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Dosage form design

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Pharmaceutical and formulation considerations

LEC-3

Omar Hamid, MSc, PhD

Reference: Ansels Pharmaceutical Dosage Forms and Drug delivery systems

The Need for Dosage Forms

• Why do we need for dosage forms?

➢ The potent nature and low dosage of most of the drugs in use today
preclude any expectation that the general public could safely obtain
the appropriate dose of a drug from the bulk material.

➢ Most drug substances are administered in milligram quantities.

➢ For instance, how could the person accurately obtain from a bulk
supply the 325 mg of aspirin found in the common tablet?

➢ When the dose of the drug is minute, as with ethinyl estradiol

(0.05mg), solid dosage forms such as tablets and capsules must be
prepared with fillers or diluents so that the dosage unit is large
enough to pick up with the fingertips.

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In addition, dosage forms are needed for additional reasons:

• To protect the drug substance from the destructive influences of

atmospheric oxygen or humidity (coated tablets, sealed ampules).

• To protect the drug substance from the destructive influence of

gastric acid after oral administration (enteric-coated tablets).

• To conceal the bitter, salty, or offensive taste or odor of a drug

substance (capsules, coated tablets, flavored syrups).

• To provide liquid preparations of drug substances, either as

dispersions (suspensions) or as clear preparations (solutions).

• To provide rate-controlled drug action (various controlled-release

tablets, capsules, and suspensions).

During childhood and even adulthood, a person may have difficulty in

swallowing solid dosage forms, especially uncoated tablets. For this
reason, some medications are formulated as chewable tablets. Many of
these tablets are comparable in texture to an after-dinner mint and break
down into a pleasant-tasting creamy material.

Newly available tablets dissolve in the mouth in about 10 to 15

seconds; this allows the patient to take a tablet but actually swallow a
liquid.
Capsules have been found by many to be more easily swallowed than
whole tablets. If a capsule is moistened in the mouth before it is
swallowed, it becomes slippery and readily slides down the throat with
water.
Also, a teaspoonful of gelatin dessert, liquid candy, or syrup placed in
the mouth and partially swallowed before placing the solid dosage form
in the mouth aids in swallowing them.

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• To provide optimal drug action from topical administration sites

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

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

(rectal or vaginal suppositories)

• To provide for placement of drugs directly in the bloodstream or

body tissues (injections)

• To provide for optimal drug action through inhalation therapy

(inhalants and inhalation aerosols)

General Considerations in Dosage Form Design

• Before formulating a drug substance into a dosage form, the desired

product type must be determined insofar as possible to establish the
framework for product development.

• Then, various initial formulations of the product are developed and

examined for desired features (e.g., drug release profile,
bioavailability, clinical effectiveness) and for pilot plant studies and
production scale-up.

• The formulation that best meets the goals for the product is selected
to be its master formula. Each batch of product subsequently
prepared must meet the specifications established in the master
formula.

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• There are many different forms into which a medicinal agent may be
placed for the convenient and efficacious treatment of disease.

• Most commonly, a manufacturer prepares a drug substance in several

dosage forms and strengths for the efficacious and convenient
treatment of disease.

• Before a medicinal agent is formulated into one or more dosage

forms, among the factors considered are the physical and chemical
properties of the drug substance and various therapeutic
considerations.

• If the medication is intended for systemic use and oral administration

is desired, tablets and/or capsules are usually prepared because they
are easily handled by the patient and are most convenient in the self
administration of medication.

• If a drug substance has application in an emergency in which the

patient may be comatose or unable to take oral medication, an
injectable form of the medication may also be prepared.

• Many other examples of therapeutic situations affecting dosage form

design could be cited, including motion sickness, nausea, and
vomiting, for which tablets and skin patches are used for
prevention and suppositories and injections for treatment.

• The age of the intended patient also plays a role in dosage form
design. For infants and children younger than 5 years of age,
pharmaceutical liquids rather than solid forms are preferred for oral
administration.

• These liquids, which are flavored aqueous solutions, syrups, or

suspensions, are usually administered directly into the infant’s or
child’s mouth by drop, spoon, or oral dispenser (Fig. 4.2) or
incorporated into the child’s food.

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• The palatability of some commercial products may not be

acceptable to some patients so different flavoring additives may be
indicated to enhance compliance; an example would be the
FLAVORx flavoring system.

• A single liquid pediatric preparation may be used for infants and

children of all ages, with the dose of the drug varied by the volume
administered.

• When a young patient has a productive cough or is vomiting,

gagging, or simply rebellious, there may be some question as to how
much of the medicine administered is actually swallowed and how
much is expectorated. In such instances, injections may be required.
Infant-size rectal suppositories may also be employed, although
drug absorption from the rectum is often erratic.

• During childhood and even adulthood, a person may have difficulty

in swallowing solid dosage forms, especially uncoated tablets. For
this reason, some medications are formulated as chewable tablets.
Many of these tablets are comparable in texture to an after-dinner
mint and break down into a pleasant-tasting creamy material.

• Newly available tablets dissolve in the mouth in about 10 to 15

seconds; this allows the patient to take a tablet but actually swallow
a liquid.

• Capsules have been found by many to be more easily swallowed

than whole tablets. If a capsule is moistened in the mouth before it
is swallowed, it becomes slippery and readily slides down the throat
with water.

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• Also, if a person has difficulty in swallowing a capsule, the contents

may be emptied into a spoon, mixed with jam, honey, or other
similar food to mask the taste of the medication and swallowed.

• Medications intended for the elderly are commonly formulated into

oral liquids or may be prepared into an oral liquid by the pharmacist.

• In many patient-care facilities, as nursing homes, tablet-crushing

devices are utilized by the nursing staff preparatory to mixing with
food (as applesauce) for administration.

• However, certain tablets and capsules that are designed for

controlled release should not be crushed or chewed, because that
would interfere with their integrity and intended performance.

• Many patients, particularly the elderly, take multiple medications

daily. The more distinctive the size, shape, and color of solid
dosage forms, the easier is proper identification of the medications.
Errors in taking medications among the elderly occur frequently
because of their multiple drug therapy and impaired eyesight.

• Dosage forms that allow reduced frequency of administration

without sacrifice of efficiency are particularly advantageous.

• In dealing with the problem of formulating a drug substance into a

proper dosage form, research pharmacists employ knowledge
gained through experience with other chemically similar drugs and
through the proper use of the physical, chemical, biologic, and
pharmaceutical sciences.

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Preformulation studies

• Before the formulation of a drug substance into a dosage form, it is

essential that it be chemically and physically characterized.

• The following preformulation studies (1) and others provide the

type of information needed to define the nature of the drug
substance.

• This information provides the framework for the drug’s

combination with pharmaceutical ingredients in the fabrication of
a dosage form.

Physical Description

It is important to understand the physical description of a drug

substance prior to dosage form development.

Most drug substances in use today are solid materials, pure chemical
compounds of either crystalline or amorphous constitution.

The purity of the chemical substance is essential for its identification

and for evaluation of its chemical, physical, and biologic properties.

Physical properties include such characteristics as its physical

description, particle size, crystalline structure, melting point, and
solubility.

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Drugs can be used therapeutically as solids, liquids, and gases.

Liquid drugs are used to a much lesser extent than solid drugs, gases
even less frequently.

Liquid drugs pose an interesting problem in the design of dosage forms

and delivery systems. Many liquids are volatile and must be physically
sealed from the atmosphere to prevent evaporation loss.

Amyl nitrite, for example, is a clear yellowish liquid that is volatile

even at low temperatures and is also highly flammable. It is kept for
medicinal purposes in small sealed glass cylinders wrapped with gauze
or another suitable material. When amyl nitrite is administered, the
glass is broken between the fingertips, and the liquid wets the gauze
covering, producing vapors that are inhaled by the patient requiring
vasodilation.

Propylhexedrine is another volatile liquid that must be contained in a

closed system. This drug is used as a nasal inhalant for its
vasoconstrictor action. A cylindrical roll of fibrous material is
impregnated with propylhexedrine, and the saturated cylinder is placed
in a suitable, usually plastic, sealed nasal inhaler. The inhaler’s cap
must be securely tightened each time it is used.

Even then, the inhaler maintains its effectiveness for only a limited
time because of the volatility of the drug.

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• another problem associated with liquid drugs is that those intended

for oral administration cannot generally be formulated into tablet
form, the most popular form of oral medication, without chemical
modification.
• An exception to this is the liquid drug nitroglycerin, which is
formulated into sublingual tablets that disintegrate within seconds
after placement under the tongue. However, because the drug is
volatile, it has a tendency to escape from the tablets during storage,
and it is critical that the tablets be stored in a tightly sealed glass
container.

• When a liquid drug is to be administered orally and a solid dosage

form is desired, one of two approaches is used.

➢ First, the liquid substance may be sealed in a soft gelatin capsule.

Vitamins A, D, and E, and ergoloid mesylates are liquids
commercially available in capsule form.

➢ Second, the liquid drug may be developed into a solid ester or salt
form that will be suitable for tablets or drug capsules. For instance,
scopolamine hydrobromide is a solid salt of the liquid drug
scopolamine and is easily pressed into tablets.

➢ Another approach to formulate liquids into solids is by mixing the

drug with a solid or melted semisolid material, such as a high
molecular weight polyethylene glycol. The melted mixture is poured
into hard gelatin capsules to harden, and the capsules are sealed.

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• For certain liquid drugs, especially those taken orally in large doses
or applied topically, their liquid nature may have some advantage in
therapy.

• For example, 15-mL doses of mineral oil may be administered

conveniently as such.

• Also, the liquid nature of undecylenic acid certainly does not hinder
but rather enhances its use topically in the treatment of fungus
infections of the skin.

• Formulation and stability difficulties arise less frequently with solid

dosage forms than with liquid preparations, and for this reason,
many new drugs first reach the market as tablets or dry-filled
capsules.

Microscopic Examination

Microscopic examination of the raw drug substance is an important

step in preformulation work.

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.

During some processing procedures, the solid drug powders must flow
freely and not become entangled.

Spherical and oval powders flow more easily than needle-shaped

powders and make processing easier.

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Heat of Vaporization

• The use of vapor pressure is important in the operation of

implantable pumps delivering medications as well as in aerosol
dosage forms.

• Another application is the use of nasal inhalants (propylhexedrine

with menthol and lavender oil—Benzedrex) for treating nasal
congestion.

• Some volatile drugs can even migrate within a tablet dosage form
so the distribution may not be uniform any longer. This may have
an impact in tablets that are scored for dosing where the drug in
one portion may be higher or lower than in the other portion.

Exposure of personnel to hazardous drugs due to handling, spilling, or

aerosolizing of drugs that may vaporize (oncology agents) is another
application as the increase in mobility of the hazardous drug molecules
may be related to temperature of the environment.

Some drugs, such as carmustine, experience greater vapor pressures with

increased temperature as compared to cyclophosphamide, etoposide,
cisplatin, and 5-fluorouracil.

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Melting point

• 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.

Particle Size

particle size distribution may affect on:

• Dissolution rate
• Bioavailability
• Content uniformity
• Taste, texture, color
• stability
• Flow characteristics and sedimentation rates

• It is essential to establish as early as possible how the particle size

of the drug substance may affect formulation and efficacy. Of
special interest is the effect of particle size on absorption. Particle
size significantly influences the oral absorption profiles of certain
drugs, including griseofulvin, nitrofurantoin, spironolactone, and
procaine penicillin.

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Polymorphism

• An important factor on formulation is the crystal or amorphous form

of the drug substance.

• Polymorphic forms usually exhibit different physicochemical

properties, including melting point and solubility.

• Polymorphic forms in drugs are relatively common (30% of organic

compounds).

• Compounds may also occur in noncrystalline or amorphous forms.

• 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. Therefore, the amorphous form of a compound is always
more soluble than a corresponding crystal form.

• Various techniques are used to determine crystal properties. The

most widely used methods are hot stage microscopy, thermal
analysis, infrared spectroscopy, and x-ray diffraction.

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Solubility

• An important physicochemical property of a drug substance is

solubility, especially aqueous system solubility.

• A drug must possess some aqueous solubility for therapeutic

efficacy. For a drug to enter the systemic circulation and exert a
therapeutic effect, it must first be in solution.

• Relatively insoluble compounds often exhibit incomplete or erratic

absorption.

• 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. Chemical analysis of the drug content
in solution is performed to determine degree of solubility.

Dissolution

• dissolution rate is the time it takes for the drug to dissolve in the
fluids at the absorption site,

• In many instances, dissolution rate is the rate limiting step in

absorption.

• This is true for drugs administered orally in solid forms, such as

tablets, capsules, or suspensions, and for those administered
intramuscularly.

• 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.

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Other characterizations include:

• pH

• Partition coefficient

• Membrane permeability

• Solvate and hydrates

• pKa and dissociation constant

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