Dosage Form Design 1

Introduction to dosage form design

Richard Dalby
University of Maryland School of Pharmacy

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Learning Objectives For Lectures 1 &
2
1. For a given a drug delivery system and drug (with defined
physicochemical and biological properties), a student will be able to:
a. Describe the principles upon which the drug delivery system is based.
b. Outline the important stages in its development (including excipient
and component selection, and manufacture).
c. Select and justify appropriate test procedures to assure desirable
pharmacokinetics, stability and manufacturability.
2. Given specific physicochemical & biological drug properties, a student
will be able to apply their knowledge of anatomy, physiology and
pathophysiology to justifiably select appropriate routes of
administration and drug delivery systems likely to yield optimal
treatment.
Numbered according to the course syllabus 2
Stop the Video and Think

Imagine a pharmacy
stocked with hundreds of
bottles of pure drug
substances (aka APIs)
What problems do you
envision meeting the
pharmaceutical care
needs of individual
patients?
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Not a question
patients should be
asking in a pharmacy!

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Pharmaceutics Bridges Basic Science &
Patient Care

Efficacy

Convenience Safety

Stability Reproducibility
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Life-cycle
Economy IP & Exclusivity Branding
management
You Will Soon be Dispensing “Drug
Products”
Drug Product Pharmaceutics
Drug product means “a finished Pharmaceutics is the discipline of
dosage form that contains a drug turning a new chemical entity
substance, generally, but not (NCE) or existing API into a drug
necessarily, in association with product that can be used safely
one or more other ingredients.” and effectively by patients.
This is sometimes called dosage
21 CFR 314.3; Title 21-Food And Drugs; Chapter I- form design.
Food And Drug Administration, Department Of
Health And Human Services; Subchapter D-Drugs For
Human Use; Part 314-Applications For FDA Approval
To Market A New Drug. 6
Stop the Video & Think
Imagine you have just patented a potent anti-
seizure medication. What’s your preferred
dosage form?
• Powder or granules
• Tablet or capsule (solid oral)
• Solution, suspension or emulsion (oral liquid)
• Injection or implant
• Rectal or vaginal suppository
• Cream or ointment (semisolid)
• Transdermal patch
• Pulmonary or nasal spray
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Why It’s Hard to Answer That
Question
• Will the drug be absorbed? How fast?
• How long will the drug take to reach its site of action?
• For how long will it be effective?
• What excipients and equipment do you have available?
• Will the drug product be sufficiently stable for use when it’s needed?
• Is the preferred drug delivery system affordable?
• Can the patient or caregiver administer the finished drug product?
• Does the product pose misuse concerns?

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Dosage Form Design
is Multifaceted & Complex
• Physical, organic & bio-chemistry
• Anatomy, physiology, & pathophysiology
• Physics and engineering
• Human factors & risk analysis
• Clinical sciences
• Regulatory sciences
• Business & law
Pharmacists & Pharmaceutical scientists are
often the bridge between these disciplines
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Preformulation
Collection and/or measurement of
relevant physical and chemical
information about the API to
guide product development

• Molecular properties
• Biological properties
• Physical form
• Particle size
• Solubility in water
• Solubility in organic solvents
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• Purity & stability
Stop the Video & Think

When assessing the

feasibility of making an
ophthalmological solution
(eye drops), is API particle
size likely to be critically
important preformulation
information?

What do you consider to be

the most useful
preformulation data in this
case? 11
 Potentially Useful Preformulation
Information
• Molecular properties • Solid State Properties • Perceptible Properties
• Molecular weight • Thermal Analysis • Smell
• Structure • DSC • Color
• UV/IR Spectra • TGA • Taste
• Hygroscopicity • Stability
• Biological Properties • Particle size • Temperature
• Absorption • Solubility • Light
• Distribution • Salt form • Humidity (solid state)
• Metabolism • Water • Water (dissolved)
• Elimination • Organic solvents • pH (dissolved)
• Protein binding • Complexation • Solvent (dissolved)
• Prodrugs
• Partition coefficient
• Dissolution rate 12
Formulation Objectives
• During product development choices are made concerning:
• Route of administration
• Dosage form
• Excipients and packaging
• Manufacturing (unit processes) and testing (validation & release)
• The drivers for these choices include:
• Protecting the drug from the environment before administration
• Making dosing accurate and convenient
• Rendering the drug palatable
• Protecting the drug from the body before reaching its site of action
• Minimizing the potential for accidental dosing or intentional abuse
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Excipients As Formulation Tools
• Excipients are non-medicinal components of the formulation
• Generally used because they confer
specific properties on the formation
• Drug solubility
• Chemical stability
• Bioavailability
• Microbiological preservation
• Manufacturability
• Flavor and sweetness
• Color
• Abuse deterrence Abuse-deterrent extended-release oxycodone
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Packaging as a Drug Delivery Tool
• The container closure system Ampoules
• Protects the drug
• Provides patient convenience
• Deters misuse or accidental access

Epi-Pen Autoinjector (Mylan)

TimerCap

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Stop the Video & Think
What’s Protecting The Aspirin Tablets?

