Introduction

PRINCIPLES OF PHARMACEUTICAL FORMULATION AND DOSAGE

FORM DESIGN
Need for dosage form
Pre-formulation Studies
Product Formulation

Dosage Form Design

Dosage form design: Pharmaceutical and formulation
consideration
Dosage form design: biopharmaceutical and
pharmacokinetic consideration
Pharmaceutical Technology
The application of:
• scientific knowledge or technology to
pharmacy and the pharmaceutical industry.

• It includes methods, techniques, and

instrumentation in the manufacturing,
preparation, compounding, dispensing,
packaging, and storing of drugs, and all
other preparations used in diagnostic and
determinative procedures, and in the
treatment of patients.
 Pharmaceutics
Pharmaceutics is the discipline of pharmacy that
deals with:
1. The process of turning a new chemical entity
(NCE) or old drugs into a medication to be
used safely and effectively.
2. It is also called the science of dosage form
design, manufacturing, preparation,
compounding, dispensing, packaging, and
storing of drugs.
 Need/Reasons for dosage form design

1. To protect the drug substance from the destructive influences of atmospheric

oxygen or humidity (coated tablets, sealed ampules).

2. To protect the drug substance from the destructive influence of gastric acid after
oral administration (enteric-coated tablets).

3. To conceal the bitter, salty, or offensive taste or odor of a drug substance

(capsules, coated tablets, flavored syrups).

4. To provide liquid preparations of substances those are either insoluble or

unstable in the desired vehicle (suspensions).

5. To provide clear liquid dosage forms of substances (syrups, solutions).

6. To provide rate-controlled drug action (various controlled-release tablets,

capsules, and suspensions).
 Need/Reasons for dosage form design

7. To provide optimal drug action from topical administration sites

(ointments, creams, transdermal patches, and ophthalmic, ear, and
nasal preparations).

8. To provide for insertion of a drug into one of the body’s orifices

(rectal or vaginal suppositories).

9. To provide for placement of drugs directly in the bloodstream or

body tissues (injections).

10. To provide for optimal drug action through inhalation therapy

(inhalants and inhalation aerosols).
 Pre-formulation studies
• Pre-formulation studies are basic studies
needed before actual product formulation
begins.
 Drug substances
Drug substances are available as Liquid drugs’ Solid
materials (either crystalline or amorphous constitution)
and in the form of gas.

Before the formulation of a drug substance into a dosage

form, the purity of the chemical substance is essential.

Its identification test is performed and its chemical,

physical, and biologic properties are evaluated.
 Continued
Though the physical and chemical properties of
drugs and additives (Pharmaceutical and
formulation consideration) need to be
understood, the factors influencing drug
absorption and the requirements of the disease
to be treated (biopharmaceutical and
pharmacokinetic consideration) also have to be
taken into account. It help in identifying
potential delivery routes.
 The objective of dosage form design
1. The objective is to create a high-quality efficacious
and safe dosage forms.
2. Designing the efficacious and safe dosage form
demands the highest standards, with careful analysis
and evaluation of wide-ranging information by
pharmaceutical scientists to achieve the objective.
3. It is therefore apparent that before a drug substance
can be successfully formulated into a dosage form
many factors must be considered. These can be
broadly grouped into following categories:
 Factors/properties to be considered

1. Chemical properties: Chemical properties

include structure, form, and reactivity.
2. Physical Description: Physical properties
include such characteristics as its physical
description, particle size, crystalline structure,
melting point, and solubility.
3. Biologic properties: Biologic properties relate
to its ability to get to a site of action and elicit
a biologic response.
 Chemical properties
Molecular optimization

To improve new drug’s properties, molecular

modifications can be performed to get appropriate salts,
pro drugs, solvates, polymorphs, or even new analogs.
Ephedrine hydrochloride, for example, is prepared by
addition of a proton to the basic secondary nitrogen
atom on ephedrine, resulting in a protonated drug
molecule (ephedrine- H (+)). Generally the salt is more
soluble and facilitates bioavailability.
 Physical Properties

The selection of dosage form to be prepared for

example, tablet, syrup, aerosols, depends upon
drug’s physical state as solids, liquids, and gases.
 1. Physical form of Solid
1. An important factor in formulation is the crystalline,
amorphous or Polymorphic form of the drug substance.

2. Polymorphic forms in drugs are relatively common.

During formulation process a polymorphic substance
can convert itself from one crystalline form to another
crystalline form or to an amorphous form or vice versa.

3. Evaluation of crystal structure, polymorphism, and

solvate form is an important pre-formulation activity.
Determination of crystal properties
Various techniques are used to determine
crystal properties. The most widely used
methods are:
1. hot stage microscopy,
2. Thermal analysis,
3. Infrared spectroscopy, and
4. X-ray diffraction.
 2. Polymorphism
1. Polymorphic forms usually exhibit different
physicochemical properties, including melting point and
solubility.
2. The energy required for a molecule of drug to escape
from a crystal is much greater than is required to escape
from an amorphous powder form. Therefore, the
amorphous form of a compound is always more soluble
than a corresponding crystal form.
3. The changes in crystal characteristics can influence
bioavailability and chemical and physical stability. It can
be a significant factor relating to tablet formation
because of flow and compaction.
 Microscopic Examination
Microscopic examination of the raw drug substance
is an important step in pre-formulation working. It
gives an indication of particle size and size range of
the raw material along with the crystal structure.

Photomicrographs of the initial and subsequent

batch lots of the drug substance can provide
important information in case of problems in
formulation processing attributable to changes in
particle or crystal characteristics of the drug.
 3.Melting Point Depression
• A characteristic of a pure substance is a
defined melting point or melting range. If not
pure, the substance will exhibit a change in
melting point. This phenomenon is commonly
used to determine the purity of a drug
substance and in some cases the compatibility
of various substances before inclusion in the
same dosage form.
 4. The Phase Rule
• Phase diagrams are often constructed to
provide a visual picture of the existence and
extent of the presence of solid and liquid
phases in binary, ternary, and other mixtures.
Phase diagrams are normally two-component
(binary) representations, but can also be
three-component representations.
 5. Particle Size
i. Certain physical and chemical properties of
drug substances, including dissolution rate,
bioavailability, content uniformity, taste,
texture, color, and stability, are affected by
the particle size distribution.
ii. In addition, flow characteristics and
sedimentation rates, among other
properties, are important factors related to
particle size.
 5. Particle size
iii. It is essential to establish as early as possible
how the particle size of the drug substance
may affect formulation and efficacy.

iv. The effect of particle size on absorption is

very significant. Particle size influences the
oral absorption profiles of certain drugs,
including griseofulvin, nitrofurantoin,
spironolactone, and procaine penicillin.
 5. Particle Size
• Content uniformity, in solid dosage forms
depends to a large degree on particle size and
the equal distribution of the active ingredient
throughout the formulation.
particle size analyzer

Mastersizer 2000E
 physicochemical properties
1. Solubility
i. Solubility is a physicochemical property of a
drug substance.
ii. A drug to enter the systemic circulation and
exert a therapeutic effect, must possesses some
aqueous solubility for therapeutic efficacy.
iii. A Relatively insoluble compounds often exhibit
incomplete or erratic absorption.
 1. Solubility

1. If the solubility of the drug substance is less than

desirable, consideration must be given to improve its
solubility.
2. The methods to accomplish desired solubility depend
on the chemical nature of the drug and the type of
drug product under consideration.
3. Chemical modification of the drug into salt or ester
forms is frequently used to increase solubility.
4. In many cases, it is desirable to use co-solvents or other
techniques such as complexation, micronization, or
solid dispersion to improve aqueous solubility.
 Determination of solubility
1. A drug’s solubility is usually determined by
the equilibrium solubility method, by which
an excess of the drug is placed in a solvent
and shaken at a constant temperature over a
long period until equilibrium is obtained.
2. Chemical analysis of the drug content in
solution is performed to determine degree of
solubility.
 Solubility and Particle Size

• Solubility is normally considered a

physicochemical constant.
• small increases in solubility can be accomplished
by particle size reduction as described in the
equation can be used to estimate the decrease in
particle size required to increase solubility.
• The particle size and surface area of a drug
exposed to a medium can affect actual solubility,
as explained in the following relationship:
 Equation

S 2ϒV
Log ------- = --------------
S0 2.303 RTr

where
S the solubility of the small particles,
S0 the solubility of the large particles,
γ the surface tension,
V the molar volume,
R the gas constant,
T the absolute temperature, and
r the radius of the small particles.
 Solubility and pH
1. If the drug is to be formulated into a liquid product, the adjustment of the pH of
the solvent is required. The effect of pH on solubility is critical in the formulation
of liquid dosage forms, from oral and topical solutions to intravenous solutions
and admixtures.

2. However, for many drug substances (other than electrolytes) pH adjustment is

not an effective means of improving solubility.

3. The solubility of a weak acid or base is often pH dependent. The total quantity of
a monoprotic weak acid (HA) in solution at a specific pH is the sum of the
concentrations of both the free acid and salt (A−) forms. If excess drug is
present, the quantity of free acid in solution is maximized and constant because
of its saturation solubility. As the pH of the solution increases, the quantity of
drug in solution increases because the water-soluble ionizable salt is formed. See
the expression:
 The expression is:
Ka
HA ↔ H + + A–

Where Ka is the dissociation constant

Weak acidic or basic drugs may require extremes in
pH that are outside accepted physiologic limits or that
may cause stability problems with formulation
ingredients.
In short the adjustment of pH usually has little effect
on the solubility of substances other than
electrolytes.
 2. Dissolution
1. Dissolution rate, or the time taken for the drug to dissolve in the
fluids at the absorption site, is the rate-limiting step in absorption.
2. This is true for drugs administered orally in solid forms such as
tablets, capsules, or suspensions, and for those administered
intramuscularly.
3. When the dissolution rate is the rate-limiting step, anything that
affects it will also affect absorption. Consequently, dissolution rate
can affect the onset, intensity, and duration of response and
control the overall bioavailability of the drug from the dosage form.
4. Early formulation studies should include the effects of
pharmaceutical ingredients on the dissolution characteristics of the
drug substance.
 Dissolution rate and Particle size
1. The dissolution rate of drugs may be increased by
decreasing the drug’s particle size. It may also be
increased by increasing its solubility in the diffusion layer.
2. The most effective means of obtaining higher dissolution
rates is to use a highly water-soluble salt of the parent
substance.
3. Although a soluble salt of a weak acid will precipitate as
the free acid in the bulk phase of an acidic solution, such
as gastric fluid, it will do so in the form of fine particles
with a large surface area.
 Determination of Dissolution rate
Dissolution rates of chemical compounds are
determined by two methods:

1. The constant surface method

2. The Particulate dissolution method
 The constant surface method
• The constant surface method, which provides the intrinsic
dissolution rate of the agent. The constant-surface method uses
a compressed disc of known area. This method eliminates
surface area and surface electrical charges as dissolution
variables.
• The dissolution rate obtained by this method, the intrinsic
dissolution rate, is characteristic of each solid compound and a
given solvent in the fixed experimental conditions. The value is
expressed as milligrams dissolved per minute per centimeters
squared. It has been suggested that this value is useful in
predicting probable absorption problems due to dissolution
rate.
 Particulate dissolution
• Particulate dissolution, in which a suspension of the agent is added to a
fixed amount of solvent without exact control of surface area.
• In particulate dissolution, a weighed amount of powdered sample is
added to the dissolution medium in a constant agitation system. This
method is frequently used to study the influence of particle size,
surface area, and excipients upon the active agent.
• Occasionally, the surface properties of the drug produce an inverse
relationship of particle size to dissolution. In these instances, surface
charge and/or agglomeration results in the reduced particle size form of
the drug presenting a lower effective surface area to the solvent due to
incomplete wetting or agglomeration.
• Fick’s laws describe the relationship of diffusion and dissolution of the
active drug in the dosage form and when administered in the body.
 Drug/Formulation Stability
Drugs can be classified according to their sensitivity to
breakdown:

1. Stable under all conditions (e.g. kaolin)

2. Stable if handled correctly (e.g. aspirin)
3. Very unstable (e.g. certain antibiotics in solution form).

• In general, drug substances decompose as a result of

the effects of heat, oxygen, light and moisture.
 Examples
Esters such as aspirin and procaine are susceptible to solvolytic
breakdown.
1. Solvolytic reactions are usually substitution reactions—i.e.,
reactions in which an atom or a group of atoms in a
molecule is replaced by another atom or group of atoms.
Hydrolysis is a solvolytic reaction.
2. The solvents act as or produce electron-rich atoms or groups
of atoms that displace an atom or group in the substrate
molecule.
3. To avoid hydrolysis, precautions such as minimum exposure
to moisture during preparation, low moisture content
specifications in the final product, and moisture resistant
packaging can be used.
 Other Examples
1. Oxidative decomposition occurs for
substances such as ascorbic acid. For oxygen-
sensitive drugs, antioxidants can be included
in the formulation.

2. For light-sensitive material, a suitable

packaging can reduce or eliminate the
problem.
 Continued
1. One of the principles of dosage form design is to
ensure that the chemical integrity of drug substances
is maintained during the usable life of the product. At
the same time, chemical changes involving additive
and any physical modifications to the product must be
carefully monitored to optimize formulation stability.

2. The packaging of the dosage form is an important

contributing factor to product stability and must be an
integral part of stability testing programs.
 Completed
• Physical, Chemicals and Physico-Chemical
Factors Completed.

• Next Lecture on Effect of Biological Factors on

Dosage Form Design.
 References
Ansel’s Pharmaceutical Dosage Forms and Drug
Delivery Systems
NINTH EDITION
Loyd V. Allen, Jr., PhD; Nicholas G. Popovich, PhD; Howard C. Ansel, PhD