DOSAGE FORM

ASSIGNMENT NO.3

Student Name. Nimra Ameen Student Reg.L1F19PHMD0138

Section. (C) Date. 2-1-2021

PRE-FORMULATION STUDIES

 Introduction
It is defined as the phase of research and development in which preformulation studies characterize physical
and chemical properties of a drug molecule in order to develop safe, effective and stable dosage form.

 Objectives
 To establish the physico-chemical parameters of a new drug entity
 To determine its kinetics and stability
 To establish its compatibility with common excipients
 It provides insights into how drug products should be processed and stored to ensure their quality.

Before the formulation of a drug substance into a dosage form, it is essential for it to be chemically and
physically characterized.

The following pre-formulation studies are carried out to define the nature of the drug substance.

1. Physical description
2. Microscopic Examination
3. Partition coefficient
4. Particle size
5. Polymorphism
6. Solubility
7. Dissolution
8. Membrane permeability
9. Drug Stability
 10. Other official tests

 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.

 Chemical properties include structure, form, and reactivity.

 Physical properties include such characteristics as its physical description, particle size,
crystalline structure, melting point, and solubility.
 Biologic properties relate to its ability to get to a site of action and elicit a biologic response.

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:
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
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.

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.

For the most part, when a liquid drug is to be administered orally and a solid dosage form is desired, one of
two approaches is used.

 First approach:
The liquid substance may be sealed in a soft gelatin capsule. Liquids commercially available in capsule
form:

 Vitamins A, D, and E
 Cyclosporin (Neoral, Sandimmune)
 Ergoloid mesylates (Hydergine LC)

 Second approach:
The liquid drug may be developed into a solid ester or salt form that will be suitable for tablets or drug
capsules. For instance, scopol- amine hydrobromide is a solid salt of the liquid drug scopolamine and is
easily pressed into tablets.
However, for the most part, pharmacists prefer solid materials in formulation work because they can easily
form them into tablets and capsules. 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.

Later, when the pharmaceutical problems are resolved, a liquid form of the same drug may be marketed.

 Microscopic Examination
o Microscopic examination of the raw drug substance is an important step in preformulation work.
o It gives an indication of particle size and size range of the raw material along with the crystal
structure.
Photomicrographs:
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.
o 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.
 Particle Size
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. In
addition, flow characteristics and sedimentation rates, among other properties, are important factors related
to particle size.

It is essential to establish as early as possible how the particle size of the drug substance may affect
formulation and efficacy.

Effect of particle size on absorption:

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
 Procaine penicillin
Also, satisfactory 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.

Mastersizer 2000E particle size analyzer

  Polymorphism
It is the ability of the compound to crystallize as more than one distinct crystalline species with different
internal lattice. Different crystalline forms are called polymorphs.
Polymorphs are of 2 types
 Enatiotropic
 Monotropic
Polymorphs differ from each other with respect to their physical property such as
 Solubility
 Melting point
 Density
 Hardness
 Compression characteristic
Chloromphenicol: It exist in A, B & C forms, of these B form is more stable & most preferable.
In addition to polymorphic forms, compounds may 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.

ANALYTICAL METHODS FOR THE CHARACTERIZATION OF SOLID FORMS:

1) Microscopy
2) Hot stage microscopy
3) Thermal analysis
4) X-ray diffraction
5) Infrared (IR) spectroscopy
6) Proton magnetic resonance (PMR)
7) Nuclear magnetic resonance (NMR)
8) Scanning electron microscopy (SEM)

 Solubility
o 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.
 o If the solubility of the drug substance is less than desirable, consideration must be given to improve
its solubility. The methods to accomplish this depend on the chemical nature of the drug and the type
of drug product under consideration.
o Chemical modification of the drug into salt or ester forms is frequently used to increase solubility.
o 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.
 Membrane Permeability
Modern preformulation studies include an early assessment of passage of drug molecules across biologic
membranes. To produce a biologic response, the drug molecule must first cross a biologic membrane. The
biologic membrane acts as a lipid barrier to most drugs and permits the absorption of lipid-soluble
substances by passive diffusion, while lipid-insoluble substances can diffuse across the barrier only with
considerable difficulty if at all.

pH partition theory:
The interrelationship of the dissociation constant, lipid solubility, and pH at the absorption site with the
absorption characteristics of various drugs are the basis of the pH partition theory.

Basic physicochemical studies:

Data obtained from the basic physicochemical studies, specifically, pKa, solubility, and dissolution rate,
provide an indication of absorption. To enhance these data, a technique using the everted intestinal sac may
be used to evaluate absorption characteristics of drug substances.

In this method, a piece of intestine is removed from an intact animal, is everted, and is filled with a solution
of the drug substance, and the degree and rate of passage of the drug through the membrane sac are
determined. This method allows evaluation of both passive and active transport. In the latter stages of
preformulation testing or early formulation studies, animals and humans must be studied to assess the
absorption efficiency and pharmacokinetic parameters and to establish possible in vitro and in vivo
correlation for dissolution and bioavailability.

 Dissolution
Release of drug from a dosage form involves diverse factors as:
A drug is expected to be release from the solid dosage forms (granules, tablets, capsules etc.) & immediately
go into molecular solution. This process is called dissolution.
Dissolution (molecular dispersion) is a prerequisite for the drug absorption.
Dissolution is of 2 types.
1) Intrinsic dissolution
2) Particulate dissolution
Dissolution is expressed in terms of a rate process.
Greater the rate, faster the dissolution.
Dissolution rate may be defined as
“The amount of drug substance that goes into solution per unit time under standardized
conditions of liquid/solid interface, temperature & solvent composition”
Noyes-Whitney’s equation is useful for estimating the rate of dissolution.
  Partition Coefficient
Inherent in this procedure is the selection of appropriate extraction solvents, drug stability, use of salting-out
additives, and environmental concerns. The octanol–water partition coefficient is commonly used in
formulation development. Following the illustrations provided earlier, it is defined as:

P depends on the drug concentration only if the drug molecules have a tendency to associate in solution. For
an ionizable drug, the following equation is applicable:

Where α equals the degree of ionization.

 DRUG AND DRUG PRODUCT STABILITY

One of the most important activities of preformulation work is evaluation of the physical and chemical
stability of the pure drug substance. It is essential that these initial studies be conducted using drug samples
of known purity. The presence of impurities can lead to erroneous conclusions in such evaluations.

Stability studies conducted in the preformulation phase include

 Solid-state stability of the drug alone

 Solution phase stability
 Stability in the presence of expected excipients

Initial investigation begins with knowledge of the drug’s chemical structure, which allows the
preformulation scientist to anticipate the possible degradation reactions.

Drug and Drug Product Stability: Kinetics and Shelf Life

Stability is the extent to which a product retains within specified limits and throughout its period of storage
and use (i.e., its shelf life) the same properties and characteristics that it possessed at the time of its
manufacture.

Five types of stability concern pharmacists:

1) Chemical:
Each active ingredient retains its chemical integrity and labeled potency within the specified limits.
1) Physical:
The original physical properties, including appearance, palatability, uniformity, dissolution, and
suspendability are retained.
2) Microbiologic:
Sterility or resistance to microbial growth is retained according to the specified requirements.
Antimicrobial agents retain effectiveness within specified limits.
3) Therapeutic:
The therapeutic effect remains unchanged.
4) Toxicologic:
No significant increase in toxicity occurs.