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• Cap
• Protection from air, light, water & oxygen
Quality Assurance
• Cap liner
• Ensures seal between cap & container
• Product contact (shedding)
• Tamper evident seal
• Product contact (adhesive)
Assembly
• Container
• Protection from air, light,
water & oxygen
• Polyester wadding
• Mitigate friability
• Product contact (contamination) Material Selection
• Desiccant capsule & desiccant
• Product contact (desiccant escape) 17
Stop the Video & Think
What’s Protecting The Aspirin Particles
Inside the Tablet?

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From the Bayer Safety Coated
Aspirin
Package Insert

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• Bulking agents and lubricants protect ASA from damage (heat or
punch contact) during manufacture and maintain tablet integrity
• Carnauba wax and shellac protect from moisture during storage
• Methacrylic acid copolymer protects ASA from acid environment of
stomach (the basis for enteric coating)

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What Preformulation Information
May have Motivated the Choice of
Excipients?
“…Needle-like…”
• Poor powder flow
• Bulking agents
…hydrolyses…
• Degradation by water
• Keep drug dry using
coating and packaging

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 Stop the Video & Think
Formulation necessarily involves
calculations

Assuming the total weight of a Low Strength ASA

81mg tablet is 200mg exclusive of coating materials,
and the blender that dry-mixes the tablet excipients
and API requires a minimum fill of 1 kg, what is the
minimum weight of ASA needed to make a batch of
81mg ASA tablets?
TURBULA shaker mixer 22
Formulation calculation
Minimum batch size / Tablet weight = Theoretical batch yield

(1kg x 106 mg/kg) / 200 mg = 5000 tablets

No. of tablets in batch x 81mg ASA / tablet = Total weight of ASA needed

5000 tablets x 81 mg / tablet = 405,000 mg (405g or 0.405kg)

Pay attention to unit conversions and units of the answer

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 Where Formulation Fits in Drug Development
Research Area Definition
Market opportunities
Scientific strengths

Rapid Screen Development

Drug Identification
Cell culture
Synthesis or isolation
Lab on a chip
Lead optimization
Whole animal

Candidate Nomination
Basic chemistry
and biology elucidated Preformulation
Market potential assessed
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 Pre-clinical Evaluation
Analytical development
Scale-up synthesis
Preformulation
Preformulation
Pharmacology and ADME
Short term toxicology
Pre IND
Meeting with
FDA
Investigational New Drug Application
Outlines existing data
Proposes design of clinical trials
Reviewed by FDA

CMC
Clinical Trial Long Term Formulation
Phase 1 – Single dose safety and Toxicology Scale-up Formulation
tolerability on volunteers 2 Years Packaging
QA/QC
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 Clinical Trial End of Phase
Phase 2 – Short term efficacy in patients 2 Meeting
Any formulation
changes after the
Production Scale
Clinical Trial Manufacturing start of Phase 2
Phase 3 – Long term safety and efficacy in
patients against standard therapy
Labeling
Batch Documentation
typically requires
“bridging studies”
to demonstrate
that the changes
NDA Submission
Pre-clinical (animal pharmacology) did not impact
Clinical trial results / ADRs
CMC including samples product
Statistical methods
Proposed indications and labelling
performance
Review by FDA
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 Collaborative effort usually
Formulation Workflow orchestrated by a Project
Manager
1. Define formulation objectives
2. Initial formulation development
3. Demonstrate proof of concept Risks and rewards must be
4. Product and excipient optimization weighed at every stage
5. Scale-up and manufacturing optimization
6. Define specifications
7. Clinical testing, approval & marketing Pharmaceutical and
clinical science intersects
with legal, ethical and
This is typically repeated to expand the business considerations
dosage forms and doses available 27
 Naloxone
Naloxone HCl USP

Injection IV www.narcan.com
Injection Sub Q
Injection IM
Sublingual tablet
Buccal tablet
Buccal film
NARCAN® (naloxone HCl) Nasal Spray was
Nasal spray
the first FDA-approved nasal form of
naloxone for the emergency treatment of a
known or suspected opioid overdose. 28
Stop the Video & Think
Should a Pharmacist be Permitted to Legally
Compound Naloxone HCl as a Nasal Spray?

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Compounding & Manufacturing
• Many dosage forms can be compounded
• Compounding places more reliance on skill and experience, and less
on formal product development and testing
• Compounding a dosage form usually results in a shorter expiry
(beyond use) date
• Compounding is intended to meet specific patient needs/desires
when a manufactured product is not available
• Compounding is not intended as a way to circumvent the intellectual
property rights of drug manufactures

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Summary
Before Designing a Manufactured or
Compounded Dosage Form Consider:

• Physical & organic chemistry

• Biochemistry & Physiology
• Disease characteristics
• Patient characteristics
• Circumstances surrounding administration
• Business, legal and regulatory environment

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