1

Drug Product Development in the

Pharmaceutical Industry
Gurvinder Singh Rekhi
Leon Shargel

I. INTRODUCTION
A. Active pharmaceutical ingredient (API)
1. A drug substance is the API or component that produces pharmacological activity.
2. The API may be produced by chemical synthesis, recovery from a natural product, enzymatic
reaction, recombinant DNA technology, fermentation, or a combination of these processes.
Further purification of the API may be needed before it can be used in a drug product.
3. A new chemical entity (NCE) is a drug substance with unknown clinical, toxicologic, physical, and
chemical properties. In addition, the U.S. Food and Drug Administration (FDA) considers an NCE as
an API that has not been approved for marketing in the United States.
4. The identity, strength, quality, and purity of a drug substance depend on proper control of
the manufacturing and synthetic process.
B. Drug product
1. A drug product is the finished dosage form (e.g., capsule, tablet, injectable) that contains the
API, generally in association with other excipients, or inert ingredients.
2. The excipients in the drug product may affect the functionality and performance of the drug
product, including modification of the rate of drug substance release, improving drug stability, and
masking the drug taste.
3. Different approaches are generally used to produce drug products that contain NCEs, product line
extensions, generic drug products, and specialty drug products. C. New drug product development
Drug products containing NCE are developed sequentially in the following phases. 1. Preclinical.
Animal pharmacology and toxicology data are obtained to determine the safety and efficacy of the drug.
Because little is known about the human and the therapeutic/toxicologic potential, many drug products
will not reach the marketplace. No attempt is made to develop a final formulation during the preclinical
stage. Nonclinical studies are nonhuman studies that may continue at any stage of research to obtain
additional information concerning the pharmacology and toxicology of the drug.
2. Phase I
a. An Investigational New Drug (IND) application for human testing is submitted to the FDA. Clinical
testing takes place after the IND application is submitted. P.2
b. Healthy volunteers are used in phase I clinical studies to determine drug tolerance and
toxicity.
c. For oral drug administration, a simple hard gelatin capsule formulation containing the API is usually
used for IND studies.
d. Toxicologic studies—including acute, chronic, subchronic, and mutagenicity—and other such studies
in various animal species are planned during this phase. 3. Phase II
a. A limited number of patients with the disease or condition for which the drug was developed are
treated under close supervision.
b. Dose-response studies, bioavailability, and pharmacokinetics are performed to determine the
optimum dosage regimen for treating the disease. c. Safety is measured by attempting to determine
the therapeutic index (ratio of toxic dose to effective dose).
d. A drug formulation having good physico-chemical stability is developed. e. Chronic toxicity
studies are started in two species; such studies normally last more than 2 years' duration.
4. Phase III
a. Large-scale, multicenter clinical studies are performed with the final dosage form developed in
phase II. These studies are done to determine the safety and efficacy of the drug product in a large
patient population who have the disease or condition for which the drug was developed.
b. Side effects are monitored. In a large population, new toxic effects may occur that were not
evident in previous clinical trials.
5. Submission of a New Drug Application (NDA). An NDA is submitted to the FDA for review and
approval after the completion of clinical trials that show to the satisfaction of the medical community
that the drug product is effective by all parameters and is reasonably safe as demonstrated by animal
and human studies. 6. Phase IV
a. After the NDA is submitted, and before approval to market the product is obtained from the FDA,
manufacturing scale-up activities occur. Scale-up is the increase in the batch size from the clinical
batch, submission batch, or both to the full-scale production batch size, using the finished, marketed
product.
b. The drug product may be improved as a result of equipment, regulatory, supply, or market
demands.
c. Additional clinical studies may be performed in special populations, such as the elderly, pediatric,
and renal-impaired, to obtain information on the efficacy of the drug in these subjects.
d. Additional clinical studies may be performed to determine if the drug can be used for a new or
additional labeling indications.
7. Phase V
a. After the FDA grants market approval of the drug, product development may continue.
b. The drug formulation may be modified slightly as a result of data obtained during the
manufacturing scale-up and validation processes.
c. Changes in drug formulation should always be within the scale-up and post approval change
(SUPAC) guidelines.
D. Product line extensions are dosage forms in which the physical form or strength, but not
the use or indication, of the product changes. Product line extension is usually performed
during phase III, IV, or V.
1. Developing a transdermal patch when only tablets have been available, for example:

• Progesterone
• Nicotine
• Estradiol
• Nitroglycerin

2. Additional strengths—as long as these strengths are within the total daily dose, for example:

• Ibuprofen

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3. Controlled-release or modified-release dosage forms when only an immediate release dosage form
is available. This is an ongoing project for all brand companies; almost every NCE has or will eventually
have a modified-release dosage form of the immediate-release product.
E. Biologic products
1. A biologic product is any virus, serum, toxin, antitoxin, vaccine, blood, blood component or
derivative, allergenic product, or analogous product applicable to the prevention, treatment, or cure of
diseases or injuries.
2. Biologic products are a subset of drug products, distinguished by their manufacturing processes
(biologic vs. chemical). In general, the term drugs includes biologic products.
3. Biologic license application (BLA). Biologic products are approved for marketing under
the provisions of the Public Health Service (PHS) Act. F. Generic drug products
1. After patent expiration of the API and /or brand drug product, a generic drug product may be
marketed. A generic drug product is therapeutically equivalent to the brand name drug product and
contains the same amount of the drug in the same type of dosage form (e.g., tablet, liquid, injectable).
2. A generic drug product must be bioequivalent (i.e., have the same rate and extent of drug
absorption) to the brand drug product. Therefore, a generic drug product is expected to give the
same clinical response (Chapter 7). These studies are normally performed with healthy human
volunteers.
3. Some generic products are not absorbed; for some others bioequivalence is not a good marker.
Under those conditions, comparative clinical trials or studies with
pharmacodynamic end points are considered to measure the equivalence of two products. Inhalation
products and nonabsorbed drug products fall into this category. 4. The generic drug product may differ
from the brand product in physical appearance (i.e., size, color, shape) or in the amount and type of
excipients used in the formulation.
5. A generic drug product may not differ in both the qualitative and the quantitative compositions for
liquids, injectables, semisolids, transdermal patches, inhalation products, and ophthalmic products,
unless adequate safety studies have been performed.
6. Before a generic drug product is marketed, the manufacturer must submit an Abbreviated New
Drug Application (ANDA) to the FDA for approval. Because preclinical safety and efficacy studies
have already been performed for the NDA approved brand product, human bioequivalence studies,
instead of clinical trials, are generally required for the ANDA. The chemistry, manufacturing, and
controls requirements for the generic drug product are similar to those for the brand name drug
product.
G. Specialty drug products are existing products developed as a new delivery system or for a new
therapeutic indication. The safety and efficacy of the drug product were established in the initial
NDA-approved dosage form. For example, the nitroglycerin transdermal delivery system (patch) was
developed after experience with nitroglycerin sublingual tablets.

II. PRODUCT DEVELOPMENT.

For each drug, various studies are required to develop a safe, effective, and stable dosage form.
A. New chemical entities
1. Preformulation is the characterization of the physical and chemical properties of the active drug
substance and dosage form. The therapeutic indication of the drug and the route of administration
dictate the type of drug product or drug delivery system (e.g., immediate release, controlled release,
suppository, parenteral, transdermal) that needs to be developed.
a. Preformulation activities are usually performed during the preclinical stage. However, these
activities may continue into phases I and II.
b. The following information is obtained during preformulation.
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(1) Physical, including particle size and shape, crystallinity, polymorphism, density, surface area,
hygroscopicity (ability to take up and retain moisture), and powder flow
(2) Solubility, including intrinsic dissolution, pH solubility profile, and general solubility
characteristics in various solvents
(3) Chemical, including surface energy, pH stability profile, pKa, temperature stability (dry or
under various humidity conditions), and excipient interactions
(4) Analytical methods development, including development of a stability indicating method (measures
both the API and the related substances), and cleaning methods 2. Formulation development is a
continuing process. Initial drug formulations are developed for early clinical studies. When the
submission of an NDA is considered, the manufacturer attempts to develop the final (marketed) dosage
form. The dose of the drug and the route of administration are important in determining the
modifications needed.
a. Injectable
(1) A final injectable drug product is usually developed in the preclinical phase. (2) Major concerns
include the stability of the drug in solution and the sterility of the product.
(3) Because few excipients are allowed in injectable products, the formulator must choose a final
product early in the development process.
(4) If the formulation is changed, bioavailability studies are not required for intravenous solution
injections because the product is injected directly into the body.
(5) Formulation changes may require acute toxicity studies.
b. Topical (for local application). Includes antibacterials, antifungals, corticosteroids,
and local anesthetics.
(1) The final dosage form for a topical drug product is usually developed during phase I studies
because any major formulation changes may require further clinical trials.
(2) The release of the drug from the matrix is measured in vitro with various diffusion cell
models.
(3) Significant problems encountered with locally acting topical drug products include local irritation,
skin senistization and systemic drug absorption. c. Topical (for systemic drug absorption). Includes
drug delivery through the skin (transdermal), mucous membranes (intranasal), and rectal mucosa. (1)
A prototype formulation is developed for phase I.
(2) A final topical drug product is developed during phase III after the available technology and
desired systemic levels are considered.
d. Oral
(1) Prototype dosage forms are often developed during the preclinical phase to ensure that the
drug is optimally available and that the product dissolves in the gastrointestinal tract.
(2) In the early stages of product development, hard gelatin capsule dosage forms are often
developed for phase I clinical trials. If the drug shows efficacy, the same drug formulation may be used
in phase II studies.
(3) Final product development begins when the drug proceeds during phase II and before initiating
phase III clinical studies.
3. Marketed Product. Considerations in the development of a final dosage form include the
following:
a. Color, shape, size, taste, viscosity, sensitivity, skin feel, and physical appearance of the
dosage form
b. Size and shape of the package or container
c. Production equipment
d. Production site
e. Country of origin in which the drug is to be manufactured
f. Country in which the drug will be marketed
B. Product line extensions are generally defined as drug products containing an NDA-approved
drug in a different dosage strength or in a different dosage form (e.g., modified release, oral liquid).
1. Oral product line extensions
a. The simplest dosage form to develop is a different dosage strength of a drug in a tablet or capsule.
Only bioequivalence studies are needed.
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b. A modified-release dosage form is more difficult to develop when only an immediate-release

dosage form exists. Clinical trials are normally required. c. Considerations in developing these dosage
forms are similar to those for the final drug product (see II.A.3).
d. Marketing has a role in the choice of the dosage form.
e. Because the original brand drug product information contributes to the body of knowledge about the
drug, no preformulation is needed. All other factors considered for the original product are similar. If the
relation between in vitro dissolution and in vivo bioavailability is known, the innovator can progress to
a finished dosage form relatively quickly.
f. Regulatory approval is based on the following:
(1) Analytical and manufacturing controls
(2) Stability information
(3) Bioavailability and bioequivalence studies
(4) Clinical trials (in the case of modified-release dosage forms) g. A new therapeutic indication for a
drug requires new efficacy studies and a new NDA.
2. Liquid product line extensions
a. If the current marketed product is a liquid preparation, then the same factors as for the solid oral
dosage forms are considered (see II.B.1.a, b, c, d, e, f and g). b. If the marketed product is a solid oral
dosage form and the product line extension is a liquid, product development must proceed with caution
because the rate and extent of absorption for liquid and solid dosage forms may not be the same. c.
Regulatory approval requires
(1) Analytical and manufacturing controls
(2) Stability information
(3) Bioavailability and bioequivalence studies
(4) Safety studies (e.g., depending on the drug substance, local irritation) (5) Clinical trials, if the
rate and extent of drug absorption are drastically altered from the original dosage form
C. Combination products are made up of two or more regulated components (e.g., drug/device,
biologic/device, drug/biologic, or drug/device/biologic) that are
physically, chemically, or otherwise combined or mixed and produced as a single entity.
1. These may be two or more separate products packaged together in a single package or as a unit
and may be composed of drug and device products, device and biologic products, or biologic and drug
products.
2. An example is an inhalation steroid (e.g., beclomethasone inhalation aerosol) in which the device

component is important for delivery of the steroid. III. PREAPPROVAL

INSPECTIONS (PAIs)
A. The manufacturing facility is inspected by the FDA after an NDA, abbreviated antibiotic drug
application (AADA), or ANDA is submitted and before the application is approved.
B. A PAI may also be initiated if a major change is reported in a supplemental application to an
NDA, AADA, or ANDA.
C. During the PAI, the FDA investigator:
1. Performs a general current good manufacturing practice (cGMP) inspection relating
specifically to the drug product intended for the market 2. Reviews the development report to
verify that the drug product has enough supporting documentation to ensure a validated product
and a rationale for the manufacturing directions
3. Consults the chemistry, manufacturing, and control (CMC) section of the NDA, AADA, or ANDA
and determines the capability of the manufacturer to produce the drug product as described
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4. Verifies the traceability of the information submitted in the CMC section to the original laboratory
notebooks, electronic information, and batch records 5. Verifies and ensures that all the quality
systems are in place to manufacture the product so it retains the identity, strength, quality, and purity of
the drug product that were approved by the center.
6. Recommends approval for the manufacture of the drug product based on the status of the
inspection

IV. SCALE-UP AND POSTAPPROVAL CHANGES

(SUPACs)
A. Purpose. These guidelines are intended to reduce the number of manufacturing changes that
require pre-approval by the FDA. The guidelines are published by the FDA on the Internet
(http://www.fda.gov/cder/guidance/index.htm). B. Function. These guidelines provide
recommendations to sponsors of NDAs, AADAs, and ANDAs during the postapproval period when
1. Making slight changes in the amount of the excipient to aid in the processing of the product during
scale-up
2. Changing the site of manufacture
3. Scaling up (increasing) or scaling down (decreasing) the batch size of the formulation
4. Changing the manufacturing process or equipment
C. The FDA must be notified about a proposed change to a drug product through different regulatory
documentation, depending on the type of change proposed. 1. Annual report. Changes that are
unlikely to have any detectable effect on formulation quality and performance can be instituted
without approval by the FDA and reported annually. Examples of these changes include:
a. Compliance with an official compendium
b. Label description of the drug product or how it is supplied (not involving dosage strength or dosage
form)
c. Deletion of an ingredient that affects only the color of the product d. Extension of the
expiration date based on full shelf-life data obtained from a protocol approved in the application
e. Container and closure system for the drug product (except a change in container size for
nonsolid dosage forms) based on equivalency to the approved system under a protocol approved
in the application or published in an official compendium
f. Addition or deletion of an alternate analytical method
2. Changes being effected (CBE) supplement. Changes that probably would not have any detectable
effect but require some validation efforts require specific documentation, depending on the change. A
supplement is submitted, and the change can be implemented without previous approval (CBE-0) by the
FDA or, in some cases, the FDA has 30 days to review the change (CBE-30). FDA may reject this
supplement. Examples of reasons for submitting a supplement include a. Addition of a new
specification or test method or changes in methods, facilities, or controls
b. Label change to add or strengthen a contraindication, warning, precaution, or adverse reaction
c. Use of a different facility to manufacture the drug substance and drug product (the manufacturing
process in the new facility does not differ materially from that in the former facility, and the new facility
has received a satisfactory cGMP inspection within the previous 2 years covering that manufacturing
process) 3. Pre-approval supplement. Changes that could have a significant effect on formulation
quality and performance require specific documentation. This supplement must be approved before the
proposed change is initiated. Appropriate examples for pre-approval supplement are:
a. Addition or deletion of an ingredient
b. Relaxation of the limits for a specification
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c. Establishment of a new regulatory analytical method

d. Deletion of a specification or regulatory analytical method
e. Change in the method of manufacture of the drug product, including changing or relaxing an
in-process control
f. Extension of the expiration date of the drug product based on data obtained under a new or
revised stability testing protocol that was been approved in the application
D. W hen any change to a drug product is proposed, the manufacturer must show that the resultant
drug product is bioequivalent and therapeutically equivalent to the original approved drug product
(see Chapter 7).
1. A minor change is a change that has minimal potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the
product. If the proposed change is considered minor by the FDA, bioequivalence may be demonstrated
by comparative dissolution profiles for the original and new formulations.
2. A major change is one that has substantial potential to have an adverse effect on the identity,
strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the
product. If the proposed change is considered major by the FDA, bioequivalence must be

demonstrated by an in vivo bioequivalence study comparing the original and new formulations. V.
GOOD MANUFACTURING PRACTICES (GMPs)
are regulations developed by the FDA. GMPs are minimum requirements that the industry must meet
when manufacturing, processing, packing, or holding human and veterinary drugs. These regulations,
also known as cGMPs, establish criteria for personnel, facilities, and manufacturing processes to
ensure that the finished drug product has the correct identity, strength, quality, and purity
characteristics. A. Good Manufacturing Practices are described in the Code of Federal Regulations
(CFR), title 21, sections 210 and 211.
B. Quality control (QC) is the group within the manufacturer that is responsible for establishing
process and product specifications.
1. Specifications are the criteria to which a drug product should conform to be considered having
acceptable quality for its intended use.
2. The QC unit tests the product and verifies that the specifications are met. QC testing includes the
acceptance or rejection of the incoming raw materials, packaging components, drug products, water
system, and environmental conditions (e.g., heating, ventilation, air-conditioning, air quality, microbial
load) that exist during the manufacturing process.
C. Quality assurance (QA) is the group within the manufacturer that determines that the systems and
facilities are adequate and that the written procedures are followed to ensure that the finished drug
product meets the applicable specifications for quality.
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STUDY QUESTIONS
Directions: Each statement in this section can be correctly completed by one or more of the
suggested phrases. Choose the correct answer, A-E: 1. Healthy human volunteers are used in
drug development for I. phase I testing after the submission of an investigational new drug
(IND) application.
II. generic drug development for an abbreviated new drug application (ANDA) submission.
III. phase III testing just before the submission of a new drug application (NDA).
A if I only is correct
B if III only is correct
C if I and II are correct
D if II and III are correct
E if I, II, and III are correct
View Answer1. The answer is C[see].2. The required information contained in
a new drug application (NDA) that is not included in the abbreviated new drug
application (ANDA) consists of
I. preclinical animal toxicity studies.
II. clinical efficacy studies.
III. human safety and tolerance studies.
A if I only is correct
B if III only is correct
C if I and II are correct
D if II and III are correct
E if I, II, and III are correct
View Answer2. The answer is E[see].3. A product line extension contains the new drug
application (NDA) approved drug in a new
I. dosage form.
II. dosage strength.
III. therapeutic indication.
A if I only is correct
B if III only is correct
C if I and II are correct
D if II and III are correct
E if I, II, and III are correct
View Answer3. The answer is C[see].Directions: Each statement in this section can be
correctly completed by one of the suggested phrases. Choose the best answer.
4. The regulations developed by the U.S. Food and Drug Administration (FDA) for the
pharmaceutical industry for meeting the minimum requirements in the manufacturing,
processing, packing, or holding of human and veterinary drugs are known as
(A) good manufacturing practices (GMPs).
(B) quality assurance (QA).
(C) quality control (QC).
(D) pre-approval inspection (PAI).
(E) scale-up and post-approval changes (SUPACs).
View Answer4. The answer is A[see].5. The unit within the
pharmaceutical manufacturer that ensures that the finished dosage form has met all the
specifications for its intended use is the
(A) analytical methods unit.
(B) marketing and sales unit.
(C) pre-approval inspection (PAI) unit.
(D) quality assurance (QA) unit.
(E) quality control (QC) unit.
 View Answer5. The answer is E[see].6. Manufacturers may make a change in the
formulation after market approval. If the change in the formulation is considered a minor change,
the manufacturer needs to report the change to the FDA only in the
(A) annual report.
(B) pre-approval supplement.
(C) investigational new drug (IND) submission.
(D) changes being effected supplement, 30 days (CBE-30).
(E) no report is required for a minor change.
View Answer6. The answer is A[see].P.9

ANSWERS AND EXPLANATIONS

1. The answer is C (I, II) [see I.C.2.b; I.F.2].
Phase I testing is the first set of human studies performed during new drug development. Phase I
studies establish the tolerance and toxicity of the drug in humans. Bioequivalence studies for generic
drug development are most often performed in healthy human volunteers. These studies establish the
bioequivalence of the generic drug product against the brand drug product. Phase III testing entails
large-scale, multicenter clinical studies performed in patients with the disease or condition to be treated.
Phase III studies determine the safety and efficacy of the drug in a large patient population.
2. The answer is E (I, II, and III) [see I.C.5; I.F.6].
The development of a new drug requires extensive toxicity and efficacy testing in animals and
humans. The NDA documents all studies performed on the drug. The ANDA is used for generic drug
product submissions. The generic drug product is similar to the original brand drug product that has
already been marketed. Because the efficacy, safety, and toxicity of this drug product have been
studied and documented, further studies of this nature are unnecessary.
3. The answer is C (I, II) [see I.D].
Product line extensions are developed after further studies with the original NDA approved drug
product. From these studies, the manufacturer may develop a new dosage form (e.g.,
controlled-release product) or a new dosage strength. A new therapeutic indication requires an
NDA.
4. The answer is A [see V].
Quality control and quality assurance follow GMP regulations to ensure that the finished product meets
all applicable specifications for quality. The FDA may inspect a manufacturing site (PAI) before the drug
application is approved. In addition, the FDA must be notified about any proposed changes to an
approved drug product.
5. The answer is E [see V.B].
The QC unit performs the appropriate tests on the dosage form. PAI is performed by FDA compliance
inspectors, who examine the pharmaceutical manufacturer and review the procedures and records for
manufacturing the finished dosage form before the administration grants market approval. The
analytical development unit develops the analytical methods used in testing the drug product. 6. The
answer is A [see IV.C.1].
All changes in the formulation must be reported to the FDA. A minor change is a change that has
minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the
product as they may relate to the product's safety or effectiveness. Changes that are unlikely to have
any detectable effect on formulation quality and performance can be instituted without approval by the
FDA and need only to be reported in the annual report.

2
Pharmaceutical Calculations and
Statistics
Riccardo L. Boni
I. FUNDAMENTALS OF MEASUREMENT AND
CALCULATION.
The pharmacist is often required to perform or evaluate a variety of calculations in his or her
practice. Many of these calculations involve the use of direct or inverse proportions.
Dimensional (or unit) analysis and approximation can be useful in solving these problems.
In dimensional analysis, dimensions (or units) are included with each number used in the
calculation. Units common to the numerator and denominator may be canceled and the
remaining units provide the units for the final answer. In approximation, each number used in
the calculation is rounded to a single significant digit. Factors common to the numerator and
denominator may be canceled and the answer to this approximation should be reasonably
close to the final exact answer.
A. Ratio and proportion
1. Ratio. The relative magnitude of two like quantities is a ratio, which is expressed as a
fraction. Certain basic principles apply to the ratio, as they do to all fractions.
a. When the two terms of a ratio are multiplied or divided by the same number, the
value of the ratio is unchanged.

b. Two ratios with the same value are equivalent. Equivalent ratios have equal cross

products and equal reciprocals. For example:

and
1×6=3×2=6
If two ratios are equal, then their reciprocals are equal:

2. Proportion. The expression of the equality of two ratios is a proportion. The product of the
extremes is equal to the product of the means for any proportion. Furthermore, the numerator
of the one fraction equals the product of its denominator and the other fraction (i.e., one
missing term can always be found given the other three terms). Most pharmaceutical
calculations can be performed by use of proportion.
a. Proper ratios. Some pharmacists use proper ratios (in which similar units are used
in the numerator and denominator of each ratio) in their proportion calculations. Several
examples follow.
(1) If 240 mL of a cough syrup contains 480 mg of dextromethorphan hydrobromide,
then what mass of drug is contained in a child's dose, 1 teaspoonful (5 mL) of syrup?

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(2) If a child's dose (5 mL) of a cough syrup contains 10 mg of dextromethorphan

hydrobromide, what mass of drug is contained in 240 mL?
(3) If the amount of dextromethorphan hydrobromide in 240 mL of cough syrup is 480 mg,
what would be the volume required for a child's dose of 10 mg?

(4) How many milligrams of dextromethorphan base (molecular weight = 271.4) are
equivalent to 10 mg of dextromethorphan hydrobromide (molecular weight = 352.3)?

b. Mixed ratios. Some pharmacists use mixed ratios (in which dissimilar units are used in
the numerator and denominator of each ratio) in their proportion calculations. Such
computations generally give correct answers, providing the conditions in which mixed ratios
cannot be used are known. A later example shows mixed ratios leading to failure in the case
of dilution, when inverse proportions are required. For inverse proportions, similar units
must be used in the numerator and denominator of each ratio. Following is an example of a
mixed ratio calculation using the previous problem.

The same answer is obtained in this example whether we use proper ratios, with similar units
in numerator and denominator, or mixed ratios. This is not the case when dealing with inverse
proportions.
3. Inverse proportion. The most common example of the need for inverse proportion for the
pharmacist is the case of dilution. W hereas in the previous examples of proportion the
relationships involved direct proportion, the case of dilution calls for an inverse proportion
(i.e., as volume increases, concentration decreases). The necessity of using inverse
proportions for dilution problems is shown in this example. If 120 mL of a 10% stock
solution is diluted to 240 mL, what is the final concentration? Using inverse proportion,

As expected, the final concentration is one half the original concentration because the
volume is doubled. However, if the pharmacist attempts to use direct proportion and neglects
to estimate an appropriate answer, the
resulting calculation would provide an answer of 20%, which is twice the actual
concentration.

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 Likewise, the pharmacist using mixed ratios fails in this case.

and

B. Aliquot. A pharmacist requires the aliquot method of measurement when the sensitivity
(the smallest quantity that can be measured with the required accuracy and precision) of the
measuring device is not great enough for the required measurement. Aliquot calculations can
be used for measurement of solids or liquids, allowing the pharmacist to realize the required
precision through a process of measuring a multiple of the desired amount followed by
dilution and finally selection and measurement of an aliquot part that contains the desired
amount of material. This example problem involves weighing by the aliquot method, using a
prescription balance.
A prescription balance has a sensitivity requirement of 6 mg. How would you weigh 10 mg of
drug with an accuracy of ± 5%, using a suitable diluent? 1. First, calculate the least weighable
quantity for the balance with a sensitivity requirement of 6 mg, assuming ± 5% accuracy is
required.

2. Now it is obvious that an aliquot calculation is required because 10 mg of drug is required,

whereas the least weighable quantity is 120 mg to achieve the required percentage of error.
Using the least weighable quantity method of aliquot measurement, use the smallest quantity
weighable on the balance at each step to preserve materials.
a. Weigh 12 × 10 mg = 120 mg of drug.
b. Dilute the 120 mg of drug (from step a) with a suitable diluent by geometrical dilution to
achieve a mixture that will provide 10 mg of drug in each 120-mg aliquot. The amount of
diluent to be used can be determined through proportion.

c. Weigh 120 mg (1/12) of the total mixture, which will contain the required 10 mg of drug.
II. SYSTEMS OF MEASURE.
The pharmacist must be familiar with three systems of measure: the metric system and two
common systems of measure (the avoirdupois and apothecaries' systems). The primary
system of measure in pharmacy and medicine is the metric system. Most students find it
easiest to convert measurements in the common systems to metric units. A table of
conversion equivalents is provided and should be memorized by the pharmacist (see
Appendix A). The metric system, because of its universal acceptance and broad use, will not
be reviewed here.
A. Apothecaries' system of fluid measure. The apothecaries' system of fluid measure is
summarized in Appendix A.
B. Apothecaries' system for measuring weight. The apothecaries' system for measuring
weight includes units of grains, scruples, drams, ounces, and pounds (see Appendix A).
C. Avoirdupois system of measuring weight. The avoirdupois (AV) system of
measuring weight includes the grain, ounce, and pound. The grain is a unit common with
the apothecaries' system and allows for easy conversion between the systems. The
avoirdupois pound, however, P.13

is 16 AV ounces in contrast to the apothecaries' pound, which is 12 apothecaries'

ounces (see Appendix A).
D. Conversion equivalents. See Appendix A.

III. REDUCING AND ENLARGING FORMULAS.

The pharmacist is often required to reduce or enlarge a recipe. Problems of this type are
solved through proportion, or by multiplication or division by the appropriate factor to obtain
the required amount of each ingredient that will give the desired total mass or volume of the
formula. Formulas can be provided in amounts or in parts.
A. Formulas that indicate parts. When dealing with formulas that specify parts, parts by
weight will require the determination of weights of
ingredients, whereas parts by volume warrant the calculation of volumes of ingredients.
Always find the total number of parts indicated in the formula, and equate that total with the
total mass or volume of the desired formula in order to set up a proportion. Such a proportion
wil l allow calculation of the
mass or volume of each ingredient in units common to the total mass or volume.
What quantities should be used to prepare 100 g of camphorated
parachlorophenol?

Rx parachlorophenol 7 parts camphor

13 parts

7 parts + 13 parts = 20 parts total

B.
Formulas that indicate quantities. The previous prescription for cold cream provides a
100 g quantity.
What mass of each ingredient is required to provide 1 pound (AV) of cream?
 Rx white wax 12.5 g mineral

oil 60.0 g

lanolin 2.5 g

sodium borate 1.0 g

rose water 24.0 g

1 lb = 454 g

12.5 g × 4.54 = 56.8 g of white wax 60.0

g × 4.54 = 272 g of mineral oil 2.5 g ×

4.54 = 11.4 g of lanolin

1.0 g × 4.54 = 4.54 of sodium borate 24.0

g × 4.54 = 109 g of rose water

IV. CALCULATING DOSES.

Calculation of doses generally can be performed with dimensional analysis. Problems
encountered in the pharmacy include calculation of the number of doses, quantities in a dose
or total mass/volume, amount of active or inactive ingredients, and size of dose. Calculation of
children's doses is commonly performed by the pharmacist. Dosage is optimally calculated
by using the child's body weight or mass and the appropriate dose in milligrams per kilogram
(mg/kg). W ithout these data, the following formulas based on an adult dose can be used.
A. Fried's rule for infants

P.14

B. Clark's rule

C. Child's dosage based on body surface area (BSA)

D. Young's rule for children ≥ 2 years old
E. Constant rate intravenous infusions. Some drugs are administered intravenously at a constant
(zero-order) rate by using a continuous-drip infusion set or a constant-rate infusion pump. The flow rate
(volume per unit time) required can be calculated from the volume to be administered and the duration of the
infusion. The rate of drug administration can be calculated from the concentration of drug in the infused
solution and the flow rate of the infusion set or pump. Conversion factors may be required to obtain the final
answer in the correct units (drops per minute or milliliters per hour).
A vancomycin solution containing 1000 mg of vancomycin hydrochloride diluted to 250
mL with D5W is to be infused at a constant rate with a continuous-drip intravenous
infusion set that delivers 25 drops/mL. What flow rate (drops/min) should be used to
infuse all 250 mL of the vancomycin hydrochloride solution in 2 hr?

V. PERCENTAGE, RATIO STRENGTH, AND OTHER

CONCENTRATION EXPRESSIONS
A. Percentage weight in volume (w/v)
1. Definition. Percentage, indicating parts per hundred, is an important means of
expressing concentration in pharmacy practice. Percentage w/v indicates the number of
grams of a constituent per 100 mL of solution or liquid formulation. The pharmacist may be
required to perform three types of calculations: determine the weight of active ingredient in
a certain volume when given the percentage strength, determine the percentage w/v when
the weight of substance and volume of liquid formulation are known, and determine the
volume of liquid mixture when the percentage strength and amount of substance are
known.
2. Tolu balsam syrup. Tolu balsam tincture contains 20% w/v tolu balsam. What is the
percentage concentration of tolu balsam in the syrup?

tolu balsam tincture 50 mL

magnesium carbonate 10 g

sucrose 820 g

purified water, qs ad 1000 mL

a. First, determine what the amount of tolu balsam is in the 50 mL quantity of tincture used
for the syrup. Then, by proportion, calculate the concentration of tolu balsam in the syrup.
In answering this one question, the first two types of problems listed above have been
solved, while exhibiting two methods of solving percentage problems—namely, by
dimensional analysis and proportion. b. For an example of the third type of percentage
w/v problem, determine what volume of syrup could be prepared if we had only 8 g of
magnesium carbonate. Use proportion to find the total volume of syrup that can be made
using only 8 g of magnesium
P.15

carbonate. If we have 8 g of magnesium carbonate in 1000 mL of solution, then, according

to the recipe, 800 mL of solution can be prepared using all 8 g of the drug.

B. Percentage volume in volume (v/v). Percentage v/v indicates the number of milliliters of
a constituent in 100 mL of liquid formulation. The percentage strength of mixtures of liquids
in liquids is indicated by percent v/v, which indicates the parts by volume of a substance in
100 parts of the liquid preparation. The three types of problems that are encountered
involve calculating percentage strength, calculating volume of ingredient,
and calculating volume of the liquid preparation. Using the same tolu
balsam syrup formula from earlier, we'll now work a percent v/v problem. What is the percentage strength v/v of the
tolu balsam tincture in the syrup preparation? By proportion, we can solve the problem in one step.

C. Percentage weight in weight (w/w). Percentage w/w indicates the

number of grams of a constituent per 100 g of formulation (solid or liquid). Solution of
problems involving percentage w/w is straightforward when the total mass of the mixture is
available or when the total mass can be
determined from the available data. In calculations similar to those for
percentage w/v and v/v, the pharmacist might need to solve several types of problems,
including determination of the weight of a constituent, the total weight of a mixture, or the
percentage w/w.
1. How many grams of drug substance should be used to prepare 240 g of a 5% w/w
solution in water?
a. The first step in any percentage w/w problem is to attempt identification of the total mass
of the mixture. In this problem, the total mass is,
obviously, provided (240 g).
b. The problem can be easily solved through dimensional analysis.

2. When the total mass of the mixture is unavailable or cannot be

determined, an extra step is required in the calculations. Because it is
usually impossible to know how much volume is displaced by a solid
material, the pharmacist is unable to prepare a specified volume of a
solution given the percentage w/w.
How much drug should be added to 30 mL of water to make a 10% w/w solution? The
volume of water that is displaced by the drug is unknown, so the final volume is unknown.
Likewise, even though the mass of solvent is known (30 mL × 1 g/mL = 30 g), it is not known
how much drug is needed, so the total mass is unknown. The water represents 100% - 10%
= 90% of the total mixture. Then, by proportion, the mass of drug to be used can be
identified.

The common error that many students make in solving problems of this type is to
assume that 30 g is the total mass of the mixture. Solving the
problem with that assumption gives the following incorrect answer.
D. Ratio strength. Solid or liquid formulations that contain low
concentrations of active ingredients will often have concentration expressed in ratio
strength. Ratio strength, as the name implies, is the expression of concentration by means of
a ratio. The numerator and denominator of the ratio indicate grams (g) or milliliters (mL) of a
solid or liquid constituent in the total mass (g) or volume (mL) of a solid or liquid preparation.
Because percentage strength is
P.16

essentially a ratio of parts per hundred, conversion between ratio strength and percentage
strength is easily accomplished by proportion.
1. Express 0.1% w/v as a ratio strength.
a. Ratio strengths are by convention expressed in reduced form, so in setting up our
proportion to solve for ratio strength, use the numeral 1 in the numerator of the righthand
ratio as shown:

b. Likewise, conversion from ratio strength to percentage strength by proportion is easy,

as seen in the following example. Keep in mind the definition of percentage strength (parts
per hundred) when setting up the proportion.
2. Express 1:2500 as a percentage strength.

E. Other concentration expressions

1. Molarity (M) is the expression of the number of moles of solute dissolved per liter of
solution. It is calculated by dividing the moles of solute by the volume of solution in liters.

2. Normality. A convenient way of dealing with acids, bases, and

electrolytes involves the use of equivalents. One equivalent of an acid is the quantity of that
acid that supplies or donates 1 mole of H+ ions. One equivalent of a base is the quantity that
furnishes 1 mole of OH- ions. One equivalent of acid reacts with 1 equivalent of base.
Equivalent weight can be calculated for atoms or molecules.

The normality (N) of a solution is the number of gram-equivalent weights (equivalents) of solute per liter of solution.
Normality is analogous to
 molarity; however, it is defined in terms of equivalents rather than moles.

3. Molality (m) is the moles of solute dissolved per kilogram of solvent.

Molality is calculated by dividing the number of moles of solute by the
number of kilograms of solvent. Molality offers an advantage over molarity because it is
based on solvent weight and avoids problems associated with volume expansion or
contraction owing to the addition of solutes.

4. Mole fraction (X) is the ratio of the number of moles of one component to the total
moles of a mixture or solution.

VI. DILUTION AND CONCENTRATION.

If the amount of drug remains constant in a dilution or concentration, then any change in
the mass or volume of a mixture is inversely proportional to the concentration.
A. Dilution and concentration problems can be solved by:
1. Inverse proportion (as mentioned earlier)
2. The equation quantity 1 × concentration1 = quantity 2 × concentration2
3. Determining the amount of active ingredient present in the initial mixture and, with the
assumption that the initial quantity does not change,
calculating of the final concentration of the new total mass or volume
P.17

4. Alligation medial. A method for calculating the average concentration of a mixture of two
or more substances
5. Alligation alternate. A method for calculating the number of parts of two or more
components of known concentration to be mixed when the final
desired concentration is known
B. Dilution of alcohols and acids
1. Dilution of alcohols. When alcohol and water are mixed, a contraction of volume
occurs. As a result, the final volume of solution cannot be determined accurately. Nor can
the volume of water needed to dilute to a certain percentage v/v be identified. Accordingly,
percentage w/w is often used for solutions of alcohol.
2. The percentage strength of concentrated acids is expressed as percentage w/w. The
concentration of diluted acids is expressed as percentage w/v. Determining the volume of
concentrated acid to be used in preparing a diluted acid requires the specific gravity of the
concentrated acid.
C. Dilution and concentration of liquids and solids. Dilution and concentration problems
are often easily solved by identifying the amount of drug involved followed by use of an
appropriate proportion. 1. How many milliliters of a 1:50 stock solution of ephedrine
sulfate should be used in compounding the following prescription?
 Rx ephedrine sulfate 0.25% rose

water, ad 30 mL

2. How many milliliters of a 15% w/v concentrate of benzalkonium chloride should

be used in preparing 300 mL of a stock solution such that 15 mL diluted to 1 L will
yield a 1: 5000 solution?
a. First, determine the amount of drug in 1 L of a 1:5000 solution.
b. Now, because 15 mL of the stock solution is being diluted to 1 L, a stock solution is
needed in which 15 mL contain 0.2 g of drug. The amount of
drug required to make 300 mL of the stock solution is found by proportion.

c. Finally, to determine the amount of 15% concentrate required,

3. When the relative amount of components must be determined for

preparation of a mixture of a desired concentration, the problem is most
easily solved using alligation alternate.
How many grams of 2.5% hydrocortisone cream should be mixed with
360 g of 0.25% cream to make a 1% hydrocortisone cream?

The relative amounts of the 2.5% and 1% creams are 1 to 2, respectively. By proportion, the
mass of 2.5% cream to use can be determined. If 2 parts of 0.25% cream is represented
by 360 g, then the total mass (3 parts) is represented by what mass?

P.18

With the total mass known, the amount of 2.5% cream can be identified. If 3 parts represent
the total mass of 540 g, then 1 part represents the mass of 2.5% cream (x g = 180 g).

VII. ELECTROLYTE SOLUTIONS.

Electrolyte solutions contain species (electrolytes) that dissociate into ions. The
milliequivalent (mEq) is the unit used to express the concentration of
electrolytes in solution. Table 2-1 exhibits some physiologically important ions and their
properties.
A. Milliequivalents. The milliequivalent is the amount, in milligrams, of a solute equal to
1/1000 of its gram-equivalent weight. Conversion of concentrations in the form of
milliequivalent to concentrations in percentage strength, milligrams per milliliters (mg/mL) or
any other terms, begins with calculation of the number of milliequivalents of drug. The
following examples demonstrate the computation of milliequivalents and manipulation of data
from Table 2-1 to perform the required calculations for preparing electrolyte solutions.
What is the concentration, in percent w/v, of a solution containing 2 mEq of
potassium chloride per milliliter?
Calculations involving milliequivalents are easily solved if the practitioner follows a predefined
procedure to determine the milliequivalent weight. This involves three steps.
1. Find the molecular weight (mol wt).

Atomic wt K = 39

Atomic wt Cl = 35.5

39 + 35.5 = 74.5 g = mol wt of KCl

2. Calculate the equivalent weight (Eq wt) of KCl.

3. Determine the milliequivalent weight, which is of the equivalent weight. mEq wt = 74.5 g
/ 1000 = 0. 745 g or 74.5 mg

Table 2-1. Valences, Atomic Weights, and Milliequivalent Weights of

Selected Ions
 Atomic/Formula
Milliequivalent
Ion Formula Valence
Weight
Weight (mg)

Aluminum A+++ 3 27 9 Ammonium NH4+1 18 18 Calcium Ca++ 2 40

20 Ferric Fe+++ 3 56 18.7 Ferrous Fe++ 2 56 28 Lithium Li+1 7 7

Magnesium Mg++ 2 24 12 Bicarbonate HCO3-1 61 61 Carbonate

CO3-1 60 30 Chloride Cl 1 35.5 35.5 Citrate C6H5O7--- 3 189 63

Gluconate C6H11O7-1 195 195 Lactate C3H5O3-1 89 89 Phosphate

H2PO4-1 97 97 Sulfate SO4-- 2 96 48 Potassium K+1 29 39

 Sodium Na+1 23 23 Acetate C2H3O2-1 59 59

P.19

Now that we know the milliequivalent weight, we can calculate by

dimensional analysis and proportion the concentration in percentage in a
fourth step.
4. 0.0745 g/mEq × 2 mEq = 0.149 g of drug

How many milliequivalents of Na + would be contained in a 15-mL

volume of the following buffer?

Na2HPO4·7H2O 180 g

NaH2PO4·H2O 480 g

Purified water ad 1000 mL

For each salt, the mass (and milliequivalents) must be found in a 15-mL
dose.
B. Milliosmoles (mOsmol). Osmotic pressure is directly proportional to the total number of
particles in solution. The milliosmole is the unit of measure for osmotic concentration. For
nonelectrolytes, 1 millimole represents 1 milliosmole. However, for electrolytes, the total
number of particles in solution is determined by the number of particles produced in solution
and influenced by the degree of dissociation. Assuming complete dissociation, 1 millimole of
KCl represents 2 milliosmoles of total particles, 1 millimole of CaCl 2 represents 3 milliosmoles
of total particles, etc. The ideal osmolar concentration can be calculated with the following
equation.
The pharmacist should recognize the difference between ideal osmolar concentration and
actual osmolarity. As the concentration of solute increases, interaction between dissolved
particles increases, resulting in a reduction of the actual osmolar values.
C. Isotonic solutions. An isotonic solution is one that has the same osmotic pressure as
body fluids. Isosmotic fluids are fluids with the same osmotic pressure. Solutions to be
administered to patients should be
isosmotic with body fluids. A hypotonic solution is one with a lower osmotic pressure than
body fluids, whereas a hypertonic solution has an osmotic pressure that is greater than body
fluids.
1. Preparation of isotonic solutions. Colligative properties, including freezing point
depression, are representative of the number of particles in solution and considered in
preparation of isotonic solutions. a. When 1 g mol wt of any nonelectrolyte is dissolved in
1000 g of water, the freezing point of the solution is depressed by 1.86°C. By proportion, the
weight of any nonelectrolyte needed to make the solution isotonic with body fluid can be
calculated.
P.20

b. Boric acid (H3BO3 ) has a mol wt of 61.8 g. Thus 61.8 g of H3BO3 in 1000 g of water
should produce a freezing point of 1.86°C. Therefore, knowing that the freezing point
depression of body fluids is -0.52°C,

and 17.3 g of H3BO3 in 1000 g of water provides a solution that is isotonic. c. The degree of
dissociation of electrolytes must be taken into account in such calculations. For example,
NaCl is approximately 80% dissociated in weak solutions, yielding 180 particles in solution
for each 100 molecules of NaCl. Therefore,

indicating
that 9.09 g of NaCl in 1000 g of water (0.9% w/v) should make a solution isotonic. Lacking
any information on the degree of dissociation of
an electrolyte, the following dissociation values (i) may be used. (1) Substances
that dissociate into two ions: 1.8
(2) Substances that dissociate into three ions: 2.6
(3) Substances that dissociate into four ions: 3.4
(4) Substances that dissociate into five ions: 4.2
2. Sodium chloride equivalents. The pharmacist will often be required to prepare an isotonic
solution by adding an appropriate amount of another substance (drug or inert electrolyte or
nonelectrolyte). Considering that isotonic fluids contain the equivalent of 0.9% NaCl, the
question arises, How much of the added ingredient is required to make the solution isotonic?
A common method for computing the amount of added ingredient to use for reaching
isotonicity involves the use of sodium chloride equivalents. a. Definition. The sodium
chloride equivalent represents the amount of NaCl that is equivalent to the amount of
particular drug in question. For
every substance, there is one quantity that should have a constant tonic effect when
dissolved in 1000 g of water. This is 1 g mol wt of the substance divided by its
dissociation value (i).
b. Examples
(1) Considering H3BO3 , from the last section, 17.3 g of H3BO3 is equivalent to 0.52 g of NaCl
in tonicity. Therefore, the relative quantity of NaCl that is equivalent to H3BO3 in tonicity
effects is determined as follows:

Applying this
method to atropine sulfate, recall that the molecular weight of NaCl and the molecular weight
of atropine sulfate are 58.5 and 695 g, respectively, and their i values are 1.8 and 2.6,
respectively. Calculate the mass of NaCl represented by 1 g of atropine sulfate (Table 2-2).

Table 2-2. Sodium Chloride (NaCl) Equivalents

Substance NaCl Equivalent Atropine sulfate

(H2O) 0.12

Boric acid 0.52

Chlorobutanol 0.24

Dextrose (anhydrous) 0.18

Ephedrine hydrochloride 0.29

Phenacaine hydrochloride 0.20

Potassium chloride 0.78

P.21

(2) An example of the practical use of sodium chloride equivalents is seen in the following
problem.
How many grams of boric acid should be used in compounding the
following prescription?
 Rx phenacaine hydrochloride 1%

chlorobutanol 0.5%

boric acid qs

purified water, ad 60.0 mL

make isotonic solution

The prescription calls for 0.3 g of chlorobutanol and 0.6 g of phenacaine.

How much boric acid is required to prepare this prescription? The question
is best answered in four steps.
(a) Find the mass of sodium chloride represented by al l ingredients.

0.20 ×
= 0.120
of sodium chloride represented by phenacaine
0.6
g
hydrochloride

0.24 ×
= 0.072
of sodium chloride represented by chlorobutanol
0.3
g

0.192
of sodium chloride represented by the two active
g
ingredients

(b) Find the mass of sodium chloride required to prepare an equal volume
of isotonic solution.

(c) Calculate, by subtraction, the amount of NaCl required to make the

solution isotonic.
 0.540 g NaCl required for isotonicity

0.192 g NaCl represented by ingredients

0.348 g NaCl required to make isotonic solution

(d) Because the prescription calls for boric acid to be used, one last step is required.

VIII. STATISTICS
A. Introduction. Statistics can be used to describe and compare data distributions. Such
frequency distributions are constructed by classifying individual observations into
categories corresponding to fixed numeric intervals and plotting the number of observations
in each such category (i.e., interval frequency) versus the category descriptor (e.g., the
interval mean or range). Because of random errors, repeated observations or
measurements (of the same value) are not identical. These observations have a normal
distribution. Normally distributed data are described by a bell-shaped (Gaussian) curve
with a maximum, µ (population mean), corresponding to the central tendency of the
population and a spread characterized by the population standard deviation (σ). Statistics
derived from a sample or subset of a population can be used as estimates of the population
parameters.
B. Frequency distribution
1. Estimates of population mean. The population mean, µ, is the best estimate of the
true value.
a. The sample mean. For a finite number of observations, the arithmetic average or mean
([X with bar above]) is the best estimate of the true value, µ.

where Σxi is the sum of all (n) observations.

P.22

(1) Accuracy is the degree to which a measured value (X or [X with bar above]) agrees
with the “true” value (µ).
(2) Error (or bias) is the difference between a measured value (X or [X with bar above]) and
the “true” value (µ).
b. Median. The median is the midmost value of a data distribution. W hen all the values are
arranged in increasing (or decreasing) order, the median is the middle value for an odd
number of observations. For an even number of observations, the median is the arithmetic
mean of the two middle values. For a normal distribution, the median equals the mean.
The median is less affected by “outliers” or by a skewed distribution.
c. Mode. The mode is the most frequently occurring value (or values) in a frequency
distribution. The mode is useful for non-normal distributions, especially those that are
bimodal.
2. Estimates of variability. For an infinite number of observations, the population
variance (σ2) can be used to describe the variability or “spread” of observations in a data
distribution. For a finite number of observations, the sample variance (s2) can be used
to describe the variability or spread of observations in a data distribution. a. Sample
variance (s2) is estimated by

where [X with bar above] is the mean and (n - 1) is the number of degrees of freedom (df).
b. Range. For a very small number of observations, the range (w) can be used to
describe the variability in the data set:
w = |Xl a r g e s t - Xs ma l l e s t |
c. The standard deviation (s or SD), one of the most commonly encountered
estimates of variability, is equal to the square root of the variance.

or

d. Precision (reproducibility) is the degree to which replicate measurements “made in

exactly the same way” agree with each other. Precision is often expressed as the relative
standard deviation (RSD or %RSD):

3. The standard deviation of the mean (s m), or standard error of the mean (SEM), is an
estimate of the variability or error in the mean obtained from n observations. It is often used
to establish confidence intervals for describing the mean of a data set or when comparing the
means of two data sets.

P.23

STUDY QUESTIONS
Directions for questions 1-30: Each question, statement, or incomplete statement in this
section can be correctly answered or completed by one of the suggested answers or
phrases. Choose the best answer. 1. If a vitamin solution contains 0.5 mg of fluoride ion
in each milliliter, then how many milligrams of fluoride ion would be provided by a
dropper that delivers 0.6 mL?
(A) 0.3 mg
(B) 0.1 mg
(C) 1 mg
(D) 0.83 mg
View Answer1. The answer is A[see].2. How many
chloramphenicol capsules, each containing 250 mg, are needed to provide 25 mg per
kg per day for 7 days for a person weighing 200 lb? (A) 90 capsules
(B) 64 capsules
(C) 13 capsules
(D) 25 capsules
View Answer2. The answer is B[see].3. If 3.17 kg of a drug is used to
make 50,000 tablets, how many milligrams will 30 tablets contain?
(A) 1.9 mg
(B) 1900 mg
(C) 0.0019 mg
(D) 3.2 mg
View Answer3. The answer is B[see].4. A capsule contains 1/8 gr of ephedrine
sulfate, ¼ gr of theophylline, and gr of phenobarbital. What is the total mass of the
active ingredients in milligrams? (A) 20 mg
(B) 8 mg
(C) 28 mg
(D) 4 mg
View Answer4. The answer is C[see].5. If 1 fluid ounce of a cough syrup
contains 10 gr of sodium citrate, how many milligrams are contained in 10 mL?
(A) 650 mg
(B) 65 mg
(C) 217 mg
(D) 20 mg
View Answer5. The answer is C[see].6. How many capsules, each containing ¼
gr of phenobarbital, can be manufactured if a bottle containing 2 avoirdupois ounces
of phenobarbital is available? (A) 771 capsules
(B) 350 capsules
(C) 3500 capsules
(D) 1250 capsules
View Answer6. The answer is C[see].7. Using the formula for
calamine lotion, determine the amount of calamine (in grams) necessary
to prepare 240 mL of lotion.
 Calamine 80 g

Zinc oxide 80 g

Glycerin 20 mL

Bentonite magma 250 mL

Calcium hydroxide topical solution sufficient quantity to make 1000 mL

(A) 19.2 g
(B) 140 g
(C) 100 g
(D) 24 g
View Answer7. The answer is A[see].8. From the following
formula, calculate the amount of white wax required to make 1 lb of cold cream.
Determine the mass in grams.

Cetyl esters wax 12.5 parts

White wax 12.0 parts

Mineral oil 56.0 parts

Sodium borate 0.5 parts

Purified water 19.0 parts

 (A) 56.75 g
(B) 254.24 g
(C) 54.48 g
(D) 86.26 g
View Answer8. The answer is C[see].9. How many grams of aspirin should be
used to prepare 1.255 kg of the powder?

ASA 6 parts

Phenacetin 3 parts

Caffeine 1 part

(A) 125 g
(B) 750 g
(C) 175 g
(D) 360 g
View Answer9. The answer is B[see].P.24

10. A solution contains 1.25 mg of a drug per milliliter. At what rate should the solution be
infused (drops/min) if the drug is to be administered at a rate of 80 mg/hr? (1 mL = 30 drops)
(A) 64 drops/min
(B) 1.06 drops/min
(C) 32 drops/min
(D) 20 drops/min
View Answer10. The answer is C[see].11. The recommended maintenance dose of
aminophylline for children is 1.0 mg/kg/hr by injection. If 10 mL of a 25- mg/mL solution of
aminophylline is added to a 100-mL bottle for dextrose, what should be the rate of delivery in
mL/hr for a 40-lb child?
(A) 2.30 mL/hr
(B) 8.00 mL/hr
(C) 18.9 mL/hr
(D) 18.2 mL/hr
View Answer11. The answer is B[see].12. For children, streptomycin is to be
administered at a dose of 30 mg/kg of body weight daily in divided doses every 6-12 hr. The dry
powder is dissolved by adding water for injection, USP in an amount to yield the desired
concentration as indicated in the following table (for a 1-g vial).
 Approximate

Concentration (mg/mL) Volume (mL)

200 4.2

250 3.2

400 1.8

Reconstituting at the lowest possible concentration, what volume (in mL) would be withdrawn to
obtain one day's dose for a 50-lb child?
(A) 3.4 mL
(B) 22.73 mL
(C) 2.50 mL
(D) 2.27 mL
View Answer12. The answer is A[see].13. The atropine sulfate is available only in the
form of 1/150 gr tablets. How many atropine sulfate tablets would you use to compound the
following prescription?

Atropine sulfate 1/200 gr

Codeine phosphate 1/4 gr

Aspirin 5 gr

d.t.d. #24 capsules Sig: 1 capsule

p.r.n.

(A) 3 tablets
(B) 6 tablets
(C) 12 tablets
(D) 18 tablets
View Answer13. The answer is D[see].14. In 25.0 mL of a solution for injection,
there are 4.00 mg of the drug. If the dose to be administered to a patient is 200 µg, what
quantity (in mL) of this solution should be used? (A) 1.25 mL
(B) 125 mL
(C) 12.0 mL
(D) None of the above
View Answer14. The answer is A[see].15. How many milligrams of papaverine
will the patient receive each day?
 Rx papaverine 1.0 g

hydrochloride aqua 30.0 mL

syrup tolu, qs ad 90.0 mL

Sig: 1 teaspoon t.i.d.

(A) 56 mg
(B) 5.6 mg
(C) 166 mg
(D) 2.5 mg
View Answer15. The answer is C[see].16. Considering the following formula, how
many grams of sodium bromide should be used in filling this prescription?

Rx sodium bromide 1.2 g syrup tolu 2.0

mL

syrup wild cherry, qs ad 5.0 mL

d.t.d. #24

(A) 1.2 g
(B) 1200 g
(C) 28.8 g
(D) 220 g
View Answer16. The answer is C[see].17. How many milliliters of a 7.5% stock solution
of KMnO4 should be used to obtain the KMnO needed? KMnO4, qs
Distilled water, ad 1000
Sig: 2 teaspoons diluted to 500 mL yield a 1:5000 solution
(A) 267 mL
(B) 133 mL
(C) 26.7 mL
(D) 13.3 mL
View Answer17. The answer is B[see].18. The formula for Ringer's solution
follows. How much sodium chloride is needed to make 120 mL?
 Rx sodium chloride 8.60 g potassium

chloride 0.30 g

calcium chloride 0.33 g

water for injection, qs ad 1000 mL

(A) 120 g
(B) 1.03 g
(C) 0.12 g
(D) 103 g
View Answer18. The answer is B[see].P.25

19. How many grams of talc should be added to 1 lb of a powder containing 20 g of zinc
undecylenate per 100 g to reduce the concentration of zinc undecylenate to 3%?
(A) 3026.7 g
(B) 2572.7 g
(C) 17 g
(D) 257 g
View Answer19. The answer is B[see].20. How many milliliters of a 0.9% aqueous
solution can be made from 20.0 g of sodium chloride? (A) 2222 mL
(B) 100 mL
(C) 222 mL
(D) 122 mL
View Answer20. The answer is A[see].21. The blood of a reckless driver contains 0.1%
alcohol. Express the concentration of alcohol in parts per million.
(A) 100 ppm
(B) 1000 ppm
(C) 1 ppm
(D) 250 ppm
View Answer21. The answer is B[see].22. Syrup is an 85% w/v solution of sucrose in
water. It has a density of 1.313 g/mL. How many milliliters of water should be used to make 125
mL of syrup?
(A) 106.25 mL
(B) 164.1 mL
(C) 57.9 mL
(D) 25.0 mL
View Answer22. The answer is C[see].23. How many grams of
benzethonium chloride should be used in preparing 5 gal. of a 0.025% w/v solution?
(A) 189.25 g
(B) 18.9 g
(C) 4.73 g
(D) 35 g
 View Answer23. The answer is C[see].24. How many grams of menthol should be
used to prepare this prescription?

Rx menthol 0.8%

alcohol, qs ad 60.0 mL

(A) 0.48 g
(B) 0.8 g
(C) 4.8 g
(D) 1.48 g
View Answer24. The answer is A[see].25. How many milliliters of a 1:1500 solution can be
made by dissolving 4.8 g of cetylpyridinium chloride in water? (A) 7200 mL
(B) 7.2 mL
(C) 48 mL
(D) 4.8 mL
View Answer25. The answer is A[see].26. The manufacturer specifies that one Domeboro
tablet dissolved in 1 pint of water makes a modified Burow's solution approximately equivalent
to a 1:40 dilution. How many tablets should be used in preparing ½ gal of a 1:10 dilution?
(A) 16 tablets
(B) 189 tablets
(C) 12 tablets
(D) 45 tablets
View Answer26. The answer is A[see].27. How many milliosmoles of calcium
chloride (CaCl 2 ·2H2O - mol wt = 147) are represented in 147 mL of a 10% w/v calcium
chloride solution?
(A) 100 mOsmol
(B) 200 mOsmol
(C) 300 mOsmol
(D) 3 mOsmol
View Answer27. The answer is C[see].28. How many grams of boric acid should be
used in compounding the following prescription? Phenacaine HCl 1.0% (NaCl eq = 0.17)
Chlorobutanol 0.5% (NaCl eq = 0.18)
Boric acid, qs (NaCl eq = 0.52)
Purified H2O, ad 30 mL
Make isotonic solution
Sig: 1 drop in each eye
(A) 0.37 g
(B) 0.74 g
(C) 0.27 g
(D) 0.47 g
View Answer28. The answer is A[see].29. A pharmacist prepares 1 gal of KCl solution by
mixing 565 g of KCl (valence = 1) in an appropriate vehicle. How many milliequivalents of K+ are
in 15 mL of this solution? (atomic weights: K = 30; Cl = 35.5)
(A) 7.5 mEq
(B) 10 mEq
(C) 20 mEq
(D) 30 mEq
(E) 40 mEq
View Answer29. The answer is D[see].P.26

30. A vancomycin solution containing 1000 mg of vancomycin hydrochloride diluted to 250 mL

with D5W is to be infused at a constant rate with an infusion pump in 2 hr. What is the rate of
drug administration?
(A) 2.08 mg/min
(B) 8.33 mg/min
(C) 4.17 mg/min
(D) 16.7 mg/min
(E) 5.21 mg/min
View Answer30. The answer is B[see].For questions 31-34: Five ibuprofen tablets were
assayed for drug content, and the following results were obtained by high-pressure liquid
chromatography (HPLC) analysis: 198.2 mg, 199.7 mg, 202.5 mg, 201.3 mg, 196.4 mg.
31. What is the mean ibuprofen content?
(A) 196.9 mg
(B) 200.2 mg
(C) 199.6 mg
(D) 249.5 mg
(E) 202.5 mg
View Answer31. The answer is C[see].32. What is the standard deviation of ibuprofen
content in the analyzed tablets?
(A) 2.17 mg
(B) 3.35 mg
(C) 2.42 mg
(D) 3.00 mg
(E) -2.17 mg
View Answer32. The answer is C[see].33. What is the percent relative standard
deviation (%RSD) for this ibuprofen tablet analysis? (A) 1.69%
(B) 1.21%
(C) 8.25%
(D) 3.35%
(E) 1.50%
View Answer33. The answer is B[see VIII.B.4].34. What is the standard deviation of
the mean drug content of this sample?
(A) 0.480 mg
(B) 0.605 mg
(C) 1.21 mg
(D) 1.08 mg
(E) 0.825 mg
View Answer34. The answer is D[see VIII.C].P.27

ANSWERS AND EXPLANATIONS

1. The answer is A [see I.A.2].
2. The answer is B [see II].
3. The answer is B [see II].
4. The answer is C [see II].
5. The answer is C [see I.A.2].
6. The answer is C [see II].
7. The answer is A [see III].
8. The answer is C [see II; III.A].
The formula tells the pharmacist that white wax (W.W.) represents 12 parts out of the total 100 parts
in the prescription. What we wish to determine is the mass of white wax required to prepare 454 g (1
lb) of the recipe. This can be easily solved by proportion:

9. The answer is B [see III.A].

10. The answer is C [see IV.E].
11. The answer is B [see II; IV].
12. The answer is A [see IV].
13. The answer is D [see II; III.B].
14. The answer is A [see I.A.2; II].
Dimensional analysis is often useful for calculating doses. Considering that 4 mg of the drug is present
in each 25 mL of solution, we can easily calculate the number of milliliters to be used to give a dose of
0.200 mg (200 µg). Always include units in your calculations.

15. The answer is C [see III.B].

16. The answer is C [see III.B].
17. The answer is B [see V.A; VI].
First, determine the mass of drug in the final diluted solution.

Now, if 0.1 g of drug is present in 500 mL of 1:5000 solution, 2 teaspoonfuls (10 mL) of the
prescription contains the same amount of drug (0.1 g) before dilution. From this, the amount of drug in
1000 mL (the total volume) of the prescription can be determined:

Finally, to obtain the correct amount of drug to formulate the prescription (10 g), we are to use a 7.5%
stock solution. Recalling the definition of percentage strength w/v:

P.28

18. The answer is B [see III.B].

19. The answer is B [see V.C; VI.C].
20. The answer is A [see I.A.2; V.A].
Using dimensional analysis

21. The answer is B [see V.D.1].

22. The answer is C [see I.A; V.A.1].
Using the density, the weight of 125 mL of syrup can be calculated: 125 mL ×
1.313g/mL = 164.125 g
Using proportion and the sucrose concentration in w/v, the weight of sucrose in 125 mL of syrup can be
calculated:
Finally, the weight of water in 125 mL of syrup can be calculated: 164.125 g -
106.25 g = 57.875 g
which has a volume of 57.9 mL.
23. The answer is C [see I; II; V].
24. The answer is A [see I; V].
25. The answer is A [see I; V].
The problem is easily solved by proportion. The question to be answered is, If 1 g of drug is present in
1500 mL of solution, what volume can be made with 4.8 g of drug?

26. The answer is A [see I; V].

27. The answer is C [see VII.B].
Recalling the expression for ideal osmolar concentration:

28. The answer is A [see VII.C].

29. The answer is D [see VII.A].
30. The answer is B [see IV.E].
Using dimensional anaylsis:

31. The answer is C [see VIII.B.1].

The mean is calculated directly from the equation:

P.29

32. The answer is C [see VIII.B.3].

The standard deviation can be calculated with the most commonly used equation:
33. The answer is B [see VIII.B.4].

34. The answer is D [see VIII.C].

3
Pharmaceutical Principles and Drug
Dosage Forms
Lawrence H. Block

I. INTRODUCTION.
Pharmaceutical principles are the underlying physicochemical principles that allow a
drug to be incorporated into a pharmaceutical dosage form (e.g., solution, capsule).
These principles apply whether the drug is extemporaneously compounded by the
pharmacist or manufactured for commercial distribution as a drug product.
A. The finished dosage form contains the active drug ingredient in association with nondrug
(usually inert) ingredients (excipients) that make up the vehicle, or formulation matrix.
B. The drug delivery system concept, which has evolved since the 1960s, is a more holistic
concept. It embraces not only the drug (or prodrug) and its formulation matrix, but also the
dynamic interactions among the drug, its formulation matrix, its container, and the physiologic
milieux of the patient. These dynamic interactions are the subject of biopharmaceutics (see
Chapter 4).

II. INTERMOLECULAR FORCES OF ATTRACTION

A. Introduction. The application of pharmaceutical principles to drug dosage forms is
illustrated when drug dosage forms are categorized according to their physical state,
degree of heterogeneity, and chemical composition. The usual relevant states of matter
are gases, liquids, and solids. Intermolecular forces of attraction are weakest in gases and
strongest in solids. Conversions from one physical state to another can involve simply
overcoming intermolecular forces of attraction by adding energy (heat). Chemical composition
can have a dramatic effect on physicochemical properties and behavior. For this reason, it is
necessary to distinguish between polymers, or macromolecules, and more conventional
(i.e., smaller) molecules, or micromolecules.
B. Intermolecular forces of attraction. Because atoms vary in their electronegativity,
electron sharing between different atoms is likely to be unequal. This asymmetric electron
distribution causes a shift in the overall electron cloud in the molecule. As a result, the
molecule tends to behave as a dipole (i.e., as if it had a positive and a negative pole). The
dipole associated with each covalent bond has a corresponding dipole moment (µ) defined
as the product of the distance of charge separation (d) and the charge (q):
µ=q×d
The molecular dipole moment may be viewed as the vector sum of the individual bond
moments.
1. Nonpolar molecules that have perfect symmetry (e.g., carbon tetrachloride)
have dipole moments of zero (Figure 3-1).
2. Polar molecules are asymmetric and have nonzero dipole moments. 3. When dipolar
molecules approach one another close enough—“positive to positive” or “negative to
negative”—so that their electron clouds interpenetrate, intermolecular repulsive forces
arise. W hen these dipolar molecules approach one another so that the positive
P.31

pole of one is close to the negative pole of the other, molecular attraction occurs
(dipoledipole interaction). W hen the identically charged poles of the two molecules are
closer, repulsion occurs.

Figure 3-1. The carbon tetrachloride molecule.

C. Types of intermolecular forces of attraction include the following: 1. Nonpolar

molecules do not have permanent dipoles. However, the instantaneous electron
distribution in a molecule can be asymmetric. The resultant transient dipole moment can
induce a dipole in an adjacent molecule. This induced dipole-induced dipole interaction
(London dispersion force), with a force of 0.5-1 kcal/mol, is sufficient to facilitate order in
a molecular array. These relatively weak electrostatic forces are responsible for the
liquefaction of nonpolar gases.
2. The transient dipole induced by a permanent dipole, or dipole-induced dipole
interaction (Debye induction force), is a stronger interaction, with a force of 1-3 kcal/mol.
3. Permanent dipole interactions (Keesom orientation forces), with a force of 1-7
kcal/mol, together with Debye and London forces, constitute van der Waals forces.
Collectively, they are responsible for the more substantive structure and molecular ordering
found in liquids. 4. Hydrogen bonds. Because they are small and have a large electrostatic
field, hydrogen atoms can approach highly electronegative atoms (e.g., fluorine, oxygen,
nitrogen, chlorine, sulfur) and interact electrostatically to form a hydrogen bond. Depending
on the electronegativity of the second
atom and the molecular environment in which hydrogen bonding occurs, hydrogen bond
energy varies from approximately 1 to 8 kcal/mol. 5. Ion-ion, ion-dipole, and ion-induced
dipole forces. Positive-negative ion interactions in the solid state involve forces of
100-200 kcal/mol. Ionic interactions are reduced considerably in liquid systems in the
presence of other electrolytes. Ion-dipole interaction, or dipole induction by an ion, can

also affect molecular aggregation, or ordering, in a system. III. STATES OF

MATTER
A. Gases. Molecules in the gaseous state can be pictured as moving along straight paths, in
all directions and at high velocities (e.g., mean velocity for H2O vapor: 587 m/sec; for O2 : 440
m/sec), until they collide with other molecules. As a result of these random collisions,
molecular velocities and paths change, and the molecules continue to collide with other
molecules and with the boundaries of the system (e.g., the walls of a container holding the
gas). This process, repeated incessantly, is responsible for the pressure exhibited within the
confines of the system.
1. The interrelation among volume (V), pressure (P), and the absolute temperature
(T) is given by the ideal gas law, which is the equation of state for an ideal gas:
PV = nRT
PV = (g/M)RT
where n is the number of moles of gas—equivalent to the number of grams (g) of gas
divided by the molecular weight of the gas (M)—and R is the molar gas constant (0.08205
L atm/mole deg).
2. Pharmaceutical gases include the anesthetic gases (e.g., nitrous oxide, halothane).
Compressed gases include oxygen (for therapy), nitrogen, and carbon dioxide. Liquefiable
gases, including certain halohydrocarbons and hydrocarbons, are used as propellants in
aerosol products (pressurized packaging), as are compressed gases, such as nitrous
oxide, nitrogen, and carbon dioxide. Ethylene oxide is a gas used to sterilize or disinfect
heat-labile objects.
3. In general, as the temperature of a substance increases, its heat content, or
enthalpy, increases as well.
a. Substances can undergo a change of state, or phase change, from the solid to the
liquid state (melting) or from the liquid to the gaseous state (vaporization).
b. Volatile liquids (e.g., ether, halothane, methoxyflurane) are used as inhalation
anesthetics. Amyl nitrite is a volatile liquid that is inhaled for its vasodilating effect in acute
angina.
c. Sublimation occurs when a solid is heated directly to the gaseous, or vapor, state
without passing through the liquid state (e.g., camphor, iodine). Ice sublimes at pressures
below
P.32
3 torr. The process of freeze-drying, or lyophilization, is a form of vacuum drying in which
water is removed by sublimation from the frozen product. It is an especially useful process for
drying aqueous solutions or dispersions of heat- or oxygen-sensitive drugs and biologicals
(e.g., proteins, peptides). d. The reverse process (i.e., direct transition from the vapor state to
the solid state) is also referred to as sublimation, but the preferred term is deposition. Some
forms of sulfur and colloidal silicon dioxide are prepared in this way.
4. The intermolecular forces of attraction in gases are virtually nonexistent at room
temperature. Gases display little or no ordering.
B. Liquids. The intermolecular forces of attraction in liquids (van der Waals forces) are
sufficient to impose some ordering, or regular arrangement, among the molecules. Hydrogen
bonding increases the likelihood of cohesion in liquids and further affects their
physicochemical behavior. However, these forces are much weaker than covalent or ionic
forces. Therefore, liquids tend to display short-range rather than long-range order.
Hypothetically, although molecules of a liquid would tend to aggregate in localized clusters,
no defined structuring would be evident. 1. Surface and interfacial tension
a. Molecules in the bulk phase of a liquid are surrounded by other molecules of the same kind
(Figure 3-2A). Molecules at the surface of a liquid are not completely surrounded by like
molecules (Figure 3-2B). As a result, molecules at or near the surface of a liquid experience a
net inward pull from molecules in the interior of the liquid. Because of this net inward
intermolecular attraction, the liquid surface tends to spontaneously contract. Thus liquids tend
to assume a spherical shape (i.e., a volume with the minimum surface area). This
configuration has the least free energy. b. Any expansion of the surface increases the free
energy of the system. Thus surface free energy can be defined by the work required to
increase the surface area A of the liquid by 1 area unit. This value is expressed as the
number of milli-Newtons (mN) needed to expand a 1-m2 surface by 1 unit:
work = γ × ∆A
where ∆A is the increase in surface area and γ is the surface tension, or surface free
energy, in mN m- 1—equivalent to centimeter-gram-second (CGS) units of dynes cm- 1 . At
20°C. water has a surface tension of 72 mN m- 1 , whereas n-octanol has a surface tension of
27 mN m- 1 . Thus more work must be expended to expand the surface of water than to
expand the surface of n-octanol (i.e., to proceed from a given volume of bulk liquid to the
corresponding volume of small droplets).
c. At the boundary, or interface, between two immiscible liquids that are in contact with one
another, the corresponding interfacial tension (i.e., free energy, or work required to expand
the interfacial area) reflects the extent of the intermolecular forces of attraction and repulsion
at the interface.
When the interface is between two liquids, substantial molecular interaction occurs across
the interface between the two phases. This interaction P.33

reduces the imbalance in forces of attraction within each phase. The interfacial tension
between n-octanol and water is reduced to 8.5 mN m- 1 from 72 mN m- 1 (γ air/water). This
reduction indicates, in part, the
interfacial interaction between n-octanol and water.
 Figure 3-2. A. Molecules in the bulk phase.
B. Molecules at the surface of a liquid.

Figure 3-3. Liquid flow.

2. The flow of a liquid across a solid surface can be examined in terms of the velocity, or
rate of movement, of the liquid relative to the surface across which it flows. More insight can
be gained by visualizing the flow of liquid as involving the movement of numerous parallel
layers of liquid between an upper, movable plate and a lower, fixed plate (Figure 3-3). The
application of a constant force (F) to the upper plate causes both this plate and the
uppermost layer of liquid in contact with it to move with a velocity ∆y/∆x. The interaction
between the fixed bottom plate and the liquid layer closest to it prevents the movement of the
bottom layer of liquid. The
velocity (v) of the remaining layers of liquid between the two plates is proportional to their
distance from the immovable plate (i.e., ∆y/∆x). The velocity gradient leads to deformation
of the liquid with time. This deformation is the rate of shear, dv/dx, or D. Newton defined flow
in terms of the ratio of the force F applied to a plate of area A—shear stress (τ)— divided by
the velocity gradient (D) induced by τ:

or

The proportionality constant η is the coefficient of viscosity. It indicates the resistance to

flow of adjacent layers of fluid. The reciprocal of η is fluidity. Units of viscosity in the CGS
system are dynes cm- 2 s- 1 , or poise. In the SI system, the units are Newtons m- 2 s- 1 ,
which corresponds to 10 poise. The viscosity of water at 20°C is approximately 0.01 poise,
or 1 centipoise (cps), which corresponds to 1 mN m- 2 s- 1.
a. Substances that flow in accordance with the equation in III.B.2 (Newton's law) are known
as Newtonian substances. Liquids that consist of simple molecules and dilute dispersions
tend to be Newtonian. For a Newtonian fluid, a plot of shear stress as a function of shear
rate (a flow curve or rheogram) yields a straight line with a slope of η (Figure 3-4, Curve 1).
b. Non-Newtonian substances do not obey Newton's equation of flow. These substances
tend to exhibit shear-dependent or time-dependent viscosity. In either case, viscosity is
more aptly termed apparent viscosity because Newton's law is not strictly obeyed.
Heterogeneous liquids and solids are most likely non-Newtonian.
(1) Shear-dependent viscosity involves either an increase in apparent viscosity (i.e., shear
thickening, or dilatancy) (Figure 3-4, Curve 3) or a decrease in apparent viscosity (i.e.,
shear thinning, or pseudo-plasticity) (Figure 3-4, Curve 2) with an increase in the rate of
shear. Shear thickening is displayed by suspensions that have a high solids content of small,
deflocculated particles. Shear thinning is displayed by polymer P.34

or macromolecule solutions. Plastic, or Bingham body, behavior (Figure 3- 4, Curve 4) is

exemplified by flocculated particles in concentrated suspensions that show no apparent
response to low-level stress. Flow begins only after a limiting yield stress (yield value) is
exceeded.

Figure 3-4. Non-Newtonian flow curves.

(2) Time-dependent viscosity

(a) The yield value of plastic systems may be time dependent (i.e., may depend on the
time scale involved in the application of force). Thixotropic systems display shear-thinning
behavior but do not immediately recover their higher apparent viscosity when the rate of
shear is lowered. In a thixotropic system, structural recovery is relatively slow compared
with structural breakdown.
(b) Thixotropy occurs with heterogeneous systems that involve a three dimensional structure
or network. W hen such a system is at rest, it appears to have a relatively rigid consistency.
Under shear, the structure breaks down and fluidity increases (i.e., gel-sol transformation).
(c) Rheopexy (negative thixotropy, or antithixotropy) occurs when the apparent
viscosity of the system continues to increase with continued application of shear up to some
equilibrium value at a given shear rate. These systems display a sol-gel transformation.
One explanation for antithixotropic behavior is that continued shear increases the frequency
of particle or macromolecule interactions and leads to increased structure in the system.
C. Solids. Intermolecular forces of attraction are stronger in solids than in liquids or gases.
Molecular arrangements in solids may be characterized as either crystalline or amorphous.
1. Crystalline solids have the following attributes:
a. Fixed molecular order (i.e., molecules occupy set positions in a specific array)
b. A distinct melting point
c. Anisotropicity (i.e., their properties are not the same in all directions), with the
exception of cubic crystals
2. Amorphous solids have the following attributes:
a. Randomly arranged molecules with the short-range order typical of liquids
b. No melting points
c. Isotropicity (i.e., properties are the same in all directions) P.35

d. Less thermodynamic stability than the corresponding crystalline solid and therefore more
apt to exhibit chemical and physical instability, increased dissolution rate, etc.
3. Polymorphism is the condition wherein substances can exist in more than one
crystalline form. These polymorphs have different molecular arrangements or crystal lattice
structures. As a result, the different polymorphs of a drug solid can have different
properties. For example, the melting point, solubility, dissolution rate, density, and stability
can differ considerably among the polymorphic forms of a drug. Many drugs exhibit
polymorphic behavior. Fatty (triglyceride) excipients (e.g., theobroma oil, cocoa butter) are
recognized for their polymorphic behavior. 4. The incorporation of solvent molecules into the
crystal lattice of a solid results in a molecular adduct known as a solvate or hydrate (the
latter term is used when water is the solvent). In general, solvates or hydrates exhibit
different solubilities and dissolution rates than their unsolvated/anhydrous counterparts.
5. Melting point and heat of fusion. The melting point of a solid is the temperature at which
the solid is transformed to a liquid. When 1 g of a solid is heated and melts, the heat absorbed
in the process is referred to as the latent heat of fusion.
D. Phase diagrams and phase equilibria. A phase diagram represents the states of matter
(i.e., solid, liquid, and gas) that exist as temperature and pressure are varied (Figure 3-5). The
data
P.36

arrays separating the phases in Figure 3-5 delineate the temperatures and pressures at which
the phases can coexist. Thus gas (or vapor) and liquid coexist along “curve” BC, solid and
liquid coexist along “curve” AB, and solid and gas (or vapor) coexist along “curve” DB.
Depending on the change in temperature and pressure, evaporation or condensation occur
along curve BC, fusion or melting along curve AB, and sublimation or deposition along
curve DB. The three “curves” intersect at point B. Only at this unique temperature and
pressure, known as the triple point, do all three phases exist in equilibrium. (The triple point
for water is 0.01°C and 6.04 × 10- 3 atm.) Continuing along curve BC, to higher temperatures
and pressures, one ultimately reaches point C, known as the critical point, above which
there is no distinction between the liquid and the gas phases. Substances that exist above
this critical point are known as supercritical fluids. Supercritical fluids such as carbon
dioxide (critical point, 30.98°C and 73.8 atm) often exhibit markedly altered physicochemical
properties (e.g., density, diffusivity, or solubility characteristics) that render them
useful as solvents and processing aids in the production of pharmaceuticals and drug delivery
systems.
 Figure 3-5. Phase diagram for CO2 showing the
variation of the state of matter as pressure and
temperature are varied. The solid state exists in
the region ABD; the liquid state, in the region
ABC; and the gas state, in the region to the right
of curve CD. B corresponds to the triple point,
the pressure and temperature at which all three
phases coexist. C corresponds to the critical
point, the pressure and temperature above
which the liquid and gas phases are
indistinguishable.

IV. PHYSICOCHEMICAL BEHAVIOR

A. Homogeneous systems
1. A solution is a homogeneous system in which a solute is molecularly dispersed, or
dissolved, in a solvent. The solvent is the predominant species. Saturated solutions
are solutions that, at a given temperature and pressure, contain the maximum amount of
solute that can be
accommodated by the solvent. If the saturation, or solubility, limit is exceeded, a fraction of
the solute can separate from the solution and exist in equilibrium with it.
a. Solutes can be gases, liquids, or solids, and nonelectrolytes or
electrolytes.
(1) Nonelectrolytes are substances that do not form ions when dissolved in water.
Examples are estradiol, glycerin, urea, and sucrose. Their aqueous solutions do not conduct
electric current.
(2) Electrolytes are substances that do form ions in solution. Examples are sodium
chloride, hydrochloric acid, and atropine. As a result, their aqueous solutions conduct
electric current. Electrolytes are characterized as strong or weak. Strong electrolytes (e.g.,
sodium chloride, hydrochloric acid) are completely ionized in water at all concentrations. W
eak
electrolytes (e.g., aspirin, atropine) are partially ionized in water.
b. The colligative properties of a solution depend on the total number of ionic and
nonionic solute molecules in the solution. These properties depend on ionization but are
independent of other chemical properties of the solute.
2. Colligative properties include the following:
a. Lowering of vapor pressure. The partial vapor pressure of each volatile component
in a solution is equal to the product of the mol fraction
of the component in the solution and the vapor pressure of the pure component.
This is Raoult's law:

where pA is the partial vapor pressure above a solution in which the mol fraction of the solute
A is x A and is the vapor pressure of the pure component A. The vapor pressure is the
pressure at which an equilibrium is established between the molecules of A in the liquid state
and the molecules of A in the gaseous (vapor) state in a closed, evacuated container. The
vapor pressure is temperature dependent, but independent of the amount of liquid and vapor.
Raoult's law holds for ideal solutions of nonelectrolytes. For a binary solution (i.e., a solution
of component B in component A)
The lowering of the vapor pressure of the solution relative to the vapor pressure of the pure
solvent is proportional to the number of molecules of solute in the solution. The actual
lowering of the vapor pressure by the solute, ∆pA, is given by

b. Elevation of the boiling point. The boiling point is the temperature at which the vapor
P.37

pressure of a liquid equals an external pressure of 760 mm Hg. A solution of a nonvolatile

solute has a higher boiling point than a pure solvent because the solute lowers the vapor
pressure of the solvent. The amount of elevation of the boiling point (∆Tb ) depends on the
concentration of the solute:

where Kb is the molal boiling point elevation constant, R is the molar gas constant, T is
absolute temperature (degrees K), M1 is the molecular weight of the solute, m is the molality
of the solution, and ∆Hv a p is the molal enthalpy of vaporization of the solvent.
c. Depression of the freezing point. The freezing point, or melting point, of a pure
compound is the temperature at which the solid and the liquid phases are in equilibrium
under a pressure of 1 atmosphere (atm). The freezing point of a solution is the temperature
at which the solid phase of the pure solvent and the liquid phase of the solution are in
equilibrium under a pressure of 1 atm. The amount of depression of the freezing point (∆Tf)
depends on the molality of the solution:

where Kf is the molal freezing point constant and ∆Hf u s i o n is the molal heat of fusion.
d. Osmotic pressure. Osmosis is the process by which solvent molecules pass through a
semipermeable membrane (a barrier through which only solvent molecules may pass) from a
region of dilute solution to one of more concentrated solution. Solvent molecules transfer
because of the inequality in chemical potential on the two sides of the membrane. Solvent
molecules in a concentrated solution have a lower chemical potential than solvent molecules
in a more dilute solution.
(1) Osmotic pressure is the pressure that must be applied to the solution to prevent the
flow of pure solvent into the concentrated solution. (2) Solvent molecules move from a
region where their escaping tendency is high to one where their escaping tendency is
low. The presence of dissolved solute lowers the escaping tendency of the solvent in
proportion to the solute concentration.
(3) The van't Hoff equation defines the osmotic pressure π as a function of the number of
moles of solute n2 in the solution of volume V: πV = n2RT
3. Electrolyte solutions and ionic equilibria
a. Acid-base equilibria
(1) According to the Arrhenius dissociation theory, an acid is a substance that liberates H+
in aqueous solution. A base is a substance that liberates hydroxyl ions (OH-) in aqueous
solution. This definition applies only under aqueous conditions.
(2) The Lowry-Brønsted theory is a more powerful concept that applies to aqueous and
nonaqueous systems. It is most commonly used for pharmaceutical and biologic systems
because these systems are primarily aqueous.
(a) According to this definition, an acid is a substance (charged or uncharged) that is
capable of donating a proton. A base is a substance (charged or uncharged) that is capable
of accepting a proton from an acid. The dissociation of an acid (HA) always produces a
base (A-) according to the following formula:
HA ↔ H+ + A-
(b) HA and A- are a conjugate acid-base pair (an acid and a base that exist in equilibrium
and differ in structure by a proton). The proton of an acid does not exist free in solution, but
combines with the solvent. In water, this hydrated proton is a hydronium ion (H3O+).
(c) The relative strengths of acids and bases are determined by their ability to donate or
accept protons. For example, in water, HCl donates a proton more readily than does acetic
acid. Thus HCl is a stronger acid. Acid strength is also determined by the affinity of the
solvent for protons. For
example, HCl may dissociate completely in liquid ammonia, but only very slightly in glacial
acetic acid. Thus HCl is a strong acid in liquid ammonia and a weak acid in glacial acetic
acid.
P.38

(3) The Lewis theory extends the acid-base concept to reactions that do not involve protons.
It defines an acid as a molecule or ion that accepts an electron pair from another atom and a
base as a substance that donates an electron pair to be shared with another atom.
b. H+ concentration values are very small. Therefore, they are expressed in exponential
notation as pH. The pH is the logarithm of the reciprocal of the H+ concentration

where [H+] is the molar concentration of H+. Because the logarithm of a reciprocal equals the
negative logarithm of the number, this equation may be rewritten as:
pH = -log [H+]
or
[H+] = 10- p H
Thus the pH value may be defined as the negative logarithm of the [H+] value. For example,
if the H+ concentration of a solution is 5 × 10- 6 , the pH value may be calculated as follows:

pH = -log (5 × 10-6)

log 5 = 0.699

log 10-6= -6.0

pH = -(-6 + 0.699)

= -(-5.301)

= 5.301

c. As pH decreases, H+ concentration increases exponentially. W hen the pH decreases

from 6 to 5, the H+ concentration increases from 10- 6 to 10- 5,
or 10 times its original value. When the pH falls from 5 to 4.7, the H+ concentration increases
from 1 × 10- 5 to 2 × 10- 5 , or double its initial value. d. Dissociation constants. Ionization is
the complete separation of the ions in a crystal lattice when the salt is dissolved.
Dissociation is the separation of ions in solution when the ions are associated by interionic
attraction.
(1) For weak electrolytes, dissociation is a reversible process. The equilibrium of this
process can be expressed by the law of mass action. This law states that the rate of the
chemical reaction is proportional to the product of the concentration of the reacting
substances, each raised to a power of the number of moles of the substance in solution.
(2) For weak acids, dissociation in water is expressed as:
HA ↔ H+ + A
The dynamic equilibrium between the simultaneous forward and reverse reactions is
indicated by the arrows. By the law of mass action, rate of forward reaction = K1 [HA]
rate of reverse reaction = K2 [H+][A-]
At equilibrium, the forward and reverse rates are equal. Therefore, K1 [HA] = K2
[H+][A-]
Thus the equilibrium expression for the dissociation of a weak acid is written as:

where Ka represents the acid dissociation constant. For a weak acid, the acid dissociation
constant is conventionally expressed as pKa , which is - log Ka . For example, the Ka of acetic
acid at 25°C is 1.75 × 10- 5 . The pKa is calculated as follows:
P.39

pKa = -log (1.75 × 10-5)

log 1.75 = 0.243

log 10-5= -5

pH = -(-5 + 0.243)

= -(-4.757)

= 4.76
(3) For weak bases, dissociation may also be expressed with the Ka expression for the
conjugate acid of the base. This acid is formed when a proton reacts with the base. For a
base that does not contain a hydroxyl group,
BH+ ↔ H+ + B
The dissociation constant for this reaction is expressed as:

However, a base dissociation constant is traditionally defined for a weak base with this
expression:
B + H2O ↔ OH- + BH+

where Kb represents the dissociation constant of a weak base. This dissociation

constant can be expressed as pKb , as follows: pKb = -log Kb
(4) Certain compounds (acids or bases) can accept or donate more than one proton.
Consequently, they have more than one dissociation constant.
e. Henderson-Hasselbalch equations describe the relation between the ionized and the
unionized species of a weak electrolyte.
(1) For weak acids, the Henderson-Hasselbalch equation is obtained from the equilibrium
relation described in IV.A.3d.(2):

(2) Similarly, the Henderson-Hasselbalch equation for weak bases is as follows:

where B is the unionized weak base and BH+ is the protonated base. f. The degree of
ionization (α), the fraction of a weak electrolyte that is ionized in solution, is calculated

from the following equation:

where [I] and [U] represent the concentrations of the ionized and unionized species,
respectively. The degree of ionization depends solely on the pH of the solution and the pKa of
the weak electrolyte. When pH = pKa , the Henderson-Hasselbalch equations are, for a weak
acid and a weak base, respectively:

thus

P.40

thus
In effect, when the pH of the solution is numerical ly equivalent to the pKa of the weak
electrolyte, whether a weak base or a weak acid, [I] = [U] and the degree of ionization α = 0.5
(i.e., 50% of the solute is ionized). g. Solubility of a weak electrolyte varies as a function of
pH. (1) For a weak acid, the total solubility Cs is given by the expression: Cs = [HA] + [A-]
where [HA] is the intrinsic solubility of the unionized weak acid and is denoted as C0 ,
whereas [A-] is the concentration of its anion. Because [A-] can be expressed in terms of C0

and the dissociation constant Ka ,

Thus the solubility of a weak acid increases with increasing pH (i.e., with an
increasing degree of ionization, as the anion is more polar and therefore more water
soluble than the unionized weak acid). (2) Similarly, for weak bases,

Thus the solubility decreases with increasing pH because more of the weak base is in the
unprotonated form. This form is less polar and therefore less water soluble.
h. Buffers and buffer capacity
(1) A buffer is a mixture of salt with acid or base that resists changes in pH when small
quantities of acid or base are added. A buffer can be a combination of a weak acid and its
conjugate base (salt) or a combination of a weak base and its conjugate acid (salt). However,
buffer solutions are more commonly prepared from weak acids and their salts. They are not
ordinarily prepared from weak bases and their salts because weak bases are often unstable
and volatile.
(a) For a weak acid and its salt, the following buffer equation is satisfactory for
calculations with a pH of 4-10. It is important in the preparation of buffered
pharmaceutical solutions:

(b) For a weak base and its salt, the buffer equation is similar but also depends on the
dissociation constant of water (pK w). The equation becomes:

(2) Buffer action is the resistance to a change in pH.

(3) Buffer capacity is the ability of a buffer solution to resist changes in pH. The smaller
the pH change caused by addition of a given amount of acid or base, the greater the
buffer capacity of the solution. (a) Buffer capacity is the number of gram equivalents of
an acid or base that changes the pH of 1 L of buffer solution by 1 unit.
(b) Buffer capacity is affected by the concentration of the buffer constituents. A higher
concentration provides a greater acid or base reserve. Buffer capacity (β) is related to total
concentration (C) as follows: P.41

where C represents the molar concentrations of the acid and the salt.
(c) Thus buffer capacity depends on the value of the ratio of the salt to the acid form. It
increases as the ratio approaches unity. Maximum buffer capacity occurs when pH = pKa ,
and is represented by β = 0.576C. B. Heterogeneous (disperse) systems
1. Introduction
a. A suspension is a two-phase system that is composed of a solid material dispersed in an
oily or aqueous liquid. The particle size of the dispersed solid is usually > 0.5 µm.
b. An emulsion is a heterogeneous system that consists of at least one immiscible liquid
that is intimately dispersed in another in the form of droplets. The droplet diameter usually
exceeds 0.1 µm. Emulsions are inherently unstable because the droplets of the
dispersed liquid tend to coalesce to form large droplets until all of the dispersed droplets
have coalesced. The third component of the system is an emulsifying agent. This agent
prevents coalescence and maintains the integrity of the individual droplets.
2. Dispersion stability. In an ideal dispersion, the dispersed particles do not interact. The
particles are uniform in size and undergo no change in position other than the random
movement that results from Brownian motion. In contrast, in a real dispersion, the particles
are not uniformly sized (i.e., they are not monodisperse). The particles are subject to
particulate aggregation, or clumping, and the dispersion becomes more heterogeneous with
time. The rate of settling (separating, or creaming) of the dispersed phase in the dispersion
medium is a function of the particle size, dispersion phase viscosity, and difference in density
between the dispersed phase and the dispersion medium, in accordance with Stokes's law:

where d is the particle diameter, g is the acceleration owing to gravity, η is the viscosity of
the dispersion medium, and (ρ1 - ρ2 ) is the difference between the density of the particles (ρ1
) and the density of the dispersion medium (ρ2 ). Although Stokes's law was derived to
determine the settling, or sedimentation, of noninteracting spherical particles, it also provides
guidance for determining the stabilization of dispersion:
a. Particle size should be as small as possible. Smaller particles yield slower
sedimentation, or flotation, rates.
b. High particulate (dispersed phase) concentrations increase the rate of particle-particle
collisions and interaction. As a result, particle aggregation occurs, and instability increases as
the aggregates behave as larger particles. In the case of liquid-liquid dispersions,
particle-particle collisions can lead to coalescence (i.e., larger particles) and decrease
dispersion stability.
c. Avoidance of particle-particle interactions
(1) Aggregation can be prevented if the particles have a similar electrical charge. Particles in
an aqueous system always have some electrical charge because of ionization of chemical
groups on the particle surface or adsorption of charged molecules or ions at the interface. If
the adsorbed species is an ionic surfactant (e.g., sodium lauryl sulfate), the charge
associated with the surfactant ion (e.g., lauryl sulfate anion) will accumulate at the interface.
However, if a relatively non-surface-active electrolyte is adsorbed, the sign of the charge of
the adsorbed ion is less readily predicted.
(2) The magnitude of the charge is the difference in electrical potential between the
charged surface of the particle and the bulk of the dispersion medium. This magnitude is
approximated by the electrokinetic, or zeta, potential (ζ). The zeta potential is measured
from the fixed, avidly bound layers of ions and solvent molecules on the particle surface.
When ζ is high (e.g., ≥ 25 mV), interparticulate repulsive forces exceed the attractive
forces. As a result, the dispersion is deflocculated and relatively stable to collision and
subsequent aggregation (flocculation). When ζ is so low that interparticulate attractive
forces predominate, loose particle aggregates, or flocs, form (i.e., flocculation occurs).
d. Density can be manipulated to decrease the rate of dispersion instability. The
settling
P.42
rate decreases as (ρ1 - ρ2 ) approaches zero. However, the density of the dispersion medium
usually cannot be altered sufficiently to halt the settling (or flotation) process. In the
dispersed phase, the density of solid particles is not readily altered; altering the density of
liquid particles would require the addition of a miscible liquid of higher (or lower) density.
Altering the composition of suspensions is also problematic because most solid particles are
denser than the dispersion medium. Additives of higher (or lower) density might alter the
biopharmaceutical characteristics of the formulation (e.g., rate of drug release, residence
time at the site of administration, or absorption).
e. The sedimentation, or flotation, rate is inversely proportional to the viscosity. An
increase in the viscosity of the dispersion medium decreases the rate of settling, or
flotation. However, although the rate of destabilization can be slowed by an increase in
viscosity, it cannot be halted.
3. Emulsion stability. Coalescence occurs in emulsion systems when the liquid particles of
the dispersed phase merge to form larger particles. Coalescence is largely prevented by the
interfacial film of surfactant around the droplets. This film prevents direct contact of the
liquid phase of the droplets. Coalescence of droplets in oil in water (o/w) emulsions is also
inhibited by the electrostatic repulsion of similarly charged particles. Creaming is the
reversible separation of a layer of emulsified particles.
Because mixing or shaking may be sufficient to reconstitute the emulsion system, creaming
is not necessarily unacceptable. However, cracking, or irreversible phase separation, is
never acceptable. Phase inversion, or emulsion-type reversal, involves the reversion of an
emulsion from an o/w to a water in oil (w/o) form, or vice versa. Phase inversion can
change the consistency or texture of the emulsion or cause further deterioration in its
stability.

V. CHEMICAL KINETICS AND DRUG STABILITY

A. Introduction. The stability of the active component of a drug is a major criterion in the
rational design and evaluation of drug dosage forms. Problems with stability can determine
whether a given formulation is accepted or rejected.
1. Extensive chemical degradation of the active ingredient can cause substantial loss of
active ingredient from the dosage form. 2. Chemical degradation can produce a toxic
product that has undesirable side effects.
3. Instability of the drug product can cause decreased bioavailability. As a result, the
therapeutic efficacy of the dosage form may be substantially reduced.
B. Rates and orders of reactions
1. The rate of a reaction, or degradation rate, is the velocity with which the reaction occurs.
This rate is expressed as dC/dt (the change in concentration, or C, within a given time
interval, or dt).
a. Reaction rates depend on certain conditions (e.g., reactant concentration,
temperature, pH, presence of solvents or additives). Radiation and catalytic agents
(e.g., polyvalent cations) also have an effect.
b. The effective study of reaction rates in the body requires application of
pharmacokinetic principles (see Chapter 6).
2. The order of a reaction is the way in which the concentration of the drug or reactant in a
chemical reaction affects the rate. The rate of a reaction, dC/dt, is proportional to the
concentration to the nth power, where n is the order of the reaction—that is,

The study of reaction orders is a crucial aspect of pharmacokinetics (see Chapter 6).
Usually, pharmaceutical degradation can be treated as a zero-order, first-order, or
higher-order reaction. The first two are summarized as follows.
a. In a zero-order reaction, the rate is independent of the concentration of the reactants
(i.e., dC/dt C0) (see Chapter 6). Other factors, such as absorption of light in certain
photochemical reactions, determine the rate. P.43

Figure 3-6. Concentration (C) versus time (t)

for a zero-order reaction. The slope of the line
equals -k0. The slope of the line is not equal to
the rate constant because it includes the minus
sign.

(1) A zero-order reaction can be expressed as:

C = -k 0 t + C0
where C is the drug concentration, k 0 is the zero-order rate constant in units of
concentration/time, t is the time, and C0 is the initial concentration. (2) W hen this equation is
plotted with C on the vertical axis (ordinate) against t on the horizontal axis (abscissa), the
slope of the line is equal to -k0 (Figure 3-6). The negative sign indicates that the slope is
decreasing.
b. In a first-order reaction, the rate depends on the first power of the concentration
of a single reactant (i.e., dC/dt C1).

(1) In a first-order reaction, drug concentration decreases exponentially with time, in

accordance with the equation
C = C0 e- k1t
where C is the concentration of the reacting material, C0 is the initial concentration, k 1 is the
first-order rate constant in units of reciprocal time, and t is time. A plot of the logarithm of
concentration against time produces a straight line with a slope of -k/2.303 (Figure 3-7).
(2) The half-life (t 1 / 2 ) of a reaction is the time required for the
concentration of a drug to decrease by one half. For a first-order reaction, half-life is
expressed by:

(3) The time required for a drug to degrade to 90% of its original
concentration (t 9 0 % ) is also important. This time represents a reasonable limit of
degradation for the active ingredients. The t 9 0 % can be calculated as:

(a) Because k 1 = 0.693 / t ½ (b)

Then

P.44
 Figure 3-7. Logarithm of concentration (log C)
versus time (t) for a first-order reaction. The
slope of the line equals -k/2.303.

(4) Both t ½ and t 9 0 % are concentration independent. Thus, for t ½ , it takes the same
amount of time to reduce the concentration of the drug from 100 mM to 50 mM as it does
from 50 mM to 25 mM.
C. Factors that affect reaction rates. Factors other than concentration can affect the
reaction rate and stability of a drug. These factors include temperature, the presence of a
solvent, pH, and the presence of additives. 1. Temperature. An increase in temperature
causes an increase in reaction rate, as expressed in the equation first suggested by
Arrhenius: k = Ae- E a / RT
or

where k is the specific reaction rate constant, A is a constant known as the frequency factor,
Ea is the energy of activation, R is the molar gas constant (1.987 cal/degree × mole), and T is
the absolute temperature.
a. The constants A and Ea are obtained by determining k at several temperatures and then
plotting log k against 1/T. The slope of the resulting line equals -Ea/(2.303 × R). The
intercept on the vertical axis equals log A. b. The activation energy (Ea) is the amount of
energy required to put the molecules in an activated state. Molecules must be activated to
react. As
temperature increases, more molecules are activated, and the reaction rate increases.
2. Presence of solvent. Many dosage forms require the incorporation of a water-miscible
solvent—for example, low molecular weight alcohols, such as the polyethylene glycols
(PEGs)—to stabilize the drug. a. A change in the solvent system alters the transition state
and the activity coefficients of the reactant molecules. It can also cause simultaneous
changes in physicochemical parameters, such as pKa , surface tension, and viscosity. These
changes indirectly affect the reaction rate. b. In some cases, additional reaction
pathways are generated. For example, with an increasing concentration of ethanol in an
aqueous solution, aspirin degrades by an extra route and forms the ethyl ester of
acetylsalicylic acid. However, a change in solvent can also stabilize the drug.
P.45

3. Change in pH. The magnitude of the rate of a hydrolytic reaction catalyzed by

H+ and OH- can vary considerably with pH.
a. H+ catalysis predominates at lower pH, whereas OH- catalysis operates at higher pH. At
intermediate pH, the rate may be pH independent or may be catalyzed by both H+ and
OH-. Rate constants in the intermediate pH range are typically less than those at higher or
lower pH.
b. To determine the effect of pH on degradation kinetics, decomposition is measured at
several H+ concentrations. The pH of optimum stability can be determined by plotting the
logarithm of the rate constant (k) as a function of pH (Figure 3-8). The point of inflection of
the plot is the pH of optimum stability. This value is useful in the development of a stable drug
formulation.
4. Presence of additives
a. Buffer salts must be added to many drug solutions to maintain the formulation at optimum
pH. These salts can affect the rate of degradation, primarily as a result of salt increasing
the ionic strength.
(1) Increasing salt concentrations, particularly from polyelectrolytes (e.g., citrate, phosphate),
can substantially affect the magnitude of pKa . In this way, they change the rate constant.
(2) Buffer salts can also promote drug degradation through general acid or base
catalysis.
b. The addition of surfactants may accelerate or decelerate drug degradation.
(1) Acceleration of degradation is common and is caused by micellar catalysis.
(2) Stabilization of a drug through the addition of a surfactant is less common.
c. Complexing agents can improve drug stability. Aromatic esters (e.g., benzocaine,
procaine, tetracaine) increase in half-life in the presence of caffeine. This increased
stability appears to result from the formation of a less reactive complex between the
aromatic ester and the caffeine. D. Modes of pharmaceutical degradation. The
decomposition of active ingredients in a dosage form occurs through several pathways
(e.g., hydrolysis, oxidation, photolysis; see Chapter 12, II.A).
1. Hydrolysis is the most common type of degradation because many medicinal
compounds are esters, amides, or lactams.
a. H+ and OH- are the most common catalysts of hydrolytic degradation in solution.
b. Esters usually undergo hydrolytic reactions that cause drug instability. Because esters
are rapidly degraded in aqueous solution, formulators are reluctant to incorporate drugs
that have ester functional groups into liquid dosage forms.

Figure 3-8. Semilogarithmic plot of the

rate constant (k) versus pH. This plot is
used to determine the pH of optimum
stability.

P.46

2. Oxidation is usually mediated through reaction with atmospheric oxygen under ambient
conditions (auto-oxidation).
a. Medicinal compounds that undergo auto-oxidation at room temperature are affected by
oxygen dissolved in the solvent and in the head space of their packages. These
compounds should be packed in an inert
atmosphere (e.g., nitrogen) to exclude air from their containers.
b. Most oxidation reactions involve a free radical mechanism and a chain reaction. Free
radicals tend to take electrons from other compounds. (1) Antioxidants in the formulation
react with the free radicals by providing electrons and easily available hydrogen atoms. In this
way, they prevent the propagation of chain reactions.
(2) Commonly used antioxidants include ascorbic acid, butylated hydroxyanisole
(BHA), butylated hydroxytoluene (BHT), propyl gallate, sodium bisulfite, sodium sulfite,
and the tocopherols.
3. Photolysis is the degradation of drug molecules by normal sunlight or room light.
a. Molecules may absorb the proper wavelength of light and acquire sufficient energy
to undergo reaction. Usually, photolytic degradation occurs on exposure to light of
wavelengths < 400 nm.
b. An amber glass bottle or an opaque container acts as a barrier to this light, thereby
preventing or retarding photolysis. For example, sodium nitroprusside in aqueous solution
has a shelf life of only 4 hr if exposed to normal room light. W hen protected from light, the
solution is stable for at least 1 year.
E. Determination of shelf life. The shelf life of a drug preparation is the amount of time that
the product can be stored before it becomes unfit for use, through either chemical
decomposition or physical deterioration. 1. Storage temperature affects shelf life. It is
generally understood to be ambient temperature unless special storage conditions are
specified. 2. In general, a preparation is considered fit for use if it varies from the
nominal concentration or dose by no more than 10%, provided that the decomposition
products are not more toxic or harmful than the original material.
3. Shelf-life testing aids in determining the standard shelf life of a formulation. a. Samples
are stored at 3-5°C and at room temperature (20- 25°C). The samples are then analyzed at
various intervals to determine the rate of decomposition. Shelf life is calculated from this
rate. b. Because storage time at these temperatures can result in an extended testing time,
accelerated testing is conducted as well, with a range of higher temperatures. The rate
constants obtained from these samples are used to predict shelf life at ambient or
refrigeration temperatures. Temperature-accelerated stability testing is not useful if
temperature changes are accompanied by changes in the reaction mechanism or by
physical changes in the system (e.g., change from the solid to the liquid phase).
c. Stability at room temperature can be predicted from accelerated testing data by the
Arrhenius equation:

where k T 2 and k T 1 are the rate constants at the absolute temperatures T2 and T1 ,
respectively; R is the molar gas constant; and Ea is the energy of activation.
d. Alternatively, an expression of concentration can be plotted as a linear function of time.
Rate constants (k) for degradation at several temperatures are obtained. The logarithm of the
rate constant (log k) is plotted against
the reciprocal of absolute temperature (1/T) to obtain, by extrapolation, the rate constant for
degradation at room temperature (Figure 3-9).
e. The length of time that the drug will maintain its required potency can also be
predicted by calculation of the t 9 0 % (see V.B.2.b.(3)). This method applies to chemical
reactions with activation energies of 10-30 kcal/mol, the magnitude of the activation
energy for many pharmaceutical degradations that occur in solution.
P.47
 Figure 3-9. Semilogarithmic plot of the
rate constant (k) versus the reciprocal of
absolute temperature (1/T), showing the
temperature dependency of degradation
rates.

VI. DRUG DOSAGE FORMS AND DELIVERY

SYSTEMS
A. Oral solutions. The United States Pharmacopeia (USP) 31/National Formulary (NF)
26 categorizes oral solutions as “liquid preparations, intended for oral administration, that
contain one or more substances with or without flavoring, sweetening, or coloring agents
dissolved in water or cosolvent-water mixtures.” Oral solutions can contain certain polyols
(e.g., sorbitol, glycerin) to inhibit crystallization and to modify solubility, taste, mouth feel, and
other vehicle properties. They can be “formulated for direct oral administration to the patient
or they may be dispensed in a more concentrated form that must be diluted prior to
administration.” Drugs in solution are more homogeneous and easier to swallow than drugs
in solid form. For drugs that have a slow dissolution rate, onset of action and bioavailability
are also improved. However, drugs in solution are bulkier dosage forms, degrade more
rapidly, and are more likely to interact with constituents than those in solid form.
1. Water is the most commonly used vehicle for drug solutions. The USP recognizes
seven types of water for the preparation of dosage forms:
a. Purified water USP is water obtained by distillation, ion exchange, reverse osmosis, or
other suitable treatment. It cannot contain more than 10 parts per million (ppm) of total
solid and should have a pH between 5 and 7. Purified water is used in prescriptions and
finished manufactured products except parenteral and ophthalmic products.
b. Water for injection USP is water obtained by distillation or by reverse osmosis. It
conforms to the standards of purified water but is also free of pyrogen. Water for injection
is used as a solvent for the preparation of parenteral solutions.
c. Sterile water for injection USP is water for injection that is sterilized and packaged in
single-dose containers of type I and II glass. These containers do not exceed a capacity of
1 L. The limitations for total solids depend on the size of the container.
d. Bacteriostatic water for injection USP is sterile water for injection that contains one or
more suitable antimicrobial agents. It is also packaged in single- or multiple-dose containers
of type I or II glass. These containers do not exceed the capacity of 30 mL.
e. Sterile water for inhalation USP is water that is purified by distillation or by reverse
osmosis (i.e., water for injection) and rendered sterile. It contains no antimicrobial agents,
except when used in humidifiers or similar devices. This type of water should not be used for
parenteral administration or for other sterile dosage forms.
f. Sterile water for irrigation USP is water for injection that is sterilized and suitably
packaged. It contains no antimicrobial agents or other added substance.
P.48
g. Sterile purified water USP is purified water sterilized and suitably packaged. It
contains no antimicrobial agent. It is not intended for use in parenterals.
2. Oral drug solutions include syrups and elixirs as well as other less widely
prescribed classic (galenical) formulations, such as aromatic waters, tinctures,
fluidextracts, and spirits.
a. Syrups are traditionally peroral solutions that contain high concentrations of sucrose or
other sugars. Through common usage, the term syrup has also come to include any other
liquid dosage form prepared in a sweet, viscous vehicle, including peroral suspensions. (1)
Syrup NF (simple syrup) is a concentrated or nearly saturated aqueous solution of sugar
(85%; 65% w/w).
(2) Syrups have a low solvent capacity for water-soluble drugs because the hydrogen
bonding between sucrose and water is very strong. For this reason, it can be difficult or
impossible to dissolve a drug in a syrup. Often, the drug is best dissolved in a small quantity
of water, and the flavoring syrup is added.
(3) The sucrose concentration of syrup plays a crucial role in the control of microbial growth.
Dilute sucrose solutions are excellent media for microorganisms. As the concentration of
sucrose approaches saturation, the syrup becomes self-preserving (i.e., requires no additional
preservative). However, a saturated solution is undesirable because temperature fluctuations
may cause crystallization. Syrup NF is a selfpreserved solution with a minimal tendency to
undergo crystallization.
b. Elixirs are traditionally peroral solutions that contain alcohol as a cosolvent. Many
peroral solutions are not described as elixirs but contain alcohol.
(1) To be considered an elixir, the solution must contain alcohol. Traditionally, the alcohol
content of elixirs has varied from 5% to 40%. Most elixirs become turbid when moderately
diluted by aqueous liquids. Elixirs are not the preferred vehicle for salts because alcohol
accentuates saline taste. Salts also have limited solubility in alcohol. Therefore, the alcoholic
content of salt-containing elixirs must be low.
(2) Aromatic elixir NF, prepared in part from syrup, contains approximately 22% alcohol. The
limited usefulness of this elixir as a solvent for drugs was offset by the development of
iso-alcoholic elixir. It is a combination of low-alcoholic elixir, an elixir with low alcoholic
content (8%-10% alcohol), and high-alcoholic elixir, an elixir with high alcoholic content
(73%-78% alcohol). Mixing appropriate volumes of the two elixirs provides an alcoholic
content sufficient to dissolve the drugs.
B. Miscellaneous solutions
1. Aromatic waters are clear, saturated aqueous solutions of volatile oils or other
aromatic or volatile substances. Aromatic waters may be used as pleasantly flavored vehicles
for a water-soluble drug or as an aqueous phase in an emulsion or suspension. If a large
amount of water-soluble drug is added to an aromatic water, then an insoluble layer may form
at the top. This “salting out” is a competitive process. The molecules of water-soluble drugs
have more attraction for the solvent molecules of water than the “oil” molecules. The
associated water molecules are pulled away from the oil molecules, which are no longer held
in solution. Aromatic waters should be stored in tight, light-resistant bottles to reduce
volatilization and degradation from sunlight. Aromatic waters are usually prepared by one of
the following methods:
a. Distillation is a universal method but is not practical or economical for most products. It
is the only method, however, for preparing strong rose water and orange flower water.
b. W ith the solution method, the volatile, or aromatic, substance is admixed with water, with
or without the use of a dispersant (e.g., talc). 2. Spirits, or essences, are alcoholic or
hydroalcoholic solutions of volatile substances, that contain 50%-90% alcohol. This high
alcoholic content maintains the water-insoluble volatile oils in solution. If water is added to a
spirit, the oils separate. Some spirits are medicinal (e.g., aromatic
ammonia spirit). Many spirits (e.g., compound orange spirit, compound cardamom spirit)
are used as flavoring agents. Spirits should be stored in tight containers to reduce loss by
evaporation.
3. Tinctures are alcoholic or hydroalcoholic solutions of chemicals or soluble constituents of
vegetable drugs. Although tinctures vary in drug concentration (≤ 50%), those prepared from
potent drugs are usually 10% in strength (i.e., 100 mL of the tincture has the activity of 10 g of
the drug). Tinctures are usually considered stable. The alcohol content of the official tinctures
varies from 17% to 21% for opium tincture USP and from 74% to 80% for compound benzoin
tincture USP. Most tinctures are prepared by an extraction process of
P.49

maceration or percolation. The selection of a solvent, or menstruum, is based on the

solubility of the active and inert constituents of the crude drugs. Aging can cause precipitation
of the inactive constituents of tinctures. Glycerin may be added to the hydroalcoholic solvent
to increase the solubility of the active constituent and reduce precipitation on storage.
Tinctures must be tightly stoppered and kept from excessive temperatures. Because many of
their constituents undergo a photochemical change when exposed to light, tinctures must be
stored in light-resistant containers. 4. Fluidextracts are liquid extracts of vegetable drugs that
contain alcohol as a solvent, preservative, or both. Fluidextracts are prepared by percolation
so that each milliliter contains the therapeutic constituents of 1 g of the standard drug.
Because of their high drug content, fluidextracts are sometimes referred to as “100%
tinctures.” Fluidextracts of potent drugs are usually 10 times as concentrated, or potent, as the
corresponding tincture. For example, the usual dose of tincture belladonna is 0.6 mL; the
equivalent dose of the more potent fluidextract is 0.06 mL. Many fluidextracts are considered
too potent for self-administration by patients, so they are almost never prescribed. In addition,
many fluidextracts are simply too bitter. Today, most fluidextracts are modified by either
flavoring or sweetening agents.
5. Nasal, ophthalmic, otic, and parenteral solutions are classified separately because of
their specific use and method of preparation. 6. Mouthwashes are solutions that are used to
cleanse the mouth or treat diseases of the oral mucous membrane. They often contain
alcohol or glycerin to aid in dissolving the volatile ingredients. Mouthwashes are more often
used cosmetically than therapeutically.
7. Astringents are locally applied solutions that precipitate protein. They reduce cell
permeability without causing injury. Astringents cause constriction, with wrinkling and
blanching of the skin. Because astringents reduce secretions, they can be used as
antiperspirants.
a. Aluminum acetate and aluminum subacetate solutions are used as wet dressings in
contact dermatitis. The precipitation is minimized by the addition of boric acid.
b. Calcium hydroxide solution is a mild stringent that is used in lotions as a reactant and
an alkalizer.
8. Antibacterial topical solutions (e.g., benzalkonium chloride, strong iodine,
povidoneiodine) kill bacteria when applied to the skin or mucous membrane in the
proper strength and under appropriate conditions. C. Suspensions
1. Lotions, magmas (i.e., suspensions of finely divided material in a small amount of
water), and mixtures are all suspensions that have had official formulas for some time (e.g.,
calamine lotion USP, kaolin mixture with pectin NF). Official formulas are given in the
USP/NF.
a. A complete formula and a detailed method of preparation are available for some
official suspensions. For others, only the concentration of the active ingredients is given,
and the manufacturer has considerable latitude in the formulation.
b. Some drugs are packaged in a dry form to circumvent the instability of aqueous
dispersions. Water is added at the time of dispensing to reconstitute the suspension.
2. Purposes of suspension
a. Sustaining effect. For a sustained-release preparation, a suspension necessitates
drug dissolution before absorption.
b. Stability. Drug degradation in suspension or solid dosage forms occurs much more
slowly than degradation in solution form.
c. Taste. A drug with an unpleasant taste can be converted into an insoluble form
and then prepared as a suspension.
d. Basic solubility. W hen suitable solvents are not available, the suspension provides an
alternative. For example, only water can be used as a solvent for ophthalmic preparations
because of the possibility of corneal damage. Ophthalmic suspensions provide an alternative
to ophthalmic solutions.
3. Suspending agents include hydrophilic colloids, clays, and a few other agents. Some are
also used as emulsifying agents (see VI.D.3). a. Hydrophilic colloids (i.e., hydrocolloids)
increase the viscosity of water by binding water molecules, thus limiting their mobility, or
fluidity. Viscosity is proportional to the concentration of the hydrocolloid. These agents
support the growth of microorganisms and require a preservative. They are mostly
anionic, with the exception of methyl cellulose P.50

(neutral) and chitosan (cationic). Thus the anionic hydrocolloids are incompatible with
quaternary antibacterial agents and other positively charged drugs. Chitosan is incompatible
with negatively charged drugs and excipients. Most hydrocolloids are insoluble in alcoholic
solutions.
(1) Acacia is usually used as a 35% dispersion in water (muci lage). Its viscosity is
greatest between pH 5 and pH 9. Acacia is susceptible to microbial decomposition.
(2) Tragacanth is usually used as a 6% dispersion in water (mucilage). One advantage of
tragacanth over acacia is that less is needed. Also, tragacanth does not contain the oxidase
that is present in acacia. This oxidase catalyzes the decomposition of organic chemicals. The
viscosity of tragacanth is greatest at pH 5.
(3) Methyl cellulose is a polymer that is nonionic and stable to heat and light. It is available
in several viscosity grades. Because it is soluble in cold water, but not in hot water,
dispersions are prepared by adding methyl cellulose to boiling water and then cooling the
preparation until the material dissolves.
(4) Carboxymethylcellulose is an anionic material that is soluble in water. Prolonged
exposure to heat causes loss of viscosity.
b. Clays (e.g., bentonite, Veegum) are silicates that are anionic in aqueous dispersions.
They are strongly hydrated and exhibit thixotropy (the property of forming a gel-like structure
on standing and becoming fluid on agitation).
(1) The official form of bentonite is the 5% magma.
(2) Veegum is hydrated to a greater degree than bentonite. Thus it is more viscous at the
same concentration.
c. Other agents include agar, chondrus (carrageenan), gelatin, pectin, and gelatinized
starch. Their use is limited by their susceptibility to bacterial attack, their incompatibilities,
and their cost. Xanthan gum is used in many modern suspension formulations because of its
cosolvent compatibility, its stability, and its solution's high viscosity relative to concentration.
4. Preparation
a. Solids are wetted initially to separate individual particles and coat them with a layer of
dispersion medium. W etting is accomplished by levigation (i.e., addition of a suitable
nonsolvent, or levigating agent, to the solid material, followed by blending to form a paste),
using a glass mortar and pestle or an ointment slab. A surfactant can also be used. b.
Suspending agents are then added as dry powder along with the active ingredient. For best
results, the suspending agent is added in the form of its aqueous dispersion.
(1) The aqueous dispersion is added to the solid (or the levigated solid) by geometric
dilution.
(2) The preparation is brought to the desired volume by stirring in the appropriate
vehicle.
D. Emulsions
1. Purposes of emulsions
a. Increased drug solubility. Many drugs have limited aqueous solubility but have
maximum solubility in the oil phase of an emulsion. Drug
partitioning from the oil phase to the water phase can maintain or enhance activity.
b. Increased drug stability. Many drugs are more stable when incorporated into an
emulsion rather than an aqueous solution. c. Prolonged drug action. Incorporation of a
drug into an emulsion can prolong bioavailability, as with certain intramuscular injection
preparations. d. Improved taste. Drugs with an unpleasant taste are more palatable and
thus more conveniently administered in emulsion form.
e. Improved appearance. Oily materials intended for topical application are more appealing
in an emulsified form.
2. Phases of emulsions. Most emulsions are considered two-phase systems.
a. The liquid droplet is known as the dispersed, internal, or discontinuous
phase. The other liquid is known as the dispersion medium, external phase, or
continuous phase.
b. In pharmaceutical applications, one phase is usual ly an aqueous solution. The other
phase is usually lipid or oily. The lipids range from vegetable or hydrocarbon oils to semisolid
hydrocarbons and waxes. Emulsions are usually described in terms of water and oil. Oil is the
lipid, or nonaqueous, phase, regardless of its composition.
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(1) If water is the internal phase, the emulsion is classified as w/o. (2) If water is the
external phase, the emulsion is classified as o/w. c. The type of emulsion formed is
primarily determined by the relative phase volumes and the emulsifying agent used.
(1) For an ideal emulsion, the maximum concentration of internal phase is 74% (i.e.,
theoretically, an o/w emulsion can be prepared containing ≤ 74% oil).
(2) The choice of an emulsifying agent is more important than the relative phase volumes
in determining the final emulsion type. Most agents preferentially form one type of
emulsion or the other if the phase volume permits.
3. Emulsifying agents. Any compound that lowers the interfacial tension and forms a film at
the interface can potentially function as an emulsifying agent. The effectiveness of the
emulsifying agent depends on its chemical structure, concentration, solubility, pH, physical
properties, and electrostatic effect. True emulsifying agents (primary agents) can form and
stabilize emulsions by themselves. Stabilizers (auxiliary agents) do not form acceptable
emulsions when used alone, but assist primary agents in stabilizing the product (e.g., increase
viscosity). Emulsifying agents are either natural or synthetic.
a. Natural emulsifying agents:
(1) Acacia forms a good, stable emulsion of low viscosity. It tends to cream easily, is acidic,
and is stable at a pH range of 2-10. Like other gums, it is negatively charged, dehydrates
easily, and usually requires a preservative. It is incompatible with Peruvian balsam, bismuth
salts, and carbonates. (2) Tragacanth forms a stable emulsion that is coarser than acacia
emulsion. It is anionic, is difficult to hydrate, and is used mainly for its effects on viscosity.
Less than of the amount used for acacia is needed. (3) Agar is an anionic gum that is
primarily used to increase viscosity. Its stability is affected by heating, dehydration, and
destruction of charge. It is also susceptible to microbial degradation.
(4) Pectin is a quasi-emulsifier that is used in the same proportion as tragacanth.
(5) Gelatin provides good emulsion stabilization in a concentration of 0.5%- 1.0%. It may be
anionic or cationic, depending on its isoelectric point. Type A gelatin (+), prepared from an
acid-treated precursor, is used in acidic media. Type B gelatin (-), prepared from an
alkali-treated precursor, is used in basic media.
(6) Methyl cellulose is nonionic and induces viscosity. It is used as a primary
emulsifier with mineral oil and cod liver oil, and yields an o/w emulsion. It is usually
used in 2% concentration.
(7) Carboxymethylcellulose is anionic and is usually used to increase viscosity. It
tolerates alcohol up to 40%, forms a basic solution, and precipitates in the presence of
free acids.
b. Synthetic emulsifying agents are anionic, cationic, or nonionic. Although these
surfactants are amphiphilic molecules, their lipophilic and hydrophilic regions are seldom
inverse equals of each other: Some surfactant molecules tend to be predominantly
lipophilic, whereas others are predominantly hydrophilic. This imbalance is reflected in the
hydrophilic-lipophilic balance (HLB) scale: The larger the HLB value, the more hydrophilic
the molecule. Table 3-1 lists HLB values for surfactants and their corresponding uses.

Table 3-1. Hydrophilic-Lipophilic Balance (HLB)