Mawlana Bhashani Science and Technology University

Santosh, Tangail-1902, Bangladesh

Department of pharmacy
ASSIGNMENt No - 01
Course code: PHAR-2205
Course title: Pharmaceutical Technology I
Assignment Name: Pre-formulation.

Submitted to: Submitted by:

Netish Kumar Kundo
Assistant Professor
Department of Pharmacy
Mawlana Bhashani Science
and Technology University
Submit Date: 23/08/2020
Sabbir Ahmed
Department: Pharmacy
Student ID: PHA-19021
Session: 2018-19
Year: 2nd Semester: 2nd

Date of Submission: 31/05/2021

 PREFORMULATION
Definