidence for a service on a 3-point scale
(good, fair, or poor)

Good Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess
effects on health outcomes.

Fair Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality,
or consistency of the individual studies; generalizability to routine practice; or indirect nature of evidence on health outcomes.

Poor Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in
their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.
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582 | An Introduction to Pharmacy

of the patient. A key element to preventive care is to status. Estimated lifetime prevalences of alcohol and
make patients aware of the risk factors that exist for drug dependence were estimated to be 12.5%135
various diseases and to minimize the presence of these and 2.3%,136 respectively, of the population in the
risk factors. United States in a 2001–2002 study. Alcoholism
was estimated to be responsible for 85,000 deaths
Chemoprevention in 2000.137 In 2007, the estimated direct and indirect
Chemoprophylaxis is the use of natural or synthetic costs of illicit drug use in the United States exceeded
compounds to block, reverse, or prevent the develop- $193 billion.138 Even with these staggering numbers,
ment of a disease or undesirable outcome. Increasing substance use disorders are frequently overlooked
evidence in the literature supports the role of chemo- as healthcare issues that pharmacists can impact.
prevention to prevent the development of various Co-occurring mental health disorders such as depres-
diseases, such as the use of tamoxifen to prevent sion and anxiety disorders are frequently seen in
breast cancer development. For patients that are at those with drug dependencies and can significantly
high risk for the development of a disease because of complicate therapy and outcomes.
underlying risk factors, consideration of drug therapy As healthcare professionals, pharmacists are well
to help prevent the development of a disease may positioned to take a major role in the disease
be necessary. Typically, clinicians think of antibiotics management of substance use disorders and other
and antivirals because of their evidence against several comorbid conditions.139 Pharmacists have knowledge
infective illnesses; for example, isoniazid for tuber- of the pharmacology, pharmacokinetics, mechanisms
culosis, amoxicillin for dental prophylaxis against of action, drug interactions, and adverse events
subacute bacterial endocarditis, and antiviral agents associated with prescription medications and abused
after needlestick injuries to prevent HIV transmission. substances.140 Therefore, taking an active responsibil-
ity in assessing patients and assuring the appropriate
Clinical Guidelines use of treatments for substance use is another oppor-
tunity in the ever-increasing role of the pharmacist.
Many organizations provide guidelines for screen-
ing of various diseases, actions to prevent disease,
and effective chemoprevention methods. These rec- Emergency medicine pharmacy
ommendations can be found at the National Guide-
practice
line Clearinghouse web site at http://www.guidelines
.gov/index.asp, which is sponsored by the US Agency
Although Emergency Medicine (EM) pharmacists
for Healthcare Research and Quality in partnership
are becoming increasingly common in Emergency
with the American Medical Association and the Amer-
Departments (EDs) across the country, their role is
ican Association of Health Plans. Interested readers
still evolving within clinical pharmacy practice. For
can also search the Internet home pages of major
over 30 years, EM pharmacists have been providing
national organizations, such as the Centers for Disease
decentralized services in EDs.141,142 When EM phar-
Control and Prevention, American Diabetes Associa-
macists first established services in the ED setting,
tion, American Heart Association, and the American
they primarily facilitated medication distribution and
Cancer Society, or perform Medline searches for the
inventory control, while providing limited clinical
individual recommendations. Readers are encouraged
services.142,143 Initially, clinical services offered by
to search these guidelines routinely, because they are
EM pharmacists were met with resistance in the
updated on a regular basis, as new research and
fast-paced ED environment. However, over time, EM
evidence become available.
pharmacists have slowly but surely gained ground in
providing clinical consultation, preventing medica-
Substance abuse care tion errors, and establishing a collaborative practice
with healthcare providers in order to optimize care
Substance abuse and drug addiction permeate our across the spectrum of ED patients. By demon-
society today, irrespective of one’s socioeconomic strating their value through clinical intervention
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Patient care | 583

documentation along with advancement of the childhood and adolescence, interpretation of clini-
specialty practice area at the national level, EM cal trial data conducted on pediatric patients must
pharmacists have grown in number, particularly over be carefully analyzed and evaluated with this special
the past 10 to 15 years.144,145 population’s characteristics in mind.
EM pharmacists have worked diligently to Over the past two decades, more comprehensive
develop their clinical practice and expand the types literature guiding clinicians on effective use of medica-
of services they offer in the ED setting. Many EM tion in children, including dosing recommendations,
pharmacists not only provide clinical expertise in has become available. However, it is imperative to
medication therapy management, but also play a vital use standardized age definition (Table 13.6) to ensure
role in supporting educational and research efforts safety and avoid medication mishaps, errors as well
in the ED, providing insight and expertise in policy as omissions.
development and disaster planning, and assisting in
quality improvement initiatives.
Challenges in pediatric drug therapy
Significant improvements for addressing incomplete
Pediatric pharmacy practice pediatric clinical pharmacology data in the US have
been made in the past two decades, largely due to
Introduction
the Best Pharmaceutical for Children Act (BPCA),
Medication use in children remains a challenge in Pediatric Research Equity Act (PREA), and the
many ways. Many prescription and nonprescription National Institutes of Health Pediatric Pharmacology
medications are not approved by the FDA for use Research Unit (PPRU) network.149 – 151 The BPCA
in children under 12 or 18 years of age. Safety provides pharmaceutical manufacturers additional 6
of medication used in children is a public health months of market exclusivity when pediatric trials
concern; however, the prevalence of data on medi- under the direction of the FDA are completed.149 The
cation use in children is limited, and thus the actual PREA mandates the studies of new and marketed
impact of proper or improper medication use is not medicines in children when use is applicable for
well described. children.149 Despite these advances, certain medica-
Based on the Slone survey published in 2009, for tion dosage recommendations may be conflicting in
the 7 days preceding a randomized phone interview,
56% of children had used more than one medication,
with 20% taking prescription-only medications and Table 13.6 Age definitions148
the majority taking non-prescription medications.146
Fifteen percent of the participants reported taking Terminology Age
two, 7.1% taking three, 3.1% taking four, and 1.9%
taking more than five medications.146 The survey Premature neonate Gestational age ≤37 weeks

included questions differentiating the use of prescrip-

Postnatal age ρ month
tion, non-prescription, and herbal medications (less
than 5%).146 According to IMS Health, besides occa- Full-term neonate Gestational age ≥37 weeks
sional use of medications such as antibiotics, more
than 25% of children and teenagers in the US are Postnatal age ρ month

taking prescription medications on a daily basis for

Post-term neonate Gestational age ≥43 weeks
chronic conditions including diabetes, hypertension,
Postnatal age ρ month
depression, insomnia, and hypercholesterolemia.147
Many of the medications used for such chronic con- Infant 1–12 months
ditions are not FDA approved for use in children,
and limited clinical trials are available to determine Child 1–11 years

proper dosages, efficacy, and safety. With ongo-

Pubescent or adolescent 12–16 years
ing physiologic developmental changes throughout
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584 | An Introduction to Pharmacy

children in situations of continued incomplete irritation and phlebitis or intraventricular hemorrhage

pharmacology data and differences in established in preterm infants, respectively.
off-labeled prescribing practices. Table 13.7 summarizes pharmaceutical excipients
Due to the lack of pediatric friendly dosage forms, that are known to cause adverse events in children.154
several commercially available oral and intravenous Benzyl alcohol, a common preservative found in many
medications require reformulation by pharmacists. multidose intravenous products, is an example of
Oral forms such as clonidine, metronidazole, and a pediatric therapeutic misadventure. In the early
spironolactone lack commercially available oral liquid 1980s there were several reports of neonates devel-
forms and require extemporaneous compounding by oping a gasping syndrome with severe metabolic
pharmacists for children who are unable to swallow acidosis and encephalopathy resulting in fatalities
tablets or capsules. Extemporaneous oral formulation when receiving intravascular flush solutions contain-
databases are available with product stability infor- ing 0.9% benzyl alcohol. Premature/newborn infants
mation but lack clinical absorption data.152 If no oral lack mature metabolic pathways to fully metabolize
liquid formulation exists, powder papers (aliquots benzyl alcohol, which may result in the accumulation
and titrations of tablets or capsules) or the intra- of benzoic acid, an intermediate metabolite, leading
venous dosage form for oral administration serve to the development of the aforementioned adverse
as alternative methods for oral drug delivery. Avail- effects.155 In addition, intravenous cephalosporins,
able concentrations of commonly used intravenous such as ceftazidime and cefepime, contain l-arginine
medications for premature infants often require dilu- as a buffering agent and exposure to children with a
tions to assure accuracy of dose delivery. In vitro rare form of arginase deficiency may result in severe
simulations of intravenous drug delivery for a 1 kg progressive neurological decompensation.156
neonate have shown the potential for overdoses up to Potential drug delivery issues for children include
twice the desired dose when using commercially avail- difficulties with initiating and maintaining the patency
able drug concentrations and measuring devices that of intravenous lines (especially in preterm neonates);
make measuring smaller dosage volumes (<0.05 mL) incomplete flushing of intravenous and oral lines to
impossible and inaccurate.153 In addition, administra- assure complete dose delivery; inadequate shaking
tion of undiluted hypertonic/hyperosmolar oral and of oral suspensions resulting in potential under- and
injectable medications may result in gastrointestinal overdosages; and poor tasting oral medications.157

Table 13.7 Adverse effect potential of pharmaceutical excipients9

Excipient Adverse effect

Benzyl alcohol Severe metabolic acidosis, encephalopathy, respiratory depression with gasping in premature neonates7

Propylene glycol Contact dermatitis, cardiac arrhythmias, hypotension, CNS depression, lactic acidosis and seizures

Lactose Abdominal intolerance and diarrhea

Coloring agents and sulfites Hypersensitivity reactions

Alcohol CNS depression

Sugar Dental caries

Aspartame Contraindicated in phenylketonuria (PKU)

L-Arginine Contraindicated in arginase deficiency8

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Patient care | 585

Although the use of flavoring agents may be helpful in high-throughput DNA sequencing, gene mapping,
increasing the palatability of poor-tasting oral liquid and bioinformatics. This has resulted in genomewide
medications, use of this adjuvant should be used with association studies, whereby hundreds to thousands of
discretion as overuse may result in potential future polymorphisms are studied in the content of potential
behavioral issues by which a child will take their disease associations in a patient population.165
medicines only if it is a certain flavor that they desire. DNA sequence variation that is present in
Also, using a flavoring agent may negatively affect the more than 1% of the population is defined as a
medication’s stability and absorption characteristics polymorphism.166 The most common polymorphism
as supporting data in this area are often incomplete. is known as a single nucleotide polymorphism (SNP).
Current medication delivery support systems such The resultant single base-pair change (e.g., substitu-
as electronic prescribing, smart intravenous infusion tion of adenine for guanine) may or may not change
pumps, and pharmacy computer systems are currently an amino acid sequence. The thiopurine methyltrans-
being developed to foster safe and efficient use of ferase (TPMT*3A) is an example of a nonsynonymous
mediations for children.158 – 161 Existing commercial SNP. The adenosine-triphosphate binding cassette
systems are typically adult-based systems that are protein B1 (ABCB1) 3435 C>T is an example of
not compatible for children and require the input of a synonymous SNP. The cytochrome P450 [CYP]
well-trained and experienced pediatric pharmacists to 2C19*3 polymorphism is an example of a point muta-
incorporate the necessary modifications. tion involving a premature stop codon that results
in termination of protein synthesis. Other polymor-
phism types include a gene deletion (e.g., CYP2D6*5)
Transplant pharmacy practice or gene copy number variant (e.g., CYP2D6*2N),
both of which involve large segments of the DNA
Over the past 60 years, the field of transplanta- sequence. Certain polymorphisms will affect gene
tion has evolved significantly with improvements in expression, protein function, and activity. Of note,
medical diagnostics, procedures, surgical techniques, alterations in gene expression can also occur in the
and pharmacotherapy. With the development of new absence of DNA sequence variation (e.g., epigenetics).
immunosuppressive medications and the use of com- Prior to establishing a pharmacogenomics clinical
plex pharmacologic regimens, the opportunity has practice, a systematic approach to understanding
arisen for pharmacists to become more involved in polymorphisms is recommended.167 Identification of
the management of transplant patients. In today’s the polymorphism type and the protein that is affected
clinical practice, transplant pharmacists are integral by the polymorphism is important. Affected proteins
members of multidisciplinary transplant teams. can include an enzyme, drug transporter, or receptor.
Polymorphisms may differ in functional effect,
population prevalence, and clinical relevance.167 Pop-
Pharmacogenomics in pharmacy ulation variation may exist, whereby a polymor-
practice phism is present in a higher frequency in a specific
ethnic group.168 For example, the human leuko-
The field of pharmacogenetics and pharmacoge- cyte antigen (HLA)-B*1502 allele is associated
nomics attempts to examine the interindividual with a carbamazepine-induced hypersensitivity re-
differences in drug response.162 Pharmacogenomics action.169,170 The prevalence of the HLA-B*1502
is defined as ‘‘the genome-wide analysis of genetic allele is higher in certain Asian populations, compared
determinants of drug efficacy and toxicity.’’163 This to Caucasians and African-Americans.171,172 Conse-
is in slight contrast to pharmacogenetic approaches quently, HLA-B*1502 testing is recommended in all
that generally examine variations within single genes. patients of Asian descent prior to initiating carba-
Upon completion of the Human Genome Project in mazepine therapy. With respect to clinical relevance,
2003, the field of pharmacogenomics and ‘‘genomic drug dosing, selection, efficacy, toxicity, pharmacoki-
medicine’’ rapidly expanded with the advent of netics and/or pharmacodynamics may be affected
new technologies.164 Such technologies include by the polymorphism. Finally, a polymorphism may
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586 | An Introduction to Pharmacy

influence disease prognosis and susceptibility, or be of ADEs is unknown, because most institutions rely
used as a screening test for certain diseases.173 on voluntary reporting mechanisms. However, some
studies have reported rates as high as one or more
ADEs occurring on 17% of all patient days,180 and a
Critical care pharmacy practice rate of ADEs nearly twice that of non-ICU patients.176
In many cases, patients experience more than one ADE
Over the past two decades, numerous advances in during their ICU stay.181 A number of unique factors
diagnostic testing, technological intervention, and account for the high number of ADEs detected in crit-
pharmacotherapy have led to substantial improve- ically ill patients, including disease complexity, the
ments in the outcomes of patients who require admis- presence of end-organ dysfunction, the urgency with
sion to the intensive care unit (ICU).174 At the same which underlying conditions must be treated, the dis-
time, the care provided to critically ill patients has tractions inherent in the intensive care environment,
steadily increased in complexity and intensity. Per- the use of complex (including high-risk and narrow
haps the most important strategy that has evolved therapeutic index) drug regimens, and the frequent
over the past 30 years to address these changing use of intravenous infusions.182 Increasingly, health
paradigms of ICU care is the intensivist-led, multidis- information technology such as computerized physi-
ciplinary ICU team.175 This model of care, supported cian order entry, clinical decision support systems,
by major critical care organizations and increasingly barcode technology, and electronic surveillance sys-
being implemented in ICUs across the United States, tems are being implemented in the ICU in an effort to
advocates that a board-certified intensivist-led team reduce medication error and improve the efficiency
of nurses, pharmacists, respiratory therapists, nutri- and quality of care.183 However, this technology
tionists, and physical therapists work together in a is expensive, requires a dedicated multiprofessional
multidisciplinary fashion to optimize the delivery of team to implement, and currently is supported by
safe and effective care in the ICU. only limited evidence regarding its benefit in the ICU.
Drug therapy plays a key role in the manage-
ment of critically ill patients. The average patient
admitted to an ICU receives 30 different medications Infectious diseases pharmacy
throughout his or her stay. Critical care clinicians are practice
faced with numerous decisions each day regarding
drug selection, dosing, administration, and monitor- Despite the advances in antimicrobial therapy made
ing strategies and must consider how each of these over the past 50-plus years, the burden of infectious
decisions may influence patient outcomes and health- diseases in the United States and worldwide remains
care costs.176 Even if the correct medication is chosen significant. According to 2004 data published by the
for a patient, a suboptimal dose or route of admin- World Health Organization (WHO), communicable
istration may result in either therapeutic failure or diseases are the cause of three out of ten deaths
drug toxicity. Most dosing regimens employed in the worldwide, whereas six of ten deaths are due to
ICU are extrapolated from clinical trials completed noncommunicable conditions such as cardiovascular
in non-ICU individuals, or even healthy patients, and diseases. 184 Nonetheless, approximately 15 million
therefore usually do not account for the substan- individuals die annually secondary to infectious dis-
tial pharmacokinetic, pharmacodynamic and pharma- eases, and in low-income nations, infectious diseases
cogenomic variability seen in this population.177 – 179 such as malaria are the leading causes of death.184
Failure to account for these alterations when initiating Furthermore, of the 20 leading causes of death across
medication therapy in the ICU may lead to unpre- all age groups worldwide, six include conditions that
dictable drug effects, undesirable clinical outcomes, are infectious in nature, while communicable diseases
and increased drug toxicity. account for 50% of all deaths in children under the
Adverse drug events (ADEs) are common in the age of 5 years.184
ICU and often result in increases in both morbidity Several factors are responsible for the ongoing bat-
and mortality and healthcare costs.176 The true rate tle against both old and evolving infectious pathogens.
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Gastrointestinal diseases caused by Salmonella species to infections caused by susceptible pathogens;198 the
and other bacteria are a major cause of global mor- annual attributable cost in the United States is esti-
tality and are particularly prominent in poor and mated to be upward of $34 billion.197 While infections
crowded populations with inadequate sanitary prac- caused by resistant micro-organisms were once largely
tices, while foodborne outbreaks of infection also confined to hospitalized patients, in recent years a
occur in developed nations.185 – 187 Infections with marked increase in community-acquired infections
certain pathogens are associated with an increased risk caused by resistant pathogens has been observed. In
of co-infection with additional infectious illnesses, as the late 1990s the first reports emerged of patients
in the case of the association between human immun- who had acquired MRSA in the community.199,200
odeficiency virus (HIV) infection and malaria.188 Even more concerning is Clostridium difficile, a
Disadvantaged populations that lack access to health- Gram-positive, anaerobic, spore-forming, toxigenic
care resources are disproportionately affected by a bacterium, which now rivals MRSA as the most
variety of communicable diseases, as seen in Africa, common health care-associated infectious organism,
where a particularly significant impact of HIV infec- contributing to a cost in excess of $3.2 billion annually
tion is observed.189 – 191 Compounding this inequity, in the United States.201 – 203
drug development targeted toward neglected diseases Since 2000, there has been a dramatic increase
is insufficient.192 Moreover, even in developed nations in the frequency and severity of C. difficile infection
the burden of diseases such as HIV infection may throughout North America, Europe, and Asia that has
be greater in certain disadvantaged or underserved been associated with an epidemic strain. This hyper-
populations, such as females, racial minorities, and virulent strain, known as BI/NAP1/027, has enhanced
children.190,191 Finally, deficiencies in immunization resistance to fluoroquinolone antibiotics and is char-
rates lead to the ongoing dissemination of certain acterized by increased toxin production, sporulation,
vaccine-preventable diseases. Studies have shown that morbidity, and mortality.204,205
as few as 9% of children receive recommended vac- A significant factor that drives the ongoing
cines at the appropriate ages and that trends in emergence of antimicrobial resistance and other phe-
childhood vaccination coverage, while on the rise, nomena such as C. difficile infection is antimicrobial
have not reached national goals in all cases.193,194 Fur- use. It is generally accepted that antimicrobial con-
thermore, refusal of vaccinations, based on mistaken sumption leads directly to antimicrobial resistance.
beliefs regarding the safety or efficacy of vaccinations, Humans use an estimated 3 million pounds of antimi-
adversely impacts immunization rates.195 crobial agents annually; the majority of this use occurs
Of even greater concern is the ongoing develop- in the community setting, and one half or more of out-
ment of antimicrobial resistance, which poses a grave patient prescriptions are prescribed inappropriately
public health threat. Bacterial resistance to antibiotics for such conditions as viral infections.206 A direct
has been observed since the introduction of penicillin, link between prior antimicrobial use and colonization
and clinically significant resistance to an antimicrobial or infection with antimicrobial-resistant bacteria
agent often develops just a few years after introduc- has been shown for a number of antimicrobials and
tion of that therapeutic agent.196 One of the more pathogens; examples include associations between
problematic resistant bacterial species, methicillin- fluoroquinolone use and fluoroquinolone resistance
resistant Staphylococcus aureus (MRSA), kills more in nasally carried coagulase-negative staphylococci,
patients in the United States than HIV, Parkinson fluoroquinolone exposure and acquisition of MRSA,
disease, and homicides combined. Hospital-acquired as well as correlations between exposure to a
infections, the majority of which are caused by resis- variety of antimicrobials and bacteremia caused by
tant pathogens, kill more than 90,000 Americans each extended-spectrum beta-lactamase (ESBL)-producing
year.197 Infections caused by resistant organisms are Enterobacteriaceae.207 Antibiotic use has also been
associated with increases in morbidity and mortality, linked to increases in both antimicrobial resistance
lengths of hospitalization, and cost. Infections caused and mutation frequencies in bacteria commensal
by resistant pathogens are associated with increases to the human flora, such as Escherichia coli and
of $6,000 to $30,000 in total costs when compared enterococci.208 One of the more notable studies to
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588 | An Introduction to Pharmacy

demonstrate a relationship between antimicrobial use to enhance antimicrobial development in Europe and
and resistance showed that a nationwide reduction in the United States.211,215 The Infectious Diseases Soci-
outpatient macrolide use in Finland led to a decline ety of America (IDSA) has recommended a number of
in the frequency of erythromycin resistance in group strategies to enhance antimicrobial discovery, includ-
A streptococci.209 An additional contributing factor ing provision of financial incentives to entities that
to antimicrobial resistance is the widespread use of undertake such development, and regulatory guid-
antimicrobials in the food-animal industry.210 ance designed to encourage antimicrobial research
Given the ongoing emergence and dissemination and development.197,211 The ongoing crisis of antimi-
of antimicrobial-resistant pathogens, the development crobial resistance, coupled with the lack of novel
of novel antimicrobial agents is of paramount impor- antimicrobials, supports the idea that the role of
tance. Unfortunately, the pharmaceutical industry’s pharmacists in the field of infectious diseases is more
commitment to the development of novel antimi- important than ever.
crobials is on the wane (Fig. 13.4). In the 1970s,
1980s, and 1990s, no novel antimicrobial classes were
approved, and new antimicrobials were instead ver-
Pain and palliative care
sions of existing agents. Between 2000 and 2004,
only two novel antimicrobial classes were approved;
between 2006 and 2009, only one antimicrobial was Background
approved, doripenem, which belonged to an existing Our experience with death and disease has changed
class of antimicrobials.211,212 A number of factors dramatically over the last 150 years, and with it our
are responsible for this lack of antimicrobial develop- expectations for care at the end of life. In previous
ment, including failures in the drug discovery process, centuries, death usually was caused by sudden illness
an emphasis on developing ‘‘me-too’’ versions of exist- or trauma. Infections, childbirth, and even dental pro-
ing compounds, and the targeting of research efforts cedures were dangerous. Today, the development of
only toward existing resistant pathogens.213,214 The vaccines, discovery of antibiotics, and other innova-
current stagnation in the antimicrobial pipeline has tions in modern medicine have significantly improved
led to the formation of advocacy initiatives designed our health and increased our lifespan.

18 70%
16
60%
# of new systemic antibiotic
approved by the US FDA

14
50%
12
% incidence

10 40%
8 30%
6
20%
4
2 10% MRSA
VRE
0 0%
FQRP
987 992 997 002 007 012
3–1 8–1 3–1 3–2 3–2 8–2
198 198 199 199 200 200

Figure 13.4 Inverse trajectory of declining antibiotic drug development, superimposed by the increase in the prevalence of
three concerning bacteria: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and
fluoroquinolone-resistant Pseudomonas aeruginosa (FQRP). (Data based on estimates collected from intensive care units of
hospitals that participate in the CDC’s National Nosocomial Infections Surveillance System and adapted from Boucher HW et al.,
Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009 48: 1–12.)
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These advances also have raised important ques- pain’’ – the combination of physical, emotional, and
tions about what we truly want in end-of-life care. spiritual suffering often experienced by the terminally
Intensive medical treatments often are invasive and ill. 216,217
can be painful and debilitating. Patients often give Typically, patients admitted to hospice are cared
up quality of life now, to be placed on a ventilator for at home by a family member or other caregiver.
or to go through surgery, with the expectation that Hospice staff are available at all times and assist with
their medical care will resolve the illness and pro- regular visits and by providing medications and other
vide quality of life for years to come. Unfortunately, supplies. The environment usually is an interdisci-
chronic illnesses often cause a slow functional decline plinary one, where physicians, nurses, pharmacists,
that can be difficult to predict or treat. Ultimately, social workers, clergy, and others work together to
many patients reach a point where modern medicine develop individualized care plans.
can no longer improve their condition. At this stage,
patients and their families face difficult decisions. Fur-
ther intensive treatments may cause more debility and The Palliative Care Model
reduce quality of life without providing any benefits. Modern palliative medicine arose, and is shaped by,
For these patients, hospice and palliative care pro- its origins in hospice. Its goal is ‘‘to prevent and
grams have been developed to provide quality care relieve suffering and to support the best possible
focusing on the relief of symptoms rather than the quality of life for patients and their families, regardless
removal of disease. of the stage of the disease or the need for other
therapies.’’218 As with hospice, palliative care focuses
on symptom management and improving quality of
The History of Hospice
life. But palliative care programs recently have begun
The word hospice derives from the Latin hospitium, to extend outside the scope of traditional hospice
or hospitality. Its use dates from medieval times, practice.
when hospices were resting places for travelers and In this new model, as chronic disease devel-
pilgrims.216 Later, the term was revived by religious ops, palliative medicine works together with life-
orders, who used it to denote homes that cared for prolonging therapy, with palliation becoming a more
the sick and destitute. prominent focus as the disease progresses (Fig. 13.5).
The modern hospice movement traces its origins The result is a model of comfort care that is distinctly
to the opening of St. Christopher’s Hospice in different from, yet integrated with, hospice. Palliative
London in 1967.216,217 Founded by Dame Cicely care programs can be found in hospitals, long-term
Saunders, St. Christopher’s developed new standards care facilities, nursing homes, and ambulatory clinics.
for the field and incorporated education and research Like hospice, palliative care often is provided by a
into clinical practice. Researchers at St. Christopher’s multidisciplinary team, including physicians, nurses,
pioneered investigations into understanding the pharmacists, social workers, and chaplains committed
pharmacokinetics of opioids and developed new to a patient-centric model of care. Palliative medicine
strategies for symptom management, all while allevi- incorporates aggressive symptom management with
ating what Dame Cicely Saunders described as ‘‘total psychosocial, cultural, and spiritual factors to address

Life-prolonging therapy
Diagnosis
of serious Death
Medicare
illness
hospice
Palliative care benefit

Figure 13.5 The role of palliative care and hospice in serious illness. (Adapted from National Consensus Project for Quality
Palliative Care. Clinical Practice Guidelines for Palliative Care, 2nd edn., 2009. http://www.nationalconsensusproject.org.).
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590 | An Introduction to Pharmacy

physical as well as emotional suffering. But unlike outcomes and are consistent with current profes-
hospice, palliative medicine is a model of symptom sional knowledge.’’221 The US Department of Health
management at all stages of disease. and Human Services has defined quality as ‘‘the
degree to which a health or social service meets or
exceeds established professional standards and user
Pain and Palliative Care Pharmacy
expectations.’’222 Quality of healthcare is viewed as a
Pharmacists are uniquely positioned to meet the multi-component concept that involves common ele-
challenges associated with pain management and pal- ments: provision of services that yield better patient
liative care. Medication management in these patients outcomes. We can apply this concept to quality in
often is complex and requires specialized attention to pharmacy practice and provide patients what they
understand the interactions of disease, medications, want and need to improve outcomes in accordance
and comorbid conditions that will achieve the desired with established standards of excellence. As health-
therapeutic response. According to the American Soci- care professionals, pharmacists are responsible for
ety of Health-System Pharmacists Statement on the guaranteeing the quality of the services delivered and
Pharmacist’s Role in Hospice and Palliative Care,219 ensuring continuous quality improvement.
pharmacists have a wide array of responsibilities, Why is quality so important in healthcare? With
including: the mounting emphasis on the safety of the health-
care system, cost containment, coordination of care,
• Assessing the appropriateness of medication orders pay-per-performance, patient-centered care, health
and ensuring the timely provision of effective med- information technology, public reporting, and health-
ications for symptom control care reform, quality serves as a framework to guide
• Counseling and educating the hospice team about endeavors in our ‘‘value-driven’’ healthcare.223 For
medication therapy example, the Centers for Medicare and Medicaid
• Ensuring patients and caregivers understand and services (CMS) and the US Department of Health
follow the directions provided with medications and Human Services National Quality Strategy estab-
• Providing efficient mechanisms for extemporane- lished their central goals, known as the ‘‘Triple
ous compounding of nonstandard dosage forms Aim,’’ to transform the US healthcare system. The
• Addressing financial concerns Triple Aim entails better care for individuals, bet-
• Ensuring safe and legal disposal of all medications ter health for populations, and reduction of per
after death capita costs.224
• Establishing and maintaining effective communi- Achieving better patient outcomes is not the only
cation with regulatory and licensing agencies. benefit of ensuring quality of healthcare services; the
potential financial impact of improved quality can
be immense. Research shows that better quality of
Assessing pharmacy-related quality care may generate healthcare cost savings.225,226 For
of care every US$1.00 spent on a prescription, approximately
US$1.33 will be spent on complications and drug-
Defining quality
related illness.227 In 2008, a study that measured the
Quality has many definitions in the context of health- frequency and costs of US medical errors estimated
care, and it is essential that individual healthcare that the annual cost of the harm produced by errors
organizations determine for themselves what quality amounted to US$17.1 billion.228 Adverse medication
means to their organization. Donabedian proposed events cause more than 770,000 injuries and deaths
that there are seven ‘‘pillars’’ of quality: efficacy, each year, and the cost of treating patients who are
effectiveness, efficiency, optimality, acceptability, harmed by these events is estimated to be as high
legitimacy, and equity.220 In 1990, the Institute as US$5 billion annually.229 Improved quality of care
of Medicine (IOM) defined quality ‘‘as the degree can reduce medical expenditures for patients and their
to which health services for individuals and pop- employers and improve productivity due to decreased
ulations increase the likelihood of desired health job absence.
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In order to oversee the quality of care delivered 2008, more than 65% of people over age 65 took at
and plan for continuous improvement, it is essential least three routine prescription medications daily and
to measure quality. Quality measurement can identify nearly 75% took at least one daily supplement.231
system problems and monitor the impact of quality The pharmacist, whether in the community, con-
improvement activities. sultant, or clinical setting, plays an important role in
aiding the older patient with management of medi-
cations, including appropriate use, drug interactions,
Long-term care and adverse effects. The Omnibus Budget Reconcilia-
tion Act of 1987 (the Federal Nursing Home Reform
The need for long-term care in the United States will Act), and the subsequent Act in 1990 (OBRA 90),
continue to grow in the coming decades as the ‘‘baby require that a pharmacist provide a systematic drug
boomer’’ population of US residents born during and regimen review that encompasses appropriate medica-
immediately after World War II attain retirement age tion use, including unnecessary drug use, and that this
and as advances in medicine contribute to longer review be performed on a regular basis.232 The phar-
lives. In 2009, the number of US residents aged 65 macist can employ the principles of OBRA 90 patient
and older was approximately 39.6 million or 12.9% safety and medication review to any long-term care
of the total United States population, with a projected treatment setting.
increase in this population to 72 million people by
2030. The number of individuals aged 85 and older
is expected to grow from 4.2 million in 2010 to 6.6 Chronic wound care
million in 2030.230 The number of nursing homes in
the United States has decreased over the past decade The prevention and treatment of wounds are vital
by more than 1000 facilities, with the number of beds aspects of caring for patients in diverse settings includ-
in nursing homes also falling by nearly 100,000.231 ing the disabled elderly at home, non-ambulatory
While this trend may seem alarming, given the aging hospitalized patients, and those who have under-
population increase, this shortfall in nursing home gone surgery. During recent years, interest in wound
beds is countered by the increase in assisted living care has increased with entire surgical subspecial-
facilities and use of home healthcare as desirable ties now devoted to it. There are still, however, too
alternatives to most individuals. This shift in health- few clinicians skilled in this area and it remains a
care is highlighted by the fact that occupancy rates in unique area in which pharmacists can play an impor-
nursing facilities nationwide has continued to average tant role as a part of a multidisciplinary approach.
about 83%.231 Pharmacists can aid in the selection of cost-effective
Rates of chronic medical illnesses in the older topical and systemic therapies, and dressings, and help
population have increased over the past decade. Dia- maintain the vigilance required for preventing and
betes, hypertension, and cancer diagnoses continue treating wounds.
to climb, while individuals with these diagnoses are The provision of wound care incurs an exces-
living longer, due to improved medical treatments sive burden to society, the healthcare system, and
for these conditions. The proportion of individuals its patients. In a detailed analysis on the burden
aged over 65 years with poor glycemic control fell of skin diseases in 2004, the prevalence of skin
72% during this time period, while the use of statin ulcers and wounds was 4.8 million accounting for
medications for hypercholesterolemia rose to 40 to direct costs of $9.7 billion. Indirect costs, due to
50% of the over 65 population, resulting in signifi- lost patient and caregiver workdays, and restricted
cantly lower cholesterol. The use of drug therapy as a activity, accounted for an additional $2.2 billion.233
primary means to manage chronic conditions is high- Each chronic wound requires a great deal of time and
lighted by epidemiological data showing no significant finances to change dressings, apply topical therapies,
change in tobacco use in the older population, as well and provide in-patient surgical and medical therapy
as low rates of regular exercise (less than 10%). The as needed. Chronic wounds have also been shown to
Centers for Disease Control (CDC) estimated that in significantly reduce quality of life.234,235
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592 | An Introduction to Pharmacy

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J Antimicrob Chemother 2011; 66: 1945–194–7. 234. Franks PJ, McCullagh L, Moffatt CJ. Assessing quality
216. Brooksbank M. Palliative care: where have we come of life in patients with chronic leg ulceration using
from and where are we going? Pain 2009; 144: the Medical Outcomes Short Form-36 questionnaire.
233–235. Ostomy Wound Manage 2003; 49: 26–37.
217. Clark D. From margins to centre: a review of the 235. Lindholm C et al. Quality of life in chronic leg ulcer
history of palliative care in cancer. Lancet Oncol patients. An assessment to the Nottingham Health
2007; 8: 430–438. Profile. Acta Derm Venereol 1993; 73: 440–3.
 Remington_Pharmacy bindex.tex V1 - 04/24/2013 4:19 P.M. Page 599

Index

Abbreviated New Drug Application (ANDA), 38 compounding, 497

abbreviations in prescriptions, 389 identification test, 146
absorption, 513 potency-designated drugs, 512
drugs, 90, 291, 295 active transport, 294
ionization relationship, 90, 236 Added Qualifications, 573
pH relationship, 90 cardiology, 573
resonance, 174 infectious diseases, 573
solutions, 307 adherence, 356, 359
absorption, distribution, metabolism and excretion see also patient adherence; patient compliance
(ADME), 291 administration routes see dosage forms
animal testing, 34 adsorption, 513
see also drug absorption; drug distribution; drug adsorption chromatography, 170
excretion; drug metabolism; pharmacokinetics Advanced Practice Pharmacy Experience (APPE), 473
academia, 485 adverse drug events (ADEs), 417
veterinary teaching hospitals, 488
data review, 459
accelerated approval of new drug products, 38
health system pharmacists’ role, 453
AccessPharmacy, 55
intensive care unit, 586
accidents see errors; poison control
pediatric, 584
Accountable Care Organizations (ACOs), 446, 462
sources of risk, 418
accreditation, 2, 463
see also adverse drug reactions (ADRs); adverse events
community pharmacy, 446
(AEs)
residency programs, 8, 473
adverse drug reactions (ADRs), 353, 417
see also certification
class effect, 417
Accreditation Council for Pharmacy Education (ACPE), 2,
definition, 417
472
drug evaluation monographs, 377
acetaminophen, 420
acidifiers, systemic, 68 frequency, 1
acids, 67, 80 information resources, 59
dissociation constants, 81, 83 postmarketing surveillance, 413, 543
electronegativity and, 84 reporting, 353, 411
experimental determination, 85 safety monitoring, 39
ionic strength and, 82, 84 sources of risk, 418
ionization, 81, 83 see also adverse events (AEs); serious adverse events
proton balance equation (PBE), 89 (SAEs)
preservatives, 312 adverse events (AEs), 353
species concentration, 88 clinical trials, 48
see also pH coding, 48
active pharmaceutical ingredients (API) pediatric, 584
assay, 146 see also adverse drug reactions (ADRs); serious adverse
characterization for drug discovery, 119 events (SAEs)
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600 | Index

aerosols, 330 American Medical Association (AMA) Council on Medical

advantages, 331 Education, 563
definition, 330 American Osteopathic Association (AOA), Healthcare
metered-dose inhalers (MDIs), 158 Facilities Accreditation Program (HFAP), 464
affinity chromatography, 171 American Pharmacists Association (APhA), 8, 21
affinity, drug-receptor, 94 Code of Ethics, 25, 561
aggregation, complex organic molecules, 515 health system pharmacy, 448
aging population, 591 model pharmacy act, 21
agitation, organic molecule compounding, 515 scope of pharmacy, 1
AHFS Drug Information, 376 Task Force on Specialties in Pharmacy, 564
air quality monitoring, 151 American pharmacy history, 18, 20
albuterol, 509 American Society of Consultant Pharmacists (ASCP), 8
alcohol use, 360, 582 American Society of Health-System Pharmacists (ASHP), 8
education, 363 accreditation of residency programs, 8, 473
see also substance use/abuse AHFS Drug Information: American Hospital Formulary
alcohols Service, 57
preservatives, 312 clinical pharmacy services, 452
solvents, 309 formulary document guidelines, 457
medical records guidance, 368
alert fatigue, 350
sterile compounding guidance, 316
aliquots, 511
waste management guidance, 425
alkalizers, systemic, 68
American Society of Medication Safety Officers (ASMSO),
alpha level, 43
460
alternative medicine see complementary and alternative
amino acids, 335
medicine (CAM)
ammonium carbonate, 77
aluminum
amorphates, 91
astringent, 72
amorphization, 207
inorganic chemistry, 71
amorphous precipitation, 232
packaging tubes, 165
amorphous solids, 207
AM-USP Nomenclature Committee, 133
amorphous mixtures, 212
ambulatory care pharmacy, 452, 572
glass solution, 212
certification, 572
heat capacity (C), 216
compounding, 498
thermodynamics, 207
practice, 575
see also solids
recertification, 572 amphetamine abuse, 421
ambulatory patient classification (APC) codes, 555, 556 An A–Z Guide to Pharmacogenomics, 61
American Association of Colleges of Pharmacy (AACP), 9 analogs
American Association of Pharmaceutical Scientists (AAPS), in drug design, 108
9 natural products, 107
American Board of Dermatology and Syphilology, 563 analysis see pharmaceutical analysis
American Board of Internal Medicine, 563 Animal Medicinal Drug Use Clarification Act 1996, 488
American Board of Medical Specialties (ABMS), 563 animal testing, 34, 147
American Board of Obstetrics and Gynecology, 563 disadvantages, 148
American Board of Ophthalmology, 563 reference standards, 148
American Board of Otolaryngology, 563 animal treatment see veterinary pharmacy
American Board of Surgery, 563 antacids, 68
American College of Clinical Pharmacists (ACCP), 9, 456 anti-infective agents
American Drug Index, 56 drug development, 301, 588
American Hospital Association (AHA), 447 resistance, 587
American Hospital Formulary Service (AHFS) stewardship, 454
AHFS Drug Information, 376 antibiotics,
Pharmacologic-Therapeutic Classification, 376 introduction of, 24
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Index | 601

potency, 512 bar code medication administration (BCMA), 471

resistance, 587 barcoding, 338, 348, 443
see also anti-infective agents barium, inorganic chemistry, 70
antibodies, 336 bases, 67, 80
monoclonal, 337 dissociation constants, 81, 83
radiolabeled, 481 electronegativity and, 84
antibody-mediated response, 336 experimental determination, 85
anticoagulation, 454 ionic strength and, 82, 84
management, 534 ionization, 81, 83
antidiuretic hormone (ADH), 238 proton balance equation (PBE), 89
antimicrobials see anti-infective agents species concentration, 88
antimony, inorganic chemistry, 73 see also pH
antioxidants, 159, 310 basket-stirred-flask test, 178
organic molecule compounding, 513 Baxter Healthcare Corporation, 317
Antiquity, pharmacy evolution, 12 behavioral interview, 383
apothecaries behind-the-counter (BTC) drugs, 386
America, 18, 20 belladonna collyria, 318
early modern Europe, 15, 18 benzalkonium chloride, 312
applied ethics, 346 benzoic acid preservative, 312
see also ethical issues beryllium, inorganic chemistry, 70
Arabic culture, 14 Best Pharmaceutical for Children Act (BPCA), 583
area under the concentration–time curve (AUC), 167 beta level, 43
Arrhenius plot, 249 beyond-use date, 400, 406
arsenic, inorganic chemistry, 73 bias control in clinical trials, 41
Art Science and Technology of Pharmaceutical billing, 462, 530
Compounding, The, 58 CMS-1500 claim form, 534
artificial atmospheres, 77 diabetes self-management training (DSMT), 531
aseptic processing, 314 disease state management (DSM), 555
see also sterility facility billing, 531
aspirin, 123 first-party payment, 531
assay, 146 ‘‘incident-to’’ billing, 531
bioassay procedures, 148 laboratory testing, 532
bioassay standards, 148 medication therapy management (MTM), 530
astatine, inorganic chemistry, 75 third-party contracting, 531
astringents, 72 binding, drug-receptor, 94
atomic number, 65 bioavailability, 166, 307
atomic weight, 65 changes, 166
atomizers, 318 emulsions, 307
atoms, 65, 196 solutions, 307
Aufbau principle, 66 suspensions, 307
auto-oxidation, 159, 310 testing, 166
automation, 347, 469 bioequivalence, 166, 167
automated counting machines, 400, 443 testing, 38, 166, 167
automated dispensing machines (ADMs), 449, 471 methods, 168
errors, 472 therapeutic equivalence evaluations, 168
robotics, 443 biohazardous waste, 424
intravenous (IV) robotics, 471 see also waste management
auxiliary labels, 407 bioisosterism, 96
Avogadro’s law, 222 Biological Abstracts, 54
biological testing, 146
B lymphocytes, 336 animal testing, 34, 147
Babylonians, 13 disadvantages, 148
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602 | Index

biological testing (continued) buffers, 68

reference standards, 148 drug stabilization, 248
bioassay procedures, 148 ophthalmic preparations, 322
classification, 148 use to increase solubility, 230
disadvantages of, 148 bulk powders, 306
reference standards, 148 Burrell Severs rheometer, 157
plastics, 164 business plans, 557
biomarkers, diabetes, 118
biomedical informatics, 352 cadmium, inorganic chemistry, 70
biopharmaceutics, 465 calcium, inorganic chemistry, 70
biosimilars, 465 capillary electro-chromatography (CEC), 171
BIOSIS Previews (Biological Abstracts), 54 capsules, 327
biotechnology, 332 gelatin capsules, 155, 327
background, 332 dissolution tests, 155
ethical and moral issues, 333, 337 quality control, 495
bismuth, inorganic chemistry, 73 stability, 155
bleeding, ointments, 157 carbomer, ophthalmic gels, 320
blinding, 44, 45 carbon
blister card packages, 165, 403 inorganic chemistry, 73
use in clinical trials, 45 structure, 196
block randomization, 42 carbon dioxide, 77
Board Certification-Advanced Diabetes Management absorbers, 77
(BC-ADM), 534 carboxylic acid esters, 510
Board Certified Ambulatory Care Pharmacist (BCACP), cardiology, 573
446, 572 care see care plan; healthcare; pharmaceutical care
Board Certified Nuclear Pharmacist (BCNP), 567 Care Continuum Alliance, 548
Board Certified Nutrition Support Pharmacist (BCNSP), care plan, 532, 533, 558
569 identifying patients to follow, 561
Board Certified Oncology Pharmacist (BCOP), 571 see also pharmaceutical care
Board Certified Pharmacotherapy Specialist (BCPS), 446, careers, 2
570 academia, 485
Board Certified Psychiatric Pharmacist (BCPP), community pharmacy, 6
570 disease state management, 552
Board of Pharmacy Specialties (BPS), 446, 452, government service, 7, 474
533, 551 health system pharmacy, 6, 446, 448
certification process, 565, 573 industrial pharmacy, 7, 474
development of, 564 nuclear pharmacy, 7, 475
new specialty petition process, 565 organizational management, 8
petition review and approval, 565 pharmaceutical education, 7
see also specialty pharmacy pharmaceutical journalism, 7
boiling point, 197 Carnot cycle, 225
Bonferroni correction, 49 carousel dispensing technologies (CDT), 472
boron, inorganic chemistry, 71 carriers, 294
boxed warnings, 39 Casarett and Doull’s Toxicology: The Basic Science of
Boyle’s law, 222 Poisons, 59
Brønsted and Lowry theory, 67, 80 cathartics, 78
Bragg’s law, 215 cefuroxime axetil, 511
breathing, plastic containers, 165 cell cytoskeleton, 335
British Pharmacopeia (BP), 56 cell membranes, 237, 292
bromine, inorganic chemistry, 75 lipid composition, 292
Brookfield viscometer, 156 pores, 292, 294
buccal tablets, 326 structure, 292
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Index | 603

cell-mediated response, 336 reaction mechanism, 246

Center for Biologics Evaluation and Research (CBER), 32, reaction rate, 247
337 within pharmaceutical products, 159
Center for Devices and Radiological Health, 32 decarboxylation, 161
Center for Drug Evaluation and Research (CDER), 32, 337 epimerization, 162
Investigational New Drug (IND) application, 35 hydrolysis, 160
New Drug Application (NDA), 37 interionic compatibility, 161
Office of Generic Drugs, 38 oxidation–reduction, 159
Center for Food Safety and Applied Nutrition (CSFAN), photochemical reactions, 162
32, 337 racemization, 161
Center for Veterinary Medicine, 32, 489, 397 chemistry
Centers for Disease Control and Prevention (CDC), 464, combinatorial, 33
489 in pharmacy evolution, 16, 17
Centers for Medicare and Medicaid Services (CMS), 430, chemoprophylaxis, 582
464 chemotherapy waste disposal, 425
Conditions of Participation (CoP), 464 child-resistant closures, 402
disease state management, 555 children see pediatric pharmacy practice
see also CMS-1500 claim form chiral nematic phase liquid crystals, 220
central unit, 67 chloramphenicol, 510
Certificates of Analysis, 506 chlorine, inorganic chemistry, 75
certification chlorofluorocarbons, 330, 331
diabetes care providers, 534 cholesterol, cell membranes, 292
medical specialists, 563 chromatography, 169
pharmacy specialties, 565 adsorption chromatography, 170
ambulatory care pharmacy, 572 affinity chromatography, 171
nuclear pharmacy, 567 capillary electro-chromatography (CEC), 171
nutrition support pharmacy, 569 column chromatography, 170
oncology pharmacy, 571 high-performance liquid chromatography (HPLC), 146
pharmacotherapy, 570 ion-exchange chromatography, 170
psychiatric pharmacy, 570 paper chromatography, 170
process, 573 partition chromatography, 170
value of, 573 permeation chromatography, 170
see also accreditation; recertification preparative scale chromatography, 171
Certified Anticoagulation Care Provider (CACP) credential, reversed-phase chromatography, 170
534 thin-layer chromatography, 121, 170
certified diabetes educator (CDE), 534 chromium, inorganic chemistry, 74
Certified Geriatric Pharmacist (CGP), 452 chromosomes, lighthouses, 336
cesium, inorganic chemistry, 69 chronic disease, 576
channel hydrates, 210 older population, 591
Charles’ law, 222 chronic wound care, 591
chelating agents, 310 chronology of pharmacy evolution, 27
organic molecule compounding, 513 cigarette smoking, 360
Chemical Abstracts Service (CAS) Index naming system, cinchona bark, 16
132 civil law, 523
Chemical Carcinogenesis Research Information System claims, 534, 537
(CCRIS), 60 CMS-1500 claim form, 534, 538
chemical equivalence, 167 clarity, ophthalmic preparations, 321
chemical grades, 498 Clausius inequality, 227
chemical kinetics, 245 clinical analysis, 148
flocculation kinetics, 255 clinical drug literature, 351
reaction rate, 247 clinical equivalence, 167
chemical reactions, 65, 245 clinical hold, 35
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604 | Index

clinical investigations see clinical trials CMS-1500 claim form, 534, 538
clinical pharmacokinetics, 296 CPT coding, 535
see also pharmacokinetics International Classification of Diseases (ICD-9) coding,
clinical pharmacy, 25, 452 534
definition, 456, 559 co-crystals, 92, 211
economics, 529 coagulation, 255
history, 564 coalescence time test, 157
versus pharmaceutical care, 559 coarse dispersions, 252
clinical practice guidelines, 380, 458 dispersion step, 253
clinical trials, 32, 35 interfacial properties, 254
adverse event reporting, 48 surface free energy, 254
application of intervention, 42 surface potential, 254
assignment of intervention, 41 see also suspensions
bias control, 41 coatings, 327
blinding, 44 compressed tablets
design, 41 dry-coated, 326
crossover design, 41 enteric-coated (ECT), 325
factorial design, 41 film-coated (FCT), 325, 328
parallel design, 41 press coated, 326
drug packaging, 45 sugar-coated (SCT), 325, 328
falsification of trial data, 47 process evolution, 328
feasibility, 44 reasons for coating, 327
Good Clinical Practice (GCP) monitoring, 47 cobalt, inorganic chemistry, 76
informed consent, 47 cocaine, structure–activity relationship, 110
objectives, 40 Cochrane Library, 54
outcomes, 44 Code Blue events, 454
measurement, 42 code designation, 132
patient enrolment, 44 Code of Ethics, 25, 347, 561
pharmacists’ roles, 353 Code of Federal Regulations (CFR), 34, 424
Phase I trials, 36 codons, 333
Phase II trials, 36 cold plasma, 223
Phase III trials, 36 colleges, 2, 20
Phase IV trials, 37 colligative properties, 230, 233
planning, 40 colloidal dispersions, 229, 251
population selection, 43 interfaces, 252
power, 43 collyria, 318
protocol, 42 color stability, tablets, 154
randomization, 41 column chromatography, 170
regulations, 47 combinatorial chemistry, 33
sample size, 43 CoMFA (comparative molecular field analysis), 114
statistical analysis of data, 48 Commission for Certification in Geriatric Pharmacy, 453,
subgroup analysis, 49 551
Clinical Trials Website, 38 communicable diseases, 586
Clostridium difficile, 587 see also infectious diseases
closures, 163, 166, 337 communication, 355
child-resistant, 402 see also patient communication; personnel
ophthalmic preparations, 321 communication; professional communications
parenteral preparations, 316 community pharmacy, 6, 441
requirements, 339 accreditation, 446
rubber closures, 164, 166 careers, 6
see also containers; packaging compounding practice, 339, 399, 444
clozapine, clinical trial, 45 credentialing, 446
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Index | 605

distribution of medications, 442 formulas, 496

economics, 525 guidelines, 501
evolution, 441 health system pharmacy, 450
management, 525 history, 489
marketing, 529 hydrates, 506
pharmacy technicians, 445 information sources, 497
provision for patient care, 444 inorganic salts, 508
reimbursement, 445 institutional, 499
residency training, 445 intravenous therapy, 499
technology use, 443 kits, 497
veterinary pharmacy, 488 Model Act, 505, 524
companion diagnostics, 297 nonsterile compounds, 451, 501
comparative effectiveness research (CER), 544 nuclear pharmacy, 501
comparative molecular field analysis (CoMFA), 114 organic salts, 509
compartmental models, 288 pediatrics, 584
compendia, 144 potency-designated ingredients, 512
complaints, 413 quality assurance, 505
complementary and alternative medicine (CAM), 444, 579 quality control, 450, 494
see also herbal medicines regulations, 501, 524
Complete Guide to Prescription and Nonprescription responsibilities, 490
Drugs, 60 safety issues, 450
complex formation, 67, 250 solutions, 307
between drug and carriers, 232 solvates, 506
chelate, 250 special considerations, 505
coordination complexes, 251 stability of preparations, 493, 515
drug stabilization, 249 sterile preparations, 316, 451, 502
molecular complexes, 251 supplies, 496
use to increase solubility, 231 support, 495
compliance see patient compliance suspensions, 307
compliance packaging, 403 training, 495
compounding, 21, 24, 389, 489 veterinary compounding, 500
aliquots, 511 compressed inserts, 326
ambulatory-care compounding, 498 compressed suppositories, 326
batch compounding feasibility, 492 compressed tablets (CT), 325
calculations, 505 buccal tablets, 326
chemicals, 496 controlled-release tablets (CRT), 326
commercial products, 516 dry-coated tablets, 326
community pharmacy practice, 339, 399, 444 effervescent tablets, 326
complex organic molecules, 513 enteric-coated tablets (ECT), 325
concentrates, 511 film-coated tablets (FCT), 325, 328
container selection, 339 layered tablets, 326
definitions, 491 multiple compressed tablets (MCT), 325
dilutions, 511 press-coated tablets, 326
drug shortage and, 466 sublingual tablets, 326
economic considerations, 493 sugar-coated tablets (SCT), 325, 328
emulsions, 307 tablets for solution (CTS), 326
environment, 496 computational prediction of drug-likeness, 116
equipment, 496 computer systems see technology
esters, 510 computerized provider order entry (CPOE), 453, 470
evaluating the need, 492 concentrates, compounding, 511
extracts, 307 concentration versus effect relationship, 285
filters, 513 concurrent jurisdiction, 524
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606 | Index

confidentiality, medical records, 350 counseling, 360

conjugate pairs, 67, 80 benefits of, 356
Consent Decree, 340 compounded products, 499
conservation of energy, 224 see also patient education; self care
conservative mutations, 300 counter-prescribing, 20
consultant pharmacy practice, 475 counting
consumer drug information, 60, 407 automated counting machines, 400, 443
Consumer Product Safety Commission, 402, 524 trays, 399
containers, 163, 337 covalent bond, 66
chemicals causing concern, 339 cover letters, 370
closures, 163, 166, 337 CPT (Current Procedural Terms) coding, 535, 555
child-resistant, 402 credentialing, 446, 533
requirements, 339 Council on Credentialing in Pharmacy (CCP), 551, 574
rubber, 164, 166 credentials, 574
compounded organic molecule products, 515 see also certification
dispensing, 401 criminal law, 523
glass, 164 critical care pharmacy, 586
metal, 165 critical point, 200
ophthalmic preparations, 321 critical pressure, 200
parenteral preparations, 316 critical temperature, 200
plastic, 164 cross-validation technique, 113
problems with, 338 crossover design, clinical trials, 41
risk assessment, 338 crystal growth in suspensions, 320
selection of, 339 crystalline solids, 91, 202
testing, 338 co-crystals, 92, 211
see also packaging eutectics, 211
contamination Ostwald’s rule, 206
dispensing issues, 21 polymorphism, 91, 205, 206
preservative use, 311 structural defects, 204
continuing education (CE), 469 unit cell, 203
continuing professional development (CPD), 469 see also liquid crystals; solids
contracting, 464 crystallization, 91
performance-based contracts, 464 crystallography, 111
third-party contracting, 531 cubic phase lyotropic liquid crystals, 219
Controlled Substance Act (CSA), 426 current Good Manufacturing Practices (cGMPs), 37, 182
controlled substances, 387 failure to comply, 340
labeling requirements, 403 Current Procedural Terminology (CPT) codes, 445, 535,
waste management, 426 555
controlled-release tablets (CRT), 326 curriculum vitae, 371
see also oral modified-release drug delivery systems cyclic changes, 224
coordinate covalent bond, 66 cyclotron-produced radionuclides, 129
coordination complexes, 251 cytoskeleton, 335
copper, inorganic chemistry, 70
Cordus, Valerius, 15 D values, 242
core measurements, 454 Dalton’s law, 222
correspondence see professional communications data, 194
corrosive pharmaceuticals, 424 visualization, 194
cosolvents, 230 Data Safety and Monitoring Board (DSMB), 48
cost savings programs, 465 databases, 53, 349
cost-benefit analysis, 525 compounding, 497
Council on Credentialing in Pharmacy (CCP), 551, 574 evidence-based practice, 554
Council on Drugs, 133 information resources, 51
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Index | 607

pharmacoepidemiology, 544 diffusion, 257, 293

see also specific databases facilitated, 294
decarboxylation, 161 ionic/electrochemical, 293
deflocculation, 255 nonionic, 293, 295
degradant profiling, 120 digoxin, drug interactions, 419
degradation product detection, 250 dilatant liquids, 221
degree courses, 3, 24, 550 dilemmas, 346
degrees of freedom, 201 in pharmacy practice, 345
Dehydrated Alcohol, 309 Diluted Alcohol, 309
delayed-release (DR) drug delivery systems, 329 dilutions, compounding, 511
denaturation, complex organic molecules, 515 Dioscorides, 13
density, 190 diphenhydramine hydrochloride, 509
deoxyribonucleic acid (DNA), 333 dipolarity, 295
expressed sequence tags (ESTs), 336 dipole, 66
transcription, 333 dipole–dipole bond, 67
design Directory of Open Access Journals, 52
clinical trials, 41 discipline, progressive, 384
crossover design, 41 disease state management (DSM), 547
factorial design, 41 appropriate conditions, 550
parallel design, 41 barriers, 556
drug, 106 billing and reimbursement, 555
analogs, 108 business plans, 557
fragment-based approaches, 110 care managers, 551
homologs, 109 collaboration with health providers, 554
ligand-based design, 108 components, 548, 552
models, 113 documentation, 553, 555
prodrugs, 122 equipment, 555
receptor-based design, 108 historical background, 548
Det Norske Veritas (DNV) Healthcare, National Integrated influencing stakeholders, 555
Accreditation for Healthcare Organizations objectives, 554
(NIAHO), 464 outcomes evaluation, 557
dexamethasone, 506, 511 pharmacist’s roles and responsibilities, 1, 548, 550, 551
diabetes regulation, 551
biomarkers, 118 protocol, 553
certification of care providers, 534 published reports, 552
self-management training (DSMT), 531 quality assurance, 557
Diabetex, 549 treatment guidelines, 553, 554
diagnosis-related groups (DRGs), 483, 548 dispensing, 1, 408
diagnostic contrast agents, 240 automated dispensing machines (ADMs), 449, 471
diagnostic self-care, 359, 579 carousel dispensing technologies (CDT), 472
diet see nutrition errors, 472
Dietary Supplement Health Education Act (DSHEA), 97, 98 directions to pharmacist, 389
dietary supplements, 98, 487 liquid preparations, 307
marketing, 99 packaging, 401
qualified health claims, 101 robotics, 443
safety issues, 99 short cycle dispensing, 430
see also nutrition stability and contamination issues, 21
diethylene glycol, 31 dispensing tablets (DT), 327
differential scanning calorimetry (DSC) dispersions see colloidal dispersions; emulsions; solid
modulated temperature DSC (MTDSC), 217 dispersions
solid state analysis, 215 disposal of unused medication, 424, 528
differential thermal analysis (DTA), binary mixtures, 231 community/private sector, 427
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608 | Index

disposal of unused medication (continued) nasal inhalation products, 158

collection events, 427 ointments, 157
flushing, 428 ophthalmic preparations, 317, 318
trash disposal, 428 oral modified-release dosage forms, 326, 329
hospital waste, 451 oral solid dosage forms, 324
reverse distribution, 426 packaging requirements, 338
see also waste management parenteral preparations, 315
Dispose My Meds website, 428 pediatrics, 584
dissertations, 53 powders, 305
dissociation constants, 81, 82, 84, 510 bulk powders, 306
drug-receptor affinity, 94 divided powders, 306
electronegativity and, 84 dry-powdered inhalers (DPIs), 158, 306
experimental determination, 85 dusting powders, 306
ionic strength and, 82, 84 for solutions, 319
micro dissociation constants, 86 insufflations, 306
dissolution, 177 solutions, 156, 307, 318
definition, 179 gel-forming solutions, 319, 323
salts, 233 powders for, 319
significance in aqueous suspensions, 319 suspensions, 155, 254, 307, 319, 510
testing, 178 tablets, 154, 324
gelatin capsules, 155 topical agents, 72, 324
tablets, 155 transdermal patches, 157
see also solutions see also specific forms
divided powders, 306 dose, 290
DNA see deoxyribonucleic acid (DNA) drug evaluation monographs, 377
docking, 116 health system pharmacists’ role, 454
Doctor of Pharmacy (PharmD), 2, 340, 550 double blinding, 44
documentation double helix, 333
compounding, 450, 517 dressings, surgical, 431
disease state management, 553, 555 drug absorption, 90, 291, 295
Focused Documentation, 368 ionization relationship, 90, 236
formulary document guidelines, 457 pH relationship, 90
health system pharmacy, 455 solutions, 307
home medical equipment (HME), 432 see also pharmacokinetics
medication therapy management (MTM), 369, 533 drug abuse see drug misuse; substance use/abuse
medication-related action plan (MAP), 369 Drug Abuse Act 1970, 24
patient care, 367 drug action, 288
prescriptions, 409 structural determinants, 92
renewals, 411 versus effect, 289
transfer, 411 drug activity, 236
record retention regulation, 524 pH relationship, 90
SOAP method, 368, 532 structure–activity relationships, 106, 113
dosage forms, 154 fragment-based approaches, 110
aerosols, 330 homologs, 109
metered-dose inhalers (MDIs), 158 ligand-based design, 108
capsules, 327 quantitative structure–activity relationship (QSAR),
gelatin capsules, 155 95, 111, 116
drug evaluation monographs, 377 drug administration routes see dosage forms
emulsions, 156, 256, 307 drug alert notifications, 380
extracts, 307 drug analysis see pharmaceutical analysis
forms not to be used in compounding, 517 drug approvals, 32
immediate-release (IR) dosage forms, 329 Abbreviated New Drug Application (ANDA), 38
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Index | 609

accelerated approval, 38 health system pharmacy, 448

changes to an approved product, 40 reverse distribution, 426
clinical trials, 32, 35 see also pharmacokinetics
Conditional Approval, 37 drug education, 358, 473
disapproval, reasons for, 37 drug use, 359
Food, Drug, and Cosmetic Act 1938, 31 nonmedical drug use, 362
generic drugs, 38 see also patient education
IND application, 35 drug effect, 288
natural product analogs, 107 concentration versus effect relationship, 285
New Drug Application (NDA), 37 multiple effects, 289
orphan drugs, 39 selectivity, 289
over-the-counter (OTC) drugs, 39 versus action, 289
post-approval activities, 39 see also drug action
pre-IND meetings, 34 Drug Enforcement Agency (DEA), 24, 388, 464
preclinical testing, 32, 34 record retention regulation, 524
withdrawal of approval, 39 drug evaluation monographs, 375
drug concentration authorship, 378
effect relationship, 285 budget impact, 377
versus time profile, 286
clinical efficacy, 376
drug delivery
description and pharmacology, 376
metered-dose inhalers (MDIs), 158
dosing and evaluation, 377
oral modified-release systems, 329
indications, 376
pediatric, 584
medication error possibility, 377
site-specific delivery, 329
patient monitoring and information, 377
see also dosage forms
pharmacokinetics, 376
drug design, 106
references, 378
fragment-based approaches, 110
safety and tolerability, 377
homologs, 109
summary and recommendations, 377
ligand-based design, 108
title, 375
models, 113
drug evolution, 12, 23
prodrugs, 122
drug excretion, 291
receptor-based design, 108
see also pharmacokinetics
see also drug discovery
Drug Facts and Comparisons, 57
drug development, 32, 189
anti-infective agents, 301, 588 drug formulation see formulation
pharmacokinetics, 301 drug history taking, 422
drug discovery, 16, 23, 32, 189 Drug Information: A Guide to Current
combinatorial chemistry, 33 Resources, 61
docking, 116 drug information, 351
drug modeling, 33 clinical drug literature, 351
lead compound selection, 32 compounded preparations, 57
pharmaceutical profiling, 116 consumer information, 60, 407
computational prediction of drug-likeness, 116 disease state management, 551
degradant profiling, 120 drug information centers, 354
drug formulation screening, 119 drug-related questions, 364
drug reprofiling, 119 responding to, 365
random screening, 32 health system pharmacy, 453
targeted synthesis, 33 nonprescription products, 58
see also drug design pharmacists’ responsibilities, 352
drug distribution prescription products, 57
bodily distribution, 291 product identification, 60
pharmacists’ role, 442 drug information centers, 354
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Drug Information Portal, 60 education, 358

drug interactions, 418 nonmedical drug use, 362
contributing factors, 419 see also patient education
drug abuse, 420 misuse, 360
multiple pharmacological effects, 419 prevalence, 359, 417
multiple prescribers, 419 nonprescription drugs, 359
patient noncompliance, 420 prescription drugs, 442
pharmacokinetic alterations, 419 reasons/motivations for, 360, 363
use of nonprescription products, 420 typology of drug-taking behaviors, 360, 361
herb–drug interactions, 99 see also substance use/abuse
information resources, 59 drug use evaluation (DUE), 353
risk reduction, 421 Drug-induced Diseases: Prevention, Detection, and
Drug Interactions Analysis and Management, 59 Management, 59
Drug Master Files (DMFs), 339 drug-related problems (DRPs), 559
drug metabolism, 291 recognition of, 561
identification of metabolites, 175 see also adverse drug reactions (ADRs)
see also pharmacokinetics DRUGDEX, 57
drug misuse, 360, 582 druggists, 18, 20
drug interactions and, 420 drugs, 359
narcotic stewardship, 455 availability, 417
drug modeling, 33 beliefs about, 359
drug nomenclature, 131 disposal see disposal of unused medication
CAS Index naming system, 132 evolution of, 12, 23
code designation, 132 recalls, 528
specialty drugs, 483
drug name types, 132
withdrawals, 528
generic name, 133
see also medication
history, 133
Drugs and Lactation Database (LactMed), 59
information resources, 55
Drugs in Pregnancy and Lactation: A Reference Guide to
nonproprietary name, 133
Fetal and Neonatal Risk, 59
International Nonproprietary Names (INNs), 55, 135
dry-coated tablets, 326
trademark, 132
dry-powdered inhalers (DPIs), 158, 306
trivial names, 132
durable medical equipment (DME), 444
United States Adopted Names (USAN), 131, 133
dusting powders, 306
procedure for obtaining, 136
USAN Council, 134 E values, 243
USAN Review Board, 134 e-mail, 370
drug recycling, 430 e-prescribing, 387
drug shortages, 466 economics see pharmacoeconomics
drug stability see stability of pharmaceuticals editing, 373
Drug Take-Back Network website, 428 education, 2, 472, 560
drug therapy academia, 485
individualization, 422 careers in, 7
monitoring, 422 changes, 340
health system pharmacy, 453 continuing education (CE), 469
see also Medication Therapy Management (MTM) drug education, 358, 473
Drug Topics Red Book, 57 drug use and, 359
drug transport, 293 graduate, 8
active, 294 history, 24
passive, 293 hospital practice experience, 472
physicochemical factors, 294 patient see patient education
lipid solubility, 295 pharmacists’ role, 353
drug use, 359 student responsibilities, 560
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Index | 611

see also training new production methods, 435

see also training new service/product introduction, 434
effervescent mixtures, 68 new supply sources, 435
effervescent powders, 306 see also pharmacoeconomics
effervescent tablets, 326 entropy, 197, 225
efficacy, 291 zero point, 227
clinical trials, 36 Environmental Protection Agency (EPA), 464
drug evaluation monographs, 376 waste management, 424, 426, 451
Egypt, pharmacy evolution, 13 environmental quality monitoring, 151
eigenvalues, 112 enzymes, 335
electrochemical diffusion, 293 epigenetic processes, 333
electrochemical equilibrium, 294 epimerization, 162
electrolytes, 69, 233 equation of state, 224
electromagnetic radiation, molecular interactions and, 174 equilibrium, 224
electronegativity, 66 equipment
dissociation constants and, 84 compounding, 496
electronic communication, 370 disease state management (DSM), 555
e-mail, 370 durable medical equipment (DME), 444
social media, 370 home medical equipment (HME), 431
electronic health records, 349, 351, 470, 533, 555 equivalence, 166
see also medical records chemical, 167
electronic medication administration record (eMAR), 470 clinical, 167
electrons, 65, 196 therapeutic, 167
electrostatic compounds, 66 evaluations, 168
elements to assure safe use (ETASU), 541 see also bioequivalence
Embase, 55 erodible ocular inserts, 321
emergency medicine (EM) pharmacy practice, 582 errors, 413
emulsification, 254 automated dispensing systems, 472
emulsifying agents, 256 compounding, 450
emulsions, 256, 307 medication use, 1
bioavailability, 307 mortality from medical errors, 413
ophthalmic, 320 prescribing, 389, 395, 397, 400
preparation, 307 type I, 43
stability, 156 type II, 43
Encyclopedia of Common Natural Ingredients Used in essential oils, oxidation, 310
Food, Drugs, and Cosmetics, 58 essential trace elements, 69
Encyclopedia of Pharmaceutical Technology, 60 Essentials of Genomic and Personalized Medicine, 60
end-of-life care, 588 esters
endpoints committee, 43 compounding, 510
enemas, 78 preservatives, 312
energy ethanol preservative, 312
conservation of, 224 ethical codes, 347
minimization, 117 conflicts, 347
see also free energy ethical issues
English weights and measures, 191 biotechnology, 333, 337
enrolment, clinical trials, 44 community practice, 345
enteral medication, neonatal, 239 ethics, 346
enteric-coated tablets (ECT), 325 applied ethics, 346
enthalpy, state changes and, 197 see also ethical issues
entrepreneur, 433 European Medicines Agency (EMA), 32
entrepreneurial activities, 433, 434, 525 European Pharmacopeia, 56
industrial reorganization, 435 monographs, 145
new markets, 435 European Pharmacopoeia (Ph. Eur.) Commission, 144
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612 | Index

European Union Adverse Drug Reporting Program fluorescence spectroscopy, 172

(EU-ADR), 544 fluorine, inorganic chemistry, 75
eutectics, 211 flushing, unwanted medications, 428
simple eutectic mixtures, 231 see also waste management
Evaluation and Management (E&M) codes, 535 Focused Documentation, 368
evaporation, 199 Food and Drug Administration (FDA), 32, 464
evidence-based medicine (EBM), 348, 353, 554 biotherapeutic equivalence evaluations, 168
Evidence-Based Medicine Working Group, 353 complaints, 413
excipients, 339 compounding regulation, 524
pediatric medications, 584 dietary supplement regulation, 99
selection of, 120 qualified health claims, 101
excretion, 291 drug approval, 31
see also pharmacokinetics accelerated approval, 38
exocytosis, 294 changes to an approved product, 40
expectorants, 77 orphan drugs, 39
expiration date, 152 over-the-counter (OTC) drugs, 39
prediction, 163 Investigational New Drug (IND) application, 35
see also shelf-life labeling requirements, 375
expressed sequence tags (ESTs), 336 MedGuides, 459
extended-release (ER) drug delivery systems, 329 New Drug Application (NDA), 37
extensible markup language (XML), 351 supplemental (SNDA), 40
extracts, 307 packaging requirements, 403
eyedrops see ophthalmic preparations radiopharmaceuticals, 476
risk management, 540
facilitated diffusion, 294 role of, 32
facility billing, 531 safety alerts, 353
factorial design, clinical trials, 41 safety issue reporting,
failure mode and effects analysis (FEMA), 459 adverse drug events, 353, 411
falsification of clinical trial data, 47 MedWatch program, 39, 353, 411, 413, 544
FDA see Food and Drug Administration (FDA) postmarketing product surveillance, 413, 543
feasibility, clinical trials, 44 prescription safety issues, 411
federal law, 524 Sentinel Initiative, 544
see also laws governing pharmacy USAN Council Liaison, 135
fee setting, 537 Food and Drug Amendments Act (FDAAA), 541
see also reimbursement Food Chemicals Codex, 56
fellowship programs, 8 Food, Drug, and Cosmetic Act 1938, 31, 133, 337
Ferguson’s principle, 93 compounding, 496
Fick’s law of diffusion, 293 Kefauver-Harris Amendments 1962, 32
film-coated tablets (FCT), 325, 328 radiopharmaceuticals, 475
filters, 513 Food-medication Interactions, 59
filtration, ophthalmic preparations, 321 foods, medical, 97–99
finasteride clinical trial, 41 Foods and Drugs Act 1906, 22
first law of thermodynamics, 224 Foods for Special Dietary Uses (FSDU), 99
first-party payment, 531 formulary system, 374, 456
fission by-products, 125 communications, 374
flocculated suspensions, 155, 255 drug evaluation monographs, 375
flocculation kinetics, 255 medication selection and review, 456
flocs, 255 pharmacy and therapeutics (P&T) Committee, 456
floor stock system, hospitals, 449 formulas, compounding, 496
flow-through cell, 178 formulation
fluid balance, 238 bioavailability relationship, 307
antidiuretic hormone (ADH), 238 information resources, 60
osmosis, 237 parenteral preparations, 315
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Index | 613

screening, 119 single-nucleotide polymorphisms (SNPs), 298, 299,

stability, 152 585
Fourier transform infrared-attenuated total reflection genome see human genome
(FTIR-ATR), 121 gentamicin, 516
fragment-based approaches to drug design, 110 germanium, inorganic chemistry, 73
francium, inorganic chemistry, 69 germicides
Francke, Donald, 564 oxidizing, 72
free energy, 227 precipitating, 72
Gibbs free energy, 228 Gibbs free energy, 228
Hansch Linear Free-Energy Model, 95 Gibbs’ phase rule, 202
Helmholtz free energy, 227 multicomponent systems, 202
surface free energy, 252, 254 glass, 207
free radicals, 159, 310 containers, 164
Free-Wilson method, 95 glass solutions, 212, 232
freewriting, 372 glass transition temperature, 207, 212
freeze drying, 200 glucose, parenteral infusion, 240
freezing-point depression, 242 glucose-6-phosphate dehydrogenase (G6PD) mutations,
friability test, 154 300
functional groups, 79 glycerin, 309
prodrugs, 124 goals, 462
National Patient Safety Goals (NPSGs), 454, 464
gold, inorganic chemistry, 70
gain-of-function mutations, 300
Goldfrank’s Toxicologic Emergencies, 59
Galen, 13
GOLPE (generating optimal linear PLS estimations), 115
gallium, inorganic chemistry, 71
Good Clinical Practice (GCP) monitoring, 47
gap analysis, sterile compounding, 317
good laboratory practices (GLPs), 34
gases, 197, 222
Good Manufacturing Practices see current Good
phase transitions, 197
Manufacturing Practices (cGMPs)
gastric antacids, 68
Gordon–Taylor equation, 213
gelatin capsules, 327 government
dissolution tests, 155 agencies, 462
gelatin types, 327 careers in, 7, 474
quality control, 495 veterinary pharmacists, 489
stability, 155 graduate education, 8
gels Greco-Roman culture, 14
ophthalmic preparations, 318–320, 323 Greece, pharmacy evolution, 13
quality control, 495 GRID, 115
GENE-TOX, 60 group purchasing organizations (GPOs), 464
generic drugs, 528 guidelines
approval, 38 clinical practice, 380, 458
generic substitutions, 389, 457, 528 clinical trials, 47
procurement, 465 compounding, 501
generic name, 133 disease state management, 553, 554
genes, 333 formulary document, 457
expression regulation, 333 preventive care, 582
genetic code, 333
genetic engineering, 332 hafnium, inorganic chemistry, 72
see also biotechnology haloperidol clinical trial, 45
genetic information protection, 337 Handbook of Nonprescription Drugs: An Interactive
genetic manipulation, 333 Approach to Self-Care, 58
genetic variation, 298, 585 Handbook of Pharmaceutical Excipients, 56
types of, 299 Handbook on Injectable Drugs, 57
point mutations, 299 Hansch Linear Free-Energy Model, 95
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haplotypes, 299 Healthy People 2020, 580

hard water, 308 heat capacity (C), 197
hardness, tablets, 154 amorphous solids, 216
Hazardous Substance Database (HSDB), 59 helium, 77
hazardous waste, 424 Helmholtz free energy, 227
disposal, 425 helper T cells, 336
hospital waste, 451 Henry’s law, 222
lists of hazardous pharmaceuticals, 425 herbal medicines, 96, 102–107
see also waste management complementary and alternative medicine, 444
HCPCS codes, 535 herb–drug interactions, 99, 420
health accessories, 431 information resources, 58
Health and Information Technology for Economic and prevalence of use, 359
Clinical Health Act 2009 (HITECH), 351, 470 safety issues, 99
health behavior, 354 hexagonal phase lyotropic liquid crystals, 218
Health Insurance Portability and Accountability Act 1996 high-density polyethylene (HDPE), 165
(HIPAA), 47, 534 high-performance liquid chromatography (HPLC),
technology and, 350 146
health people, 580 high-throughput formulation screening (HTFS),
health promotion, 580 120
health system, 447 high-throughput screening (HTS), 106, 119
health system pharmacy, 6, 446, 448 Hippocrates, 13, 97
ambulatory care services, 452 history, 26
careers, 6, 446, 448 American pharmacy, 18, 20
clinical pharmacy, 452 antiquity, 12
compounding, 450, 499 biotechnology, 332
documentation, 455 chronology, 27
drug distribution, 448 clinical pharmacy, 25, 564
drug information, 453 coating process, 328
floor stock system, 449 compounding, 489
hazardous waste disposal, 451 disease state management, 548
leadership, 461 drug history taking, 422
monitoring, 453 drug nomenclature, 133
adverse drug events (ADEs), 453 hospice, 589
patient prescription system, 450 legislation, 21, 24
pharmacy technicians, 448 metrology, 191
prescriptions, 449 middle ages, 14
technology, 453 ophthalmic preparations, 318
unit-dose system, 450 pharmaceutical care, 25
work schedules, 468 pharmacogenomics, 297
healthcare prehistory, 12
care transitions management, 454 professionalism, 21, 22
environment, 415 Renaissance, 15
informatics, 349, 352 specialization,
macrosystems of care, 414 in medicine, 562
microsystems of care, 414 in pharmacy, 563
quality issues, 413, 416 twenty-first century, 26
safety issues, 413, 416 hologram, molecular, 112
see also care plan; disease state management (DSM); home care, 482
pharmaceutical care services, 483
Healthcare Facilities Accreditation Program (HFAP), Home Health Care Pharmacy Services, 433
464 home infusion pharmacy practice, 482, 483
Healthways, 549 responsibilities, 484
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Index | 615

Home Medical Equipment (HME), 431 identification test, 146

professionalism, 432 ignitable pharmaceuticals, 424
Homer, 13 illness behavior, 355
homologs, in drug design, 109 imaging
homologous series, 109 agents, 78
hormones, 335 nuclear magnetic resonance (NMR), 111
therapeutic potential, 335 positron emission tomography (PET), 477
hospice history, 589 see also nuclear pharmacy; radiopharmaceuticals;
hospital pharmacy internships, 473 spectroscopy
hospital practice experience, 472 immediate-release (IR) dosage forms, 329
hospital-acquired infections, 587 immune system, 336
hospitals, 447 antibody-mediated response, 336
compounding, 499 cell-mediated response, 336
floor stock system, 449 immunization administration, 444, 587
hazardous waste disposal, 451 immunology, 296
patient prescription system, 450 Impact Factor, 52
pharmacy practice, 6, 446 implants, intraocular drug delivery, 318
prescriptions, 449 impurities, 146
transformation into health systems, 447 inclusion complexation, 231
types of, 447 incompatibility, 158, 508
unit-dose system, 450 Index Nominum: International Drug Directory, 56
work schedules, 468 indications, drug evaluation monographs, 376
see also health system pharmacy indium, inorganic chemistry, 71
human genome, 297 individualized therapy, 422
Ethical, Legal and Social Implications (ELSI) of Human indomethacin, solid state forms, 215, 217
Genetics Research program, 333, 337 industrial pharmacy, 7, 474
Human Genome Project, 297, 585 careers, 7, 474
variation, 298, 585 education, 340
types of, 299 veterinary, 488
human immunodeficiency virus (HIV), 587 industrial reorganization, 435
human resources (HR), 467 Infectious Disease Society of America (IDSA), 454, 588
performance planning, 468 infectious diseases, 586
recruitment, 467 antimicrobial resistance, 587
regulatory impact on roles, 467 pharmacy, 573, 586
work schedules, 468 informatics, 349, 469
human testing, information
clinical hold, 35 adverse reactions, 59
Investigational New Drug (IND) applications, 35 compounding, 497
see also clinical trials databases, 53
hydrates, 210 drug information, 351
compounding with, 506 clinical drug literature, 351
hydrogen bond, 67 compounded preparations, 57
hydrogen, inorganic chemistry, 69 consumer drug information, 60, 407
hydrolysis, 160 disease state management, 551
hydronium ion concentrations, pH relationship, 86 drug information centers, 354
hyperosmotic agents, 240 nonprescription products, 58
hypodermic tablets (BT), 327 pharmacists’ responsibilities, 352
prescription products, 57
ibritumomab, 481 drug interactions, 59
ideal gas law, 222 emerging trends, 61
Ident-a-drug Reference, 60 formulation, 60
IDENTIDEX System, 60 genetic information protection, 337
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616 | Index

information (continued) laxatives, 78

location of resources, 51 oxidizing germicides, 72
herbal medicines and natural products 58 pH control, 68
location of resources 51 pigments, 76
manufacturing 60 precipitating germicides, 72
Medication Guide 40 protective agents, 75
personalized medicine 60 radiopaque compounds, 78
pharmacist’s roles and responsibilities 1, 352 respiratory stimulants, 77
pharmacy informatics 349, 469 salts, compounding, 508
poisoning and toxicology 59 structural repairs, 78
primary literature 52 topical agents, 72
product identification 60 inorganic pigments, 76
professional associations 61 inpatient medication orders, 386
reviews 53 inscription, 388
secondary literature 53 inserts
tertiary literature 55 compressed, 326
information technology (IT) 348, 352, 469 ocular, 318, 321
emerging technologies, 351 instability, 236
Health Insurance Portability and Accountability Act proteins, 514
regulations, 350 see also stability of pharmaceuticals
pharmacy informatics, 349, 469 Institute for Safe Medication Practices (ISMP), 353, 387
see also technology prescription safety alerts, 389, 395
informed consent, clinical trial participation, 47 Institute for Scientific Information (ISI), 52
infrared (IR) spectroscopy, 172 Institute of Medicine (IOM), 528
solid state analysis, 213 Committee on Quality reports, 528
infusion pumps, smart, 472 Crossing the Quality Chasm: A New Health System
inhalation therapy for the 21st Century, 416
aerosols, 330 Fostering Rapid Advances in HealthCare: Learning
metered-dose inhalers (MDIs), 158 from System Demonstrations, 415
dry-powdered products, 158 Health Professions Education: A Bridge to Quality,
nasal inhalation products, 158 415
injections, Keeping Patients Safe: Transforming the Work
intraocular, 318 Environment of Nurses, 415
specifications, 180, 181 Leadership by Example: Coordinating Government
see also intravenous (IV) administration; parenteral Roles in Improving HealthCare Quality, 415
preparations Patient Safety: Achieving a New Standard for Care,
inorganic chemistry, 65 415
acids, 67 Preventing Medication Errors, 415, 416
artificial atmospheres, 77 Priority Areas for National Action Transforming
astringents, 72 HealthCare Quality, 415
bases, 67 To Err is Human: Building a Safer Health System,
buffers, 68 413, 416, 418
carbon dioxide absorbers, 77 Institutional Review Boards (IRB), 47, 354
chemical reactions, 65 insufflations, 306
electrolytes, 69 insurance plans, prescription drug costs, 442, 527
enemas, 78 Integrated Risk Information System (IRIS), 60
essential trace elements, 69 intensive care unit (ICU), 586
expectorants, 77 intention to treat analysis (ITA), 48
gastric antacids, 68 intentional non-adherence, 358
imaging agents, 78 interactive voice response (IVR) systems, 443
incompatibilities, 508 interfacial phenomena, 251
irrigation solutions, 78 interferon α, 336
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interionic compatibility, 161 ionization potential, 66

interleukins, 336 ionizing radiation effects on drug stability, 163
International Bureau of Weights and Measures, 194 iron, inorganic chemistry, 76
International Classification of Diseases (ICD-9) coding, 534 irrigation solutions, 78
International Conference on Harmonization (ICH), 32 Islamic culture, 14
clinical trial guidelines, 47 iso-osmotic solutions, 237
shelf-life recommendations, 163 isopropyl alcohol, 309
International Human Genome Sequencing Consortium isosteres, 96
(IHGSC), 298 isotonic solution V values, 244
International Journal of Pharmaceutical Compounding, 316 isotonicity, 237
International Nonproprietary Names (INNs), 55, 135 ophthalmic preparations, 323
INN Expert Group, 138 parenteral preparations, 315
selection process, 136
International Pharmaceutical Abstracts (IPA) database, 51, Japanese Accepted Names for Pharmaceuticals, 56
54, 58 Japanese Pharmacopeia, 56, 145
Internet, 349, 351 job description, 381
as an information resource, 352 job postings, 382
Internet pharmacies, 26, 443 Joint Commission (TJC), 464
intervention National Patient Safety Goals (NPSGs), 454, 464
application, 42
Joint Commission of Pharmacy Practitioners (JCPP), 26
assignment, 41
journalism careers, 7
interviewing, 382
journals, 52
inappropriate topics, 383
compounding, 498
intraocular injections, 318
Impact Factor, 52
see also ophthalmic preparations
peer review process, 52
intrapreneurship, 433, 434
just-in-time inventory, 465
intravenous (IV) administration, 241
compounding, 499
Kauzmann temperature, 209
IV robotics, 471
Keesom forces, 223
IV to PO switch programs, 457
killer T cells, 336
see also injections; parenteral preparations
kilogram, 193
introductory pharmacy practice experience (IPPE), 472
inventory, 465
control, 152 labeling
just-in-time, 465 auxiliary labels, 407
Investigational Device Exemption (IDE), 32 barcoding, 338
Investigational New Drug (IND) applications, 32, 35 blinding, 45
iodine boxed warnings, 39
inorganic chemistry, 75 compounded organic molecule products, 515
radioactive I-131, 481 controlled substances, 403
ion-exchange chromatography, 170 parenteral preparations, 316
ionic diffusion, 293 patients’ ability to read, 578
ionic equilibria, 233 poison control, 423
ionic liquids, 235 prescriptions, 403
ionic solution, 233 directions for use, 406
ionic strength, dissociation constants, 82, 84 standardization, 404
ionization quality control, 151
acids and bases, 81, 83 standardized requirements, 37, 375
proton balance equation (PBE), 89 suspensions, 320
drug absorption relationship, 90, 236 LACRISERT, 321
drug activity relationship, 236 lactulose, 239
pH relationship, 90 lamellar phase lyotropic liquid crystals, 218
water, 83 lanthanum, inorganic chemistry, 72
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latent heat liquids, 197, 220

of condensation, 198 ionic liquids, 235
of vaporization, 198 phase transitions, 197
law of mass action, 247 supercooled liquids, 207
laws governing pharmacy, 523 viscosity, 221
compounding, 524 see also liquid preparations
concurrent jurisdiction, 524 listening skills, 365
legislation history, 21, 24 liter, 193
relationship between state and federal laws, 524 literature
see also regulation; specific Acts; state law clinical drug literature, 351
laxatives, 78 location of resources, 51
osmotic, 239 primary, 52
layered tablets, 326 reviews, 53
Le Chatelier’s principle, 82 secondary, 53
lead compound selection, 32, 106 tertiary, 55
ligand similarity-based lead identification, 116 see also information
lead, inorganic chemistry, 73 lithium, inorganic chemistry, 69
leadership, 460 London forces, 223
definition, 460 long-term care, 591
health system leadership, 461 loss-of-function mutations, 300
performance improvement, 463 lymphocytes, 336
pharmacy leadership, 462 B lymphocytes, 336
strategic planning and goals, 462 T lymphocytes, 336
Lean performance improvement, 463 helper T cells, 336
leave-one-out (LOO) technique, 113 killer T cells, 336
legal aspects see laws governing pharmacy; regulation; suppressor T cells, 336
specific Acts lymphokines, 336
legend drugs see prescription drugs lyotropic liquid crystals (LLC), 218
legislation see laws governing pharmacy
length, 193 macrophages, 336
Leung, Encyclopedia of Common Natural Ingredients Used macrosystems of care, 414
in Food, Drugs, and Cosmetics, 58 magic bullet, 336
levodopa (L-dopa), 80 magnesium, inorganic chemistry, 70
licensing, state law/regulations, 2 mail-order services, 443
lidocaine hydrochloride, 506 managed care, 25
injection, 67 managed care organizations (MCOs), 548
ligand efficiency, 110 managerial activities, 433
ligand-based design, 108 managers, 461
ligand similarity-based lead identification, 116 manganese, inorganic chemistry, 76
lighthouses, 336 manufacturing, information resources, 60
linear regression model, 113 manuscripts for publication, 371
linkage disequilibrium, 299 editing, 373
lipid solubility, 295 first draft, 372
lipid-to-water partition coefficient, 295 preparation, 371
lipophilicity, 92 professional writing rules, 373
liquid crystals, 217 referencing, 373
lyotropic (LLC), 218 scholarly publications, 485
thermotropic (TLC), 219 sections of research project publications, 372
liquid preparations, 307 marijuana use, 360
quality control, 495 marine natural products, 101
solvents for, 308 market share, 464
see also emulsions; solutions; suspensions marketing, 529
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Index | 619

markets, new, 435 recalls, 528

Martindale: The Complete Drug Reference, 56, 57 safety, 458
mass spectroscopy, 175 shortages, 380
identification of drug metabolites, 175 withdrawals, 528
quantitative analysis, 176 see also drugs
matched molecular pairs analysis (MMPA), 118 medication administration record (MAR), 453, 470
maximum coordination number, 67 electronic (eMAR), 470
measure, 190 medication alert notifications, 380
see also weights and measures Medication Guide, 40
measuring, 190 Medication Therapy Management (MTM), 26, 368, 410,
MedGuides, 459 445, 528
Medicaid documentation, 369, 533
prescription drug benefits, 442 reimbursement, 445, 537, 556
see also Centers for Medicare and Medicaid Services medication therapy management services (MTMS), 455
(CMS) medication-related action plan (MAP), 369
medical claims, 534, 537 medication-use evaluation (MUE), 353, 379, 458
CMS-1500 claim form, 534, 538 background, 379
medical devices methods, 379
approval, 32
recommendations, 380
Investigational Device Exemption (IDE), 32
results, 379
Medical Dictionary for Drug Regulatory Affairs
summary, 379
(MedDRA), 48
medication-use policy, 381, 456
medical errors see errors
formulary system, 456
medical foods, 97–99
medication safety, 458
medical grade materials, 339
medication safety officer (MSO), 459
medical informatics, 349, 352
medication selection and review, 456
medical records
pharmacy and therapeutics (P&T) committee, 456
confidentiality issues, 350
strategies for managing medication use, 457
documentation of patient care, 367, 455
medicinal chemistry, 106
electronic, 349, 351, 470, 533, 555
MedlinePlus, 60
patient access to, 350
MedWatch program, 39, 353, 411, 413, 544
problem-oriented medical record (POMR), 532, 533
melting point, 198
regulations, 350
membranes see cell membranes
security self-assessment, 351
Medicare, memoranda, 370
core measurements, 454 memory cells, 336
Health Support pilot program, 549 menadione, ligand efficiency, 110
Modernization Act 2003, 26, 441, 444, 528, 530 Merck Index: An Encyclopedia of Chemicals, Drugs, and
prescription drug benefits, 442 Biologicals, 56
RBRVS reimbursement system, 537 mercury, inorganic chemistry, 70
short cycle rule, 430 mesogens, 217
see also Centers for Medicare and Medicaid Services mesophases see liquid crystals
(CMS) meta-analysis, 53
medication, metabolic engineering, 336
disposal, 424, 528 metabolism, 79
community/private sector, 427 see also drug metabolism
flushing, 428 metal containers, 165
reverse distribution, 426 metastable forms, 205, 206
trash disposal, 428 meter, 193
errors, 1 metered-dose inhalers (MDIs), 158
drug evaluation monographs, 377 methanamide, 123
process, 1 Staphylococcus aureus (MRSA), 587
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metrology, 190 My NCBI, 54

English system, 191
history, 191 nanotechnology, 252
metric system, 193 narcotic stewardship, 455
Meyer–Overton narcosis theory, 111 nasal inhalation products, 158
Meyler’s Side Effects of Drugs: An Encyclopedia of Adverse National Association for Home Care and Hospice
Reactions and Interactions, 59 (NAHC), 482
micelles, 218 National Association of Boards of Pharmacy (NABP),
micro dissociation constants, 86 Model State Pharmacy Act, 505, 524
Microsoft PowerPoint presentations, 373 National Association of Retail Druggists (NARD), 23
microsystems of care, 414 National Community Pharmacists Association (NCPA), 8,
Middle Ages, 14 433
milliosmol (mOsm), 237 National Conference of State Legislatures (NCSL), 430
Millis Commission see Study Commission on Pharmacy National Council for Prescription Drug Programs
minerals, dietary, 72 (NCPDP), 538
models National Formulary, 23, 56, 133
drug design, 113 monographs, 145
drug modeling, 33 National Guideline Clearinghouse, 554
palliative care, 589 National Health and Nutrition Examination Survey
pharmacokinetic models, 287 (NHANES), 98
physiological models, 288 National Institute for Occupational Safety and Health
modified-release drug delivery see oral modified-release (NIOSH), 464
drug delivery systems National Institute of Pharmaceutical Information and
modulated temperature differential scanning calorimetry Technology, 60
(MTDSC), 217 National Institutes of Health Pediatric Pharmacology
molded tablets, 325, 326 Research Unit (PPRU), 583
dispensing tablets (DT), 327 National Medication Errors Reporting Program (MERP),
hypodermic tablets (BT), 327 353
molecular complexes, 251 National Patient Safety Goals (NPSGs), 454, 464
molecular hologram, 112 National Prescription Drug Take Back Days, 428
molecular interactions, electromagnetic radiation and, 174 National Provider Identifier (NPI) number, 534
molecules, 196 natural killer (NK) cells, 336
molybdenum, inorganic chemistry, 74 Natural Medicines Comprehensive Database, 58
monitoring natural products, 96
adverse events, 48 complementary and alternative medicine, 444
drug therapy, 422 drug approvals, 107
health system pharmacy, 453 information resources, 58
environmental, 151 marine products, 101
Good Clinical Practice (GCP), 47 nomenclature, 132
new drugs, 39 see also herbal medicines
quality, 150 Natural Standard databases, 58
monoclonal antibodies, 337 near infrared (NIR) spectroscopy, 172
radiolabeled, 481 nebulizers, 318
monographs, 145 nematic phase liquid crystals
moral issues in biotechnology, 337 chiral, 220
morphine lyotropic, 219
extraction, 17 thermotropic, 219
functional groups, 79 neonatal medication, osmoticity issues, 239
waste management, 426 Nernst equation, 294
mortality from medical errors, 413 neurotransmitters, 335
multiple compressed tablets (MCT), 325 neutralization, 67
mutations, 299 neutron reactions, 125
 Remington_Pharmacy bindex.tex V1 - 04/24/2013 4:19 P.M. Page 621

Index | 621

neutrons, 196 nutrition, 486

New Drug Application (NDA), 37 medical foods, 97–99
supplemental (SNDA), 40 nutrients, 486
new drug development see drug development see also dietary supplements; parenteral nutrition
new service/product introduction, 434 nutrition support pharmacy, 569
newsletters, 380 certification, 569
Newton’s law of viscosity, 221 recertification, 569
Newtonian liquids, 221 nutritional pharmacotherapy, 487
Niacin Injection USP, 67
nickel, inorganic chemistry, 76 objectives
nine steps approach to pharmaceutical care, 560 clinical trials, 40
niobium, inorganic chemistry, 74 disease state management (DSM), 554
nitrogen(I) oxide, 77 Observations Medical Outcome Partnership (OMOP), 544
nitrogen, inorganic chemistry, 73, 77 Occupational Safety and Health Administration (OSHA),
nomenclature see drug nomenclature 464
non-adherence, 358, 359 ocular inserts, 318, 321
intentional, 358 Office for Civil Rights (OCR), 464
non-flocculated suspensions, 156 Office of Generic Drugs, 38
non-Newtonian liquids, 221 Office of Inspection General (OIG), 464
non-polar solvents, 230 ointments, 157
non-prescription drugs, 359 ophthalmic, 320
alcohol restrictions, 309 quality control, 495
approval process, 39 stability, 157
drug interactions, 418 OKT3 monoclonal antibody, 337
information resources, 58 older patients, 591
patients’ ability to read labels, 578 Omnibus Budget Reconciliation Act 1990 (OBRA-90), 26,
patients’ choice of, 578 367
prescription to non-prescription switch, 578 oncology pharmacy, 571
restricted, 386 certification, 571
self care, 576 recertification, 571
use of, 359 online healthcare communities, 351
see also self care open access journals, 52
noncompartmental models, 288 open-ended questions, 365
noncompliance see patient compliance ophthalmic preparations, 317
nonionic diffusion, 293, 295 additives, 323
nonproprietary name, 133 buffer, 322
International Nonproprietary Names (INNs), 55, 135 clarity, 321
nonsense mutations, 299 dosage forms, 317, 318
nuclear magnetic resonance (NMR), 111 emulsions, 320
nuclear medicine, 476 filtration, 321
diagnostic, 476 gels, 318–320, 323
radiation doses, 477 history, 318
technologists, 476 ocular inserts, 318, 321
nuclear pharmacy, 7, 475, 566 ointments, 320
careers, 7, 475 osmoticity issues, 239
certification, 567 packaging, 322
compounding, 501 pH, 322
recertification, 568 solutions, 318
training, 568 gel-forming, 319, 323
see also radiopharmaceuticals powders for, 319
nucleotides, 333 stability, 321
nursing homes, 435, 591 sterility, 322
 Remington_Pharmacy bindex.tex V1 - 04/24/2013 4:19 P.M. Page 622

622 | Index

ophthalmic preparations (continued) hyperosmotic agents, 240

suspensions, 319, 323 therapeutic effects, 239
difficulties with, 320 osmotic pressure, 237
tonicity, 323 osmoticity effects
viscosity, 323 diagnostic contrast agents, 240
opioids methods of adjusting tonicity, 242
abuse, 421 freezing-point depression, 242
narcotic stewardship, 455 isotonic solution V values, 244
opium, morphine extraction, 17 sodium chloride equivalent method, 243
oral modified-release drug delivery systems, 326, 329 neonatal medication, 239
delayed-release (DR) systems, 329 ophthalmic medication, 239
extended-release (ER) systems, 329 parenteral medication, 240, 241
rationale, 329 Ostwald’s rule, 206
Orange Book: Approved Drug Products with Therapeutic Ostwald–de Waele equation, 221
Equivalence Evaluations, 57 outcomes
organic chemistry, 79 clinical trials, 42, 44
acids, 80 disease state management, 557
bases, 80 management, 454
bioisosterism, 96 outsourcing, drug development, 44
co-crystals, 92 over-the-counter (OTC) drugs see non-prescription
complex molecules, 513 drugs
compounding, 513 oxidation reactions, 159, 310
drug absorption, 90 auto-oxidation, 159, 310
drug activity, 90 photo-oxidation, 162
drug design, 106 oxidizing germicides, 72
fragment-based approaches, 110 oxygen, 77
homologs, 109 inorganic chemistry, 74
ligand-based design, 108
models, 113 packaging, 337
receptor-based design, 108 blinding, 45
drug stability, 89 clinical trial drugs, 45
functional groups, 79 compliance packaging, 403
ionization, 81 compounded organic molecule products, 515
prodrugs, 122 dispensing, 401
receptors, 94 glass, 164
salts, 90 metal, 165
compounding, 509 ophthalmic preparations, 322
structural determinants, 92 parenteral preparations, 316
structurally specific drugs, 94 plastic, 164, 322
binding, 94 prescriptions, 401
structure–activity relationships, 106 problems with, 338
quantitative structure–activity relationship (QSAR), quality control, 151
95, 111, 116 regulations, 337
thermodynamic activity, 93 repackaging, 310, 339
organizational management careers, 8 risk assessment, 338
organizations single-dose packaging, 318, 403
safety framework, 414 stability relationships, 163, 322
see also individual organizations standards, 163, 338
Orphan Drug Act 1983, 39 unit-dose packaging, 318, 403
orphan drugs, 39 FDA requirements, 403
osmol, 237 water vapor permeation, 338
osmosis, 237, 308 see also containers; labeling
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Index | 623

paddle test method, 178 medication information, 389, 409

pain, 288, 588 patient empowerment, 355
management, 590 see also patient education
narcotic stewardship, 455 patient compliance, 354, 356
palliative care, 588 compliance packaging, 403
model, 589 drug interactions and, 420
pharmacy practice, 590 shaking of suspensions, 320
pan-coating processes, 328 patient education, 25, 473
paper chromatography, 170 diabetes self-management training (DSMT), 531
paperless practice, 349 diagnostic self-care, 579
parabens, 312 drug education, 358, 473
Paracelsus, 15 drug use, 359
parallel design, clinical trials, 41 nonmedical drug use, 362
parenteral nutrition, 454 drug interactions, 422
total parenteral nutrition (TPN), 241 Medication Guide, 40
parenteral preparations, 241, 315 need to shake suspensions, 320
components, 316 pharmacists’ role, 353
compounding, 499 patient empowerment, 355
electrolytes, 71 patient experience, 414
home infusion therapy, 482, 483 patient product information (PPI), 60, 407
manufacturing process, 315 Patient Protection and Affordable Care Act 2010, 26, 430,
osmoticity, 240, 241 446, 462, 547
methods of adjusting tonicity, 242 PDCA (Plan, Do, Check, Act), 463
packaging, 316 peak-height concentration (Cmax ), 167
processing, 315 pearl coating, 328
procurement, 315 Pediatric Drug Formulations, 58
quality control, 316, 495 pediatric pharmacy practice, 583
unique characteristics, 315 challenges, 583
see also injections; intravenous (IV) administration Pediatric Research Equity Act (PREA), 583
Parker, Paul, 564 peer review process, 52
participatory healthcare, 351 penetrometer, 157
partition chromatography, 170 penicillin development, 24
partition coefficient (P), 295 perforin proteins, 336
passive transport, 293 performance appraisal, 383
patents, 53 performance improvement, 463
patient adherence, 356, 359 performance planning, 468
non-adherence, 358, 359 performance-based contracts, 464
intentional, 358 permeation chromatography, 170
patient behavior, 354 persistence, 357
drug-taking behaviors, typology, 360 see also patient adherence; patient compliance
seeking care, 354 personalized medicine, 296
types of, 354 information resources, 60
health behavior, 354 personnel communication, 381
illness behavior, 355 interviewing, 382
sick-role/treatment behavior, 355 inappropriate topics, 383
see also patient adherence; patient compliance job postings, 382
patient care rounds, 453 performance appraisal, 383
Patient Centered Medical Home (PCMH), 446, 463, 538 policies and procedures, 384
patient centered practice, 550, 561 position description, 381
patient communication, 355 progressive discipline, 384
counseling, 360 pH, 86
benefits of, 356 chemical reaction relationships,
 Remington_Pharmacy bindex.tex V1 - 04/24/2013 4:19 P.M. Page 624

624 | Index

pH (continued) transdermal patches, 157

decarboxylation, 161 pharmaceutical care, 25, 558
epimerization, 162 definition, 559
hydrolysis, 160 identifying patients to follow, 561
interionic compatibility, 161 nine steps approach, 560
oxidation, 159 pharmacists’ role, 559
drug absorption relationship, 90 providers, 559
drug activity relationship, 90 skills importance, 560
gastric antacids, 68 versus clinical pharmacy, 559
ionization relationship, 90 see also care plan
manipulation to increase solubility, 230 pharmaceutical equivalence, 167
ophthalmic preparations, 322 pharmaceutical excipients, 339
organic molecule compounding, 513, 514 pediatric medications, 584
physiological, 238 selection of, 120
control, 68 pharmaceutical industry, 474
stability relationships, 89, 236, 322 development, 20, 23, 24
stabilization, 248 economics, 525
see also acids; bases pharmaceutical journalism careers, 7
phagocytes, 336 Pharmaceutical Manufacturer Patient Assistance Program,
pharmaceutical analysis 465
assay, 146 pharmaceutical profiling, 115
bioavailability testing, 166 drug discovery, 116
bioequivalence testing, 38, 166, 167 computational prediction of drug-likeness, 116
methods, 168 degradant profiling, 120
biological testing, 146 drug formulation screening, 119
animal testing, 147 drug reprofiling, 119
bioassay procedures, 148 pharmaceutical solvents see solvents
plastics, 164 pharmaceutical waste see waste management
chromatography, 169 pharmacists
classification of methods, 170 credentialing, 446, 533
clinical analysis, 148 education, 2, 472
dissolution testing, 178 see also education
drug description, 146 pharmacist-patient relationship, 355, 385, 396, 561
future direction, 146 see also patient communication
identification test, 146 pharmacist-prescriber relationship, 385
impurities, 146 residency programs, 8, 26, 452, 473
release, 145 community practice, 445
solid state analysis, 213 roles and responsibilities, 1
spectroscopy, 172 ambulatory care, 499
mass spectroscopy, 175 compounding, 490
theory, 172 disease state management, 1, 548, 550, 551
stability, 145, 153, 249 drug distribution, 442, 448
dry-powdered inhalation products, 158 drug information, 352
emulsions, 156 health system pharmacy, 448
gelatin capsules, 155 home infusion pharmacy services, 484
metered-dose aerosols, 158 in academia, 486
nasal inhalation products, 158 pharmaceutical care, 559
ointments, 157 poison control, 423
photostability, 162 skills, importance of, 560
solutions, 156 Pharmacists’ Pharmacopeia, 56, 57
suspensions, 155 pharmacodynamics see pharmacokinetics
tablets, 154 pharmacoeconomics, 525
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Index | 625

clinical pharmacy, 529 Pharmacy Technician Certification Board (PTCB), 448

community pharmacy, 525 pharmacy technicians, 467
pharmaceutical economics, 525 community practice, 445
terminology, 526 health system pharmacy, 448
see also entrepreneurial activities; reimbursement recruitment, 468
pharmacoepidemiology, 542 PharmaHUB, 61
pharmacogenomics, 296, 585 phase diagram, 198, 201
history, 297 multicomponent system, 202
pharmacist’s role, 297 Phase I clinical trials, 36
health system pharmacy, 455 Phase II clinical trials, 36
see also human genome dose validation, 158
Pharmacognosy, 58, 101 Phase III clinical trials, 36
pharmacokinetics, 286, 291 Phase IV clinical trials, 37
clinical pharmacokinetics, 296 phase transitions, 197
concentration versus effect relationship, 285 phases, 201
concentration versus time profile, 286 phosphorus
drug development, 301 inorganic chemistry, 73
drug evaluation monographs, 376 radioactive (P32 ), 125
drug interactions, 419 photoacoustic spectroscopy (PAS), 121
models, 287 photochemical reactions, 162
pharmacopeias, 15, 17, 23, 56 physician order entry (POE) prescriptions, 387
see also specific publications Physicians’ Desk Guide Reference for Nonprescription
pharmacophore, 80, 108 Drugs, Dietary Supplements and Herbs, 58
pharmacotherapy, 569 physiological models, 288
certification, 570 Pill Book, 60
recertification, 570 pinocytosis, 294
pharmacovigillance, 543 placebo, 44
pharmacy, 11 plagiarism, 373
evolution, 12, 339, 441 plasma, 223
American pharmacy, 18, 20 plasma membrane see cell membranes
antiquity, 12 plaster of Paris, 79
clinical pharmacy, 25 plastic containers, 164
count and pour era, 24 ophthalmic preparations, 322
future directions, 26, 538 Plumb, Veterinary Drug Handbook, 58
legislation, 21 point mutations, 299
Middle Ages, 14 poison control, 423
pharmaceutical care, 25 labeling, 423
prehistory, 12 pharmacists’ role, 423
professionalism, 21, 22 Poison Prevention Packaging Act (PPPA), 338, 402
Renaissance, 15 poisoning, information resources, 59
twenty-first century, 26 see also poison control
informatics, 349, 469 polar solvents, 229
leadership, 462 polarity, 295
legal aspects see laws governing pharmacy police powers, 524
practice policies
ethical dilemmas, 345 medication use, 381, 456
reimbursement, 444 policy statement, 384
see also specific types of practice polonium, inorganic chemistry, 74
Pharmacy and Therapeutics (P&T) Committee, 456 polymerase chain reaction (PCR), 336
pharmacy benefit managers (PBMs), 442, 445 polymorphism, 91
Pharmacy Compounding Accreditation Board, 444 crystal structure, 205, 206
Pharmacy Practice Model Initiative (PPMI), 448, 462 genetic, 585
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626 | Index

polymorphism (continued) dispensing directions, 389

single-nucleotide polymorphisms (SNPs), 298, 299, documentation, 409
585 regulation, 524
suspensions, 320 electronic submission, 387
polyvinylchloride (PVC), 165 forms, 386
populations, 195 generic substitutions, 389, 457, 528
position description, 381 history, 19, 26
positron emission tomography (PET), 477 hospitals, 449
post-approval activities, 39 inscription, 388
poster presentations, 374 labeling, 403
postgraduate training, 8 directions for use, 406
residency programs, 8, 26, 445, 452 standardization, 404
postmarketing product surveillance, 413, 543 mail-order delivery, 443
potassium, inorganic chemistry, 69 medication prescribed, 388
potency, 290, 512 numbering, 397
determination, 512 packaging, 401
potency-designated ingredients, 512 patient information, 388
powders, 305 pre-printed orders, 458
as a dosage form, 305 preparation, 399
bulk powders, 306 prescriber information, 388
divided powders, 306 prescribing authority, 385
dry-powdered inhalers (DPIs), 158 price of, 442, 527
dusting powders, 306 pricing, 410
effervescent powders, 306 processing, 396
for ophthalmic solutions, 319 drug shortage impact, 466
insufflations, 306 quality control, 400
power, 43 reading and checking, 396
sample size relationship, 543 receiving, 396
PowerPoint presentations, 373 clarification with prescriber, 397
pre-IND meetings, 34 rechecking, 407
pre-printed orders, 458 refills, 396, 410
pre-professional courses, 2 reimbursement, 527
precipitating germicides, 72 renewals, 410
precipitation reporting safety issues, 411
amorphous, 232 safety concerns, 389, 395, 397
complex organic molecules, 516 signatura, 389
preclinical testing, 32, 34 signature, 388
prehistoric pharmacy, 12 subscription, 389
preparative scale chromatography, 171 superscription, 388
Prescription Drug User Fee Act (PDUFA) 1992, 37 symbol, 388
prescription drugs, 386 transfer of prescription order, 411
drug information, 57 see also dispensing
prescription to non-prescription switch, 578 presentations, 373
prescriptions, 385 poster presentations, 374
abbreviations, 389 verbal presentations, 373
beyond-use date, 400, 406 visual aids, 373
compounded prescriptions, 389 preservatives, 311
see also compounding acids, 312
controlled substances, 387 alcohols, 312
counter-prescribing, 20 compound molecule compounding, 513
date, 388 esters, 312
dating, 397 quaternary ammonium compounds, 312
directions for patient, 389 press-coated tablets, 326
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Index | 627

pressure medication-use evaluation (MUE), 379

critical pressure, 200 newsletters, 380
state of matter relationship, 198 professional correspondence, 370
preventive care, 579 cover letters, 370
chemoprevention, 582 curriculum vitae, 371
clinical guidelines, 582 memoranda, 370
interventions, 581 resumé, 371
primary prevention, 580 verbal communications, 364
screening, 581 receiving drug orders, 367
secondary prevention, 580 telephone communications, 366
tertiary prevention, 580 written communications, 367
pricing, 410 see also manuscripts for publication
primary engineering controls (PECs), 316 professional courses, 2
primary literature, 52 professionalism
primary prevention, 580 home medical equipment (HME) field, 432
prime-vendor system, 465 pharmacy evolution, 21, 22
printing role in pharmacy evolution, 15 professional responsibilities, 561
problem-oriented medical record (POMR), 532, 533 Profiles of Drug Substances, Excipients, and Related
procainamide, 96 Methodology, 60
procedures, 384 profiling see degradant profiling; pharmaceutical profiling
processing progressive discipline, 384
aseptic, 314 prontosil, 123
parenteral preparations, 315 propylene glycol, 310, 312
procurement, 464 protective topical agents, 75
drug shortages, 466 proteins, 333
group purchasing organizations (GPOs), 464 compounding, 513
parenteral preparations, 315 diversity, 335
prime-vendor system, 465 instability, 514
wholesalers, 465 solubility, 120, 514
prodrugs, 122 transcription, 333
functional groups, 124 protocol
product identification, 60 clinical trials, 42
product recalls, 528 disease state management (DSM), 553
professional associations, information resources, 61 protolysis, 80
professional communications, 364 proton balance equation (PBE), 89
clinical practice guidelines, 380 protons, 196
displaying confidence, 366 pseudoplastic liquids, 221
drug-related questions, 364 psychiatric pharmacy, 570
responding to, 365 certification, 570
electronic communication, 370 recertification, 571
e-mail, 370 public health, 475
social media, 370 publication see manuscripts for publication
follow-up, 366 PubMed database, 51, 54, 61
formal presentations, 373 Pure Food and Drug Act 1906, 23, 31
poster presentations, 374 purified water, 308
verbal presentations, 373 ophthalmic preparations, 323
visual aids, 373 purity test, 146
formulary communications, 374
drug evaluation monographs, 375 quality, 590
listening skills, 365 definition, 590
medication alert notifications, 380 quality assurance (QA), 149
medication use policies, 381 compounding, 505
 Remington_Pharmacy bindex.tex V1 - 04/24/2013 4:19 P.M. Page 628

628 | Index

quality assurance (QA) (continued) see also nuclear medicine

disease state management, 557 radiopharmacy see nuclear pharmacy
functions and responsibilities, 149 radium, 124
quality monitoring, 150 inorganic chemistry, 70
standards, 144 Raman spectroscopy, 172
water quality, 151 solid state analysis, 213
Quality by Design (QbD), 146, 150 Randic index, 112
quality control (QC), 149 randomization, 41
compounding, 450, 494 rapid access to new drug products, 38
environmental monitoring, 151 rate constant, 248
functions and responsibilities, 150 reaction mechanism, 246
monographs, 145 reaction rate, 247
packaging, 151 reactive pharmaceuticals, 424
parenteral preparations, 316 real-time polymerase chain reaction (RT-PCR), 336
prescription processing, 400 recalls, 528
product quality complaints, 413 receptor-based design, 108
radiopharmaceuticals, 480 receptors, 94
specifications, 143 drug-receptor affinity, 94
quality issues in healthcare, 413, 416 recertification
quantitative real time polymerase chain reaction (Q-PCR), ambulatory care pharmacy, 572
336 nuclear pharmacy, 568
quantitative structure–activity relationship (QSAR), 95, nutrition support pharmacy, 569
111, 116 oncology pharmacy, 571
applications, 114 pharmacotherapy, 570
descriptors, 112 psychiatric pharmacy, 571
softwares, 117 reciprocating cylinder, 178
quantum numbers, 65 record keeping see documentation; medical records
quaternary ammonium compound preservatives, 312 recruitment, 467
questions recycling of prescription drugs, 430
drug-related, 364 reduction reactions, 160
responding to, 365 referencing
in verbal presentations, 374 drug evaluation monographs, 378
open-ended, 365 manuscripts for publication, 373
quinine extraction, 16, 17 refill prescriptions, 396, 410
refrigeration, drug stabilization, 249
racemization, 161 regulated medical waste (RMW), 425
radionuclides, 124 disposal, 425
applications, 124 see also waste management
characteristics, 126–128 regulation, 463
production, 125 clinical trials, 47
cyclotron, 129 compounding, 501, 524
fission by-products, 125 disease state management involvement, 528
neutron reactions, 125 impact on pharmacy roles, 467
radionuclide generators, 130 licensing, 2
radiopaque compounds, 78 medical records, 350
radiopharmaceuticals, 125, 475 packaging, 337
diagnostic, 476, 478 see also laws governing pharmacy
half-lives, 477 regulatory mutations, 300
preparation, 480, 501 reimbursement, 442, 444
quality control, 480 ambulatory care, 499
specific activity, 476 billing methods, 530
therapeutic, 476, 479, 481 facility billing, 531
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Index | 629

first-party payment, 531 intravenous (IV) robotics, 471

‘‘incident-to billing’’, 531 Roman Empire, 14
medication therapy management (MTM), 530 root cause analysis (RCA), 460
third-party contracting, 531 rounding, 453
claims, 534, 537 routes of administration see dosage forms
CMS-1500 claim form, 534, 538 rubber closures, 164, 166, 316
community pharmacy practice, 445 Rubbing Alcohol, 309
diabetes self-management training (DSMT), 531 rubidium, inorganic chemistry, 69
disease state management (DSM), 555 Rule of Five, 117
fee setting, 537
history, 548
laboratory testing, 532 safety, 540
prescription costs, 527 clinical trials, 36
Resource-Base Relative Value Scale (RBRVS), 537 adverse event monitoring and reporting, 48
see also pharmacoeconomics compounding, 450
relative potency, 290 drug evaluation monographs, 377
Relative Value Unit scores (RVUs), 537 drug product safety reporting programs, 411
resource-based (RBRVUs), 537 postmarketing product surveillance, 413, 543
release and stability testing, 145 elements to assure safe use (ETASU), 541
Renaissance, 15 framework, 413
renal dosing programs, 458 issues in healthcare, 413, 416
repackaging, 310, 339 medication safety, 458
reporting, 411 medication safety officer (MSO), 459
adverse events in clinical trials, 48 new drug monitoring, 39
MedWatch program, 39, 353, 411, 413, 544 prescription safety issues, 411
prescription safety issues, 411 see also adverse drug reactions (ADRs); risk
serious adverse events, 353 management; serious adverse events (SAEs)
research trials, 353 safety alerts, 353
see also clinical trials prescription concerns, 389, 395
residency programs, 8, 26, 452, 473 salts, 90
accreditation, 8, 473 compounding
community pharmacy practice, 445 inorganic salts, 508
resonance absorption, 174 organic salts, 509
Resource Conservation and Recovery Act 1976 (RCRA), formation, 233
424, 425, 451 advantages, 233
Resource-Base Relative Value Scale (RBRVS), 537 solvent selection, 119
respiratory stimulants, 77 incompatibilities, 508
resumé, 371 polymorphism, 91
reverse distribution, 426 solution, 233
reverse transcriptase, 335 phases, 202
reversed-phase chromatography, 170 solubility, 508
review articles, 53 solubility product, 235
rhenium, inorganic chemistry, 76 sample size, 43
rheology, 257 statistical power relationship, 543
risk management, 540 samples, 195
drug interactions, 421 Saunders, Dame Cicely, 589
packaging risk assessment, 338 scale-up and post-approval changes (SUPAC), 40
preventive care, 581 scandium, inorganic chemistry, 72
risk evaluation and mitigation strategy (REMS), 40, 455, Schröder–Van Laar equation, 212
457, 459, 541 scientific journals see journals
number of approved programs, 542 SciFinder Scholar, 54
robotics, 443 SciVerse Scopus, 55
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630 | Index

screening Six Sigma performance improvement, 463

disease prevention, 581 skills, importance of, 560
drug formulation, 119 slide presentations, 373
high-throughput screening (HTS), 106, 119 Slone Survey, 359
random, 32 small businesses, 434
virtual, 108 smart infusion pumps, 472
second law of thermodynamics, 225 SMARxT Disposal program, 427
secondary literature, 53 smectic phase liquid crystals, 220
secondary prevention, 580 smoking, 360
Secure and Responsible Drug Disposal Act, 426, 428 Smoluchowski equation, 255
selectivity, 289 SOAP documentation system, 368, 532
selenium, inorganic chemistry, 74 SOAP note, 368
self care, 576 SOAPEO note, 368
diabetes self-management training (DSMT), 531 social media, 370
diagnostic self-care, 359, 579 Society of Infectious Diseases Pharmacists, 573
dietary supplements, 98, 101, 487 sodium bicarbonate, 68
safety issues, 99 sodium chloride crystalline structure, 203
movement toward, 577 sodium chloride equivalent method, 243
self-medication, 359 sodium, inorganic chemistry, 69
non-prescription products, 576 solid dispersions, 231
semipermeable membranes, 237 amorphous precipitation, 232
see also cell membranes classification, 231
semipolar solvents, 230 coarse dispersions, 252
Sentinel Initiative, 544 complex formation between drug and carriers, 232
separation methods, 232 dispersion step, 253
serious adverse events (SAEs) glass solutions of suspensions, 232
clinical trials, 48 interfacial properties, 254
reporting, 353 surface free energy, 254
see also adverse drug reactions (ADRs); adverse events surface potential, 254
(AEs) simple eutectic mixtures, 231
shaking, suspensions, 320 solid solutions, 232
shamans, 12 see also suspensions
Shanidar, pharmacy evolution, 12 solids, 196
shear stress, 221 amorphous solids, 207
shelf-life, 152 amorphous mixtures, 212
compounded organic molecule products, 515 glass solution, 212
prediction, 163 heat capacity (C), 216
preservatives, 311 thermodynamics, 207
see also stability of pharmaceuticals analytical methods, 213
short cycle prescribing, 430 crystalline, 91, 211
sick-role behavior, 355 co-crystals, 92, 211
side effects see adverse drug reactions (ADRs) eutectics, 211
signatura, 389 polymorphism, 91, 205, 206
silent mutations, 299 structural defects, 204
silicon, inorganic chemistry, 73 unit cell, 203
silver, inorganic chemistry, 70 eutectics, 211
single blinding, 44 hydrates, 210
Single Nucleotide Polymorphism (SNP) Consortium, 298 phase transitions, 197
single nucleotide polymorphisms (SNPs), 298, 299, 585 solvates, 210
single-dose packaging, 403 two-component solids, 210
ophthalmic, 318 solubility
site-specific drug delivery, 329 inorganic salts, 508
 Remington_Pharmacy bindex.tex V1 - 04/24/2013 4:19 P.M. Page 631

Index | 631

methods to increase, 230 see also Board of Pharmacy Specialties (BPS); specific
buffers, 230 specialties
complexation, 231 specific activity, radiopharmaceuticals, 476
cosolvents, 230 specific gravity, 190
salt formation, 509 specific rate constant, 248
solid dispersions, 231 specifications, 143
surfactants, 231 injections, 180, 181
organic molecules, 514 tablets, 182
lipids, 295 spectroscopy, 172
proteins, 120, 514 fluorescence spectroscopy, 172
solutions, 229, 307 infrared (IR) spectroscopy, 172
absorption, 307 mass spectroscopy, 175
bioavailability, 307 identification of drug metabolites, 175
classification, 229 quantitative analysis, 176
colligative properties, 230, 233 molecular interactions, 174
glass solutions, 212, 232 near infrared (NIR) spectroscopy, 172
ionic solution, 233 photoacoustic spectroscopy (PAS), 121
irrigation solutions, 78 Raman spectroscopy, 172
solid state analysis, 213
ophthalmic, 318
theory, 172
gel-forming solutions, 319, 323
ultraviolet (UV), 172
powders for solutions, 319
spontaneous change, 225
preparation, 307
stability of pharmaceuticals, 151, 236, 310
salts, 233
chemical reactions, 159
solubility product, 235
decarboxylation, 161
solid solutions, 232
epimerization, 162
stability, 156
hydrolysis, 160
tablets for, 326
interionic compatibility, 161
see also dissolution; solubility
oxidation-reduction, 159
solvates, 210
racemization, 161
compounding with, 506
compounded preparations, 493
solvent drag, 293
complex organic molecules, 515
solvents, 229
incompatibility, 158, 508
cosolvents, 230
inorganic molecule compounding, 514
drug stabilization, 248 ionizing radiation effects, 163
for liquid preparations, 308 ophthalmic preparations, 321
alcohols, 309 packaging significance, 163, 322
water, 308 parenteral preparations, 315
for new drug salt formation, 119 pH relationship, 89, 322
sorbic acid preservative, 312 photochemical reactions, 162
sorption, 513 product stability, 153
specialization, 562 dry-powdered inhalation products, 158
history of emulsions, 156
in medicine, 562 gelatin capsules, 155
in pharmacy, 563 metered-dose aerosols, 158
value of, 563 nasal inhalation products, 158
specialty pharmacy, 444, 483 ointments, 157
Added Qualifications, 573 solutions, 156
certification process establishment, 565 suspensions, 155
current specialties, 566 tablets, 154
evolution of specialties, 566 through the supply chain, 152
pharmaceutical characteristics, 484 transdermal patches, 157
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632 | Index

stability of pharmaceuticals (continued) stratified randomization, 42

shelf-life prediction, 163 stress interview, 383
stabilization, 248 strontium, inorganic chemistry, 70
testing, 145, 249 structural determinants, 92
see also pharmaceutical analysis structural repairs, 78
types of, 152 structurally specific drugs, 94
ultrasonic energy effects, 162 binding, 94
stacking complexation, 231 structured interview, 383
standard operating procedures (SOPs), 149 structure–activity relationships, 106
compounding, 450 fragment-based approaches, 110
standards, 144 homologs, 109
bioassays, 148 ligand-based design, 108
compounding, 497 quantitative structure–activity relationship (QSAR), 95,
parenteral preparations, 316 111, 116
Joint Commission performance standards, 464 students
monographs, 145 patient encounters, 561
packaging, 163, 338 responsibilities, 560
potency-designated drugs, 512 see also education
weights and measures, 191, 193 Study Commission on Pharmacy, 351, 564
State Board of Pharmacy, 464 sublimation, 200
state function, 224 sublingual tablets, 326
state law subscription, 389
disease state management involvement, 551 Substance Abuse and Mental Health Services
federal law relationship, 524 Administration (SAMHSA), 360
licensure requirements, 2 substance use/abuse, 360
see also laws governing pharmacy alcohol, 360, 582
states of matter, 196 drug education, 362
changes between, 197 marijuana, 360
gases, 197, 222 substance abuse care, 582
liquid crystals, 217 tobacco, 360
liquids, 197, 220 see also drug use
plasma, 223 sugar-coated tablets (SCT), 325, 328
solids, 196 sulfur, inorganic chemistry, 74
statistical power, 43 summary numbers, 195
sample size relationship, 543 supercooled liquid state, 207
statistics, 194 supercritical fluid, 200
data, 194 superscription, 388
clinical trial data, 48 supplemental new drug application (SNDA), 40
visualization, 194 supply chain, drug stability, 152
populations, 195 supply sources, new, 435
samples, 195 suppositories
summary numbers, 195 compressed, 326
stem-and-leaf plot, 194 quality control, 495
sterilisation, 314 suppressor T cells, 336
sterility, 314 supramolecular heterosynthon, 211
compounding, 316, 451, 502 supramolecular homosynthon, 211
intravenous (IV) robotics, 471 surface activity, 251
ophthalmic preparations, 322 surface free energy, 252, 254
parenteral preparations, 315 surface potential, 254
storage, compounded organic molecule products, 515 surface-active agents, 253
see also shelf-life; stability of pharmaceuticals surfactants
strategic planning, 462 drug stabilization, 249
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ophthalmic preparations, 324 stability, 154

use to increase solubility, 231 color stability, 154
surgical supplies, 431 friability test, 154
surveillance see also oral modified-release drug delivery systems
pharmacovigillance, 543 tantalum, inorganic chemistry, 74
postmarketing adverse reactions, 413, 543 targeted synthesis, 33
suspensions, 254, 307, 510 Task Force on Specialties in Pharmacy, 564
bioavailability, 307 technetium, inorganic chemistry, 76
crystal growth, 320 technicians, 467
difficulties with, 320 community pharmacy practice, 445
drug stabilization, 249 health system pharmacy, 448
flocculation and deflocculation, 255 recruitment, 468
flocculation kinetics, 255 technology, 347
ophthalmic, 319 barcoding, 338, 348, 443
viscosity, 323 community pharmacy practice, 443
polymorphism, 320 emerging technologies, 351
preparation, 307 Health Insurance Portability and Accountability Act
shaking requirement, 320 regulations, 350
stability of, 155 health system pharmacy, 453
see also solid dispersions interactive voice response (IVR) systems, 443
sutures, 431 pharmacy informatics, 349, 469
system, 224, 347 robotics, 443
systematic reviews, 53 see also information technology (IT)
systems approach, 347 telephone communications, 366
receiving drug orders, 367, 387
T lymphocytes, 336 tellurium, inorganic chemistry, 74
helper T cells, 336 temperature
killer T cells, 336 critical temperature, 200
suppressor T cells, 336 state of matter relationship, 197
tablet triturates (TT), 326 terazosin clinical trial, 41
see also molded tablets tertiary literature, 55
tablets, 324 tertiary prevention, 580
compressed (CT), 325 textbooks, 55
buccal tablets, 326 thalidomide, 31
controlled-release tablets (CRT), 326 thallium, inorganic chemistry, 71
dry-coated tablets, 326 Theophrastus, 13
effervescent tablets, 326 therapeutic drug monitoring, 422
enteric-coated tablets (ECT), 325 health system pharmacy, 453
film-coated tablets (FCT), 325, 328 therapeutic equivalence, 167
layered tablets, 326 evaluations, 168
multiple compressed tablets (MCT), 325 therapeutic interchange, 457
press-coated tablets, 326 thermodynamic activity, 93
sublingual tablets, 326 thermodynamics, 223, 245
sugar-coated tablets (SCT), 325, 328 amorphous solids, 207
tablets for solution (TFS), 326 changes between states of matter, 197
dissolution testing, 155 entropy, 197, 225
for solution, 326 equilibrium, 224
hardness, 154 first law, 224
molded, 325, 326 second law, 225
dispensing tablets (DT), 327 third law, 227
hypodermic tablets (BT), 327 thermogram, 216
specifications, 182 thermotropic liquid crystals (TLC), 219
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thin-layer chromatography (TLC), 121, 170 troy weight, 146

degradant profiling, 121 tungsten, inorganic chemistry, 74
third law of thermodynamics, 227 Tyler, Honest Herbal: A Sensible Guide to the Use of Herbs
third-party contracting, 531 and Related Remedies, 58
thixotropy, 221
tight container, 164 ultrasonic energy effects on drug stability, 162
time of peak concentration (T max ), 167 ultraviolet (UV)
timolol maleate gel-forming solutions, 319 exposure to, 162
tin spectroscopy, 172
inorganic chemistry, 73 unit cell, 203
packaging tubes, 165 unit-dose packaging, 403
titanium, inorganic chemistry, 72 FDA requirements, 403
tobacco use, 360 ophthalmic, 318
tolerability, drug evaluation monographs, 377 unit-dose system, health system pharmacy, 450
tonicity, 237 United States Adopted Names (USAN), 131, 133
ophthalmic preparations, 323 Dictionary of USAN and International Drug Names, 55
topical agents, 72, 324 procedure for obtaining, 136
quality control, 495 USAN Council, 134
see also ointments; powders FDA Liaison, 135
Topliss scheme, 95 USAN Review Board, 134
total gene expression analysis (TOGA), 118 United States Pharmacopoeia (USP), 19, 23, 56, 133
total parenteral nutrition (TPN), 241 biological testing, 146
toxicity, compounded preparations, 57
animal testing, 34 Dictionary of USAN and International Drug Names, 55
toxic pharmaceuticals, 424 drug standards, 144
see also adverse drug reactions (ADRs) monographs, 145
toxicology information resources, 59 United States Pharmacopoeial (USP) Convention, 144
TOXNET databases, 54, 59 universal waste rule, 425
trace elements, essential, 69 unstructured interview, 383
trademark, 132 US Preventive Service Task Force (USPSTF), 580
training, 472 USAN see United States Adopted Names (USAN)
compounding, 495
diabetes self-management training, 531 V values, 244
nuclear pharmacy, 568 vaccination, 444, 587
pharmacy technicians, 468 vaccinia virus vector, 337
postgraduate, 8 valence electrons, 66
residency programs, 8, 26, 445, 452, 473 values, 346
see also education van der Waals equation, 223
transcription, 333 vanadium, inorganic chemistry, 74
transdermal patches, 157 verbal communications, 364
transition elements, 69 displaying confidence, 366
transparency presentations, 373 drug-related questions, 364
transplant pharmacy practice, 585 responding to, 365
transport see drug transport follow-up, 366
trash disposal, 428 receiving drug orders, 367
see also waste management telephone communications, 366
Trease and Evans, Pharmacognosy, 58 see also professional communications
treatment behavior, 355 Veterans Affairs Cooperative Study Program (CSP) trial, 41
treatment guidelines, 553, 554 veterinary pharmacy, 487
triple blinding, 44 community practice, 488
triple point, 200 compounding, 500
trivial names, 132 government sectors, 489
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industry, 488 quality, 308

scope of, 487 monitoring, 151
veterinary specialty referral centers, 488 states of, 196
veterinary teaching hospitals, 488 phase diagram, 198, 201
Virtual Pharmacy Library, 61 Watson, James, 333
virtual screening, 108 Web 2.0, 351
viscosity, 221 Web of Science, 55
ophthalmic preparations, 323 Weed documentation method, 368, 532
visual aids, 373 weighing, 190
vitamins, 97 weight, 190
oxidation, 310 weights and measures, 190
vitrification, 207 English system, 191
von Hohenheim, Philippus, 15 history, 191
metric system, 193
waste management, 424 well-closed container, 164
controlled substances, 426 white blood cells, 336
flushing, 428 wholesalers, 465
hazardous waste, 424 withdrawals, 528
disposal, 425 work schedules, 468
hospital waste, 451 World Health Organization (WHO), International
lists of, 425 Nonproprietary Names (INNs), 135
regulated medical waste (RMW), 425 wound care, 591
disposal, 425 written communications, 367
reverse distribution, 426 documentation of patient care, 367
trash disposal, 428 see also professional communications
types of pharmaceutical waste, 424
universal waste rule, 425 X-ray crystallography, 111
waste minimization, 430 X-ray diffraction
drug recycling, 430 liquid analysis, 221
short cycle prescribing, 430 solid state analysis, 214
water X-ray powder diffraction (XRPD), 215
as solvent, 308 XLHealth, 549
hydrolysis relationship, 160
impurities, 308 yttrium, inorganic chemistry, 72
ionization, 83
purified, 308 zinc, inorganic chemistry, 69, 70
ophthalmic preparations, 323 zirconium, inorganic chemistry, 72
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