PREFORMULATION

PREFORMULATION
Course Name: Pharmaceutical Technology-I
Course Code: Phrm 3125
 Preformulation

Definition:
•“It is the study of the physical and chemical properties of the drug prior to
compounding process”
• Investigation of physico-chemical properties of the new drug compound
that could affect the drug performance and the development of an
efficacious dosage form.
• Characterization of physical, chemical and mechanical properties of new
drug molecule in order to develop the elegant, stable, effective and safe
dosage form.
Objectives:

a) To develop the elegant dosage forms (stable, effective & safe)

b) It is important to have an understanding of the physical description of a
drug substance before dosage form development.
c) It is 1st step in rational development of a dosage form of a drug substance
before dosage form development.
d) It generates useful information to the formulator to design an optimum
drug delivery system.
Goals of Preformulation:

 To establish the physico-chemical parameters of new drug substance.

To establish the kinetic rate profile.
 To establish the compatibility with the common excipient.
 To choose the suitable dosage form for the drug substance.
 To formulate new dosage form of already existing drug.
 Preliminary evaluation and Molecular Optimization

• Once a pharmacologically active compounds has been identified, a project team

consisting of representatives from the disciplines has responsibility for assuring that
the compound enters the development process in its optimum molecular form.
• When the first quality sample of new drug becomes available, analytical
experiments should be conducted to determine the magnitude of each suspected
problem area.
• If a deficiency is detected the project team should decide on the molecular
modifications that would most likely improves the drug properties. Salts, prodrugs,
solvates, polymorphs or even new analogs may emerge from these modification
efforts.
• Among these modification, the salt and prodrug approaches are the most common.
Most salts of organic compounds are formed by the addition or removal of a
proton to form an ionized drug molecule, which is then neutralized with a counter
ion. For example: Ephedrine Hydrochloride is prepared by addition of a proton.
• Salt formation is limited to molecules with ionizable groups, prodrug may
be formed with any organic molecule having a chemically reactive
functional group.
• Through the formation of a prodrug, a variety of side chains or functional
groups may be added to improve the biologic and pharmaceutical properties
of a compound.
Erythromycin estolate is an example of prodrug with improved
pharmaceutical properties.
Figure: Flow diagram illustrating the multidisciplinary development of a drug candidate
 Major/ Principle Areas of Preformulation Research

Physico-Chemical Properties:

1. Bulk Characterization 2. Solubility Analysis 3. Stability Analysis

• Crystallinity and polymorphism • Ionization constant- pKa • Stability in formulations

• Hygroscopicity • pH solubility profile • Solution Stability

• Particle size • Common Ion Effect-Ksp • pH Rate Profile

• Bulk density • Thermal Effects • Solid State Stability

• Powder flow properties • Solubilization • Bulk Stability

• Partition Coefficient • Compatibility

• Dissolution
 Bulk Characterization

A drug candidate at this stage had not all of its solid forms identified, and there is a
great potential for new polymorphs to emerge. Bulk properties for the solid forms such
as particle size, bulk density and surface morphology are also likely to change during
process development.

i. Crystallinity:
• Generally most of drugs exist in solid state. Very few are in liquid state like
valproic acid and even less in gaseous form like some general anesthetics. A crystal
structure is a unique arrangement of atoms in a crystal.
• Physical properties affected by the solid-state properties can influence both the
choice of the delivery system and the activity of the drug, as determined by the rate
of delivery. Chemical stability, as affected by the physical properties, can be
significant.
• A crystalline particle is characterized by definite external and internal structures.
The crystal habit describes the outer appearance of crystals (platy, equant, needle,
blades, etc) whereas the polymorphic state refers to the definite arrangement of
molecules inside the crystal lattice.
Figure: Different habits of crystal
ii. Polymorphisms:

• Polymorphism is the ability of the compound to crystallize as more than

one distinct crystalline species with different internal structure.
• Formation of different polymorphs depends on solvents, temperature,
pressure, rate of cooling, etc.
• Polymorphic transition can also occur during milling, granulating, drying
and compressing operations.
• Different polymorphs vary in physical properties such as dissolution,
solid-state stability, compatibility, etc.
Polymorphs:
Polymorphs can be classified in two types:
a. Enantiotrophs: If one form stable over certain pressure and temperature
range, while the other polymorph is stable over different pressure and
temperature range. e. g., sulfur.
b. Monotrophs: only one polymorph is stable at all temperature below the
melting point, with all other polymorph being unstable.
For example: glyceryl stearate, chloramphenicol palmitate.
Transition temperature:

At a specified pressure, usually 1 atmosphere, the temperature at which two

polymorphs have identical free energies is the transition temperature, and at
that temperature, both forms can coexist and have identical solubilities in any
solvent as well as identical vapor pressure.
During preformulation, it is important to identify the polymorph that is stable at
room temperature and to determine whether polymorphic transitions are
possible within the temperature range used for stability studies and during
processing (drying, milling, etc.).
iii. Hygroscopicity:

• Hygroscopicity is the tendency of a solid substance to take up moisture

from the surrounding atmosphere.
• Adsorption and equilibrium moisture content can depend upon the
atmospheric humidity, temperature, surface area, exposure and
mechanism for moisture uptake.
Classified based on the amount of rate of water uptake when a solid is
exposed to controlled Relative Humidity value at a specified temperature.

a. Deliquescent : a substance which absorb sufficient moisture from the

atmosphere to dissolve itself at higher extreme. Example: sodium chloride.
b. Efflorescent: a substance which loses water to form a lower hydrate or
become anhydrous at lower level.
c. Hygroscopic : a substance that exist in a dynamic equilibrium with water.
iv. Particle size:

• Various chemical and physical properties of drug substances are affected by

their particle size distribution and shapes. The effect is not only on the
physical properties of solid drugs but also in some instances on their
biopharmaceutical behavior.
• Particle size and surface area of a solid drug are inversely related to each
other.
For example: the bioavailability of griseofulvin and phenacetin is directly
related to the particle size distributions of these drug.
v. Powder Flow
Pharmaceutical powders may be broadly classified as -
a. Free flowing
b. Cohesive (non free- flowing).

Most powder flow properties are significantly affected by-

 Changes in particle size,
 Density,
 Shape,
 Electrostatic charge, and
[[
 Adsorbed moisture, which may arise from processing or formulation.

As a result a free flowing drug candidate may become cohesive during

development, thus necessitating an entirely new formulation strategy.
Flow properties of powder can be determine by the parameters like angle of
repose, Hausner’s ratio, Carr’s index and compressibility of any powdered
sample. Flow properties based on density measurement.
Angle of Repose:
The maximum angle which is formed between the surface of pile of powder and
horizontal surface is called angle of repose.
Tan Ɵ = h/r
Where,
h = Height of heap of pile
r = radius of base of pile

Angle of Repose
 Relationship between angle of repose and flow properties:

Angle of repose Flow properties of powder

vi. Bulk Density
 Bulk density is of great importance when considering the size of high dose
capsule product or the homogeneity of a low dose formulation in which there
are large differences in drug and excipient densities.
 Bulk density of a compound varies substantially with the method of
crystallization, milling, or formulation. Once a density problem is identified, it
is often easily corrected by milling, or formulation.
Types of Density
1. True density: The true density or absolute density of a sample excludes the
volume of the pores and voids within the powder sample.
2. Bulk density: The bulk density value includes the volume of all of the pores
within the powder sample.
Bulk density:
It is obtained by measuring the volume of known mass of powder that passed
through the screen.
Bulk density = Mass
Volume
Tapped density: It is obtained by mechanically tapping the measuring cylinder
containing powder.
Carr’s index: A volume of powder is filled into a graduated glass cylinder and
repeatedly tapped for a known duration. The volume of powder after tapping is
measure. 

Carr’s index = Tapped density ─ Poured(Bulk) density × 100

Tapped density
vii. Thermal Analysis:
Differential Scanning Calorimetry (DSC) and Differential thermal analysis
(DTA) measure the heat loss or gain resulting from physical or chemical
changes within a sample as a function of temperature.
Example of endothermic (heat-absorbing) process are fusion, boiling,
sublimation, vaporization etc.
 Solubility Analysis

An important physical-chemical property of a drug substance is solubility,

especially aqueous solubility. A drug must possess some aqueous solubility for
therapeutic efficacy in the physiological pH range of 1 to 8. For a drug to enter
into systemic circulation, to exert therapeutic effect, it must be first in solution
form. If solubility of drug substance is less than desirable, than consideration
must be given to increase its solubility.
Preformulation solubility studies include-

i. pKa determination,
ii. Temperature dependence,
iii. pH solubility profile,

iv. Solubility products,

v. Solubilization mechanism
vi. Rate of dissolution
i. pKa determination (Dissociation constant):

• Determination of dissociation constant of a drug is important since solubility,

consequently absorption, can be changed by changing in pH.
• Many drugs are either weakly acidic or basic compounds and, in solution,
depending on the pH value, exist as ionized or un-ionized species.
• The un- ionized species is lipid-soluble thus dissolve in lipid material of the
membrane and hence more readily absorbed.
Whereas, The ionized species is lipid-insoluble therefore permeation is slow.
The factors that are important in the absorption of weakly acidic and basic
compounds are the pH at the site of absorption, the ionization constant, and
the lipid solubility of the un- ionized species.
The percentage of ionization can be calculated according to Henderson
Hasselbach equation-
For acidic compounds:
pH = pKa + log [ ionized drug]
[un-ionized drug]
For basic compounds:
pH = pKa + log [un-ionized drug]
[ ionized drug]
For weakly acidic drug with pKa value greater than 3, the unionized form is
present within the acidic contents of the stomach, but the drug is ionized
mainly in the neutral media of the intestine.
For basic drugs such as erythromycin and papaverine (pKa 8 to 9), the
ionized form is predominant in both the stomach and the intestine.
ii. pH Solubility Profile and common ion effect:
• The solubility of an acidic or basic drug depends on the pKa value of the
ionizing functional group and the intrinsic solubilities for both the ionized
and un-ionized form.
• The saturation solubility for such compounds (acidic or basic drug ) at particular
pH is the sum total of solubility of ionized and unionized forms .
• The common ion effect describes the effect on ​equilibrium that occurs when
a common ion (an ion that is already contained in the solution) is added to a
solution. The common ion effect generally decreases ​solubility of a solute.
iii. Effect of Temperature:
• The solubility of solute in a solvent is dependent on temperature, nature of
solute and nature of solvent.
• The heat of solution represents the heat released or absorbed when a mole of
solute is dissolve in a large quantity of solvent.
• Most of the substances are endothermic, absorbing heat in the process of
dissolution. For these substances, an increase in temperature results in
increase in solubility.
 Effect of temperature cont…

• Exothermic substances give off heat in the process of dissolution. The

solubility of such substances would decrease with increase in temperature.
• Care should be taken as heat may destroy a drug or cause other changes in
the solution e.g., on excess of heating the sucrose solution converted into the
invert sugar.
iv. Solubilization
For drug candidates, with either poor water solubility or insufficient solubility for
projected solution dosage form, preformulation study should include limited
experiments to identify possible mechanism for solubilization.

Methods for Increasing Solubility:

a) Change in pH e) Complexation
b) Co-Solvency f) Hydrotropy
c) Dielectric Constant g) Chemical Modification of drug
d) Solubilization by Surfactant
v. Partition Coefficient:

The partition coefficient is defined as the ratio of unionized drug distributed

between the organic and aqueous phase at equilibrium.

Measurement of a drug’s lipophilicity and an indication of its ability to cross cell

membrane is the oil/water partition coefficient in systems such as octanol/water
and chloroform/water.
vi. Dissolution:
In many instances, dissolution rate in the fluids at the absorption site, is the rate
limiting steps in the absorption process.
For example: drugs that are administered orally in the solid dosage forms such as
tablet, capsule, suspension and drug administered I.M. in form of pellets or
suspension.
The dissolution rate of a solid in its own solution is adequately described by the
Noyes-Nernst equation:
AD (Cs – C) Where,
dC / dt = --------------------
dC/dt = rate of dissolution
hv
A = surface area of the dissolving solid
D = diffusion coefficient
C= solute concentration in the bulk medium
h= diffusion layer thickness
V = volume of the dissolution medium
Cs = solute concentration in the diffusion layer
 Stability Analysis

• Preformulation stability studies are usually the first quantitative assessment of

chemical stability of a new drug. Factor effecting chemical stability critical in

rational dosage form design include temperature, pH and dosage form diluents.
• The method of sterilization of potential product will be largely dependent on the
temperature stability of the drug. Drugs having decreased stability at elevated
temperatures cannot be sterilized by autoclaving but must be sterilized by another
means, e.g., filtration.
• The effect of pH on drug stability is important in the development of oral drugs.
Oral dosage forms must be protected from the highly acidic environment of the
stomach.
i. Solid state stability:
• Chemical instability normally results from either of the following reaction
hydrolysis, oxidation, photolysis and pyrolysis. Chemical structure of the drug is
the determination of drug to either of these attacks.
• Esters and lactase and to lesser extent, amides are to prone to solvolysis,
instauration or electron rich center in the structure make the molecule vulnerable
for free radical mediated or photo-catalyzed oxidation, physical properties of
drugs. Amorphous materials are less stable than their crystalline forms. Denser
materials are more stable to ambient stress.
ii. Solution stability:
• As compared with the dry form, the degradation is much rapid in solution
form. It is important ascertain that the drug doesn’t degrade when exposed
to GI fluid.
• The pH based stability study, using different stimulator GI condition can be
designed.
• A poor solution stability of drug may urge the formulator to choose a less
soluble salt form, provided the bioavailability is not compromised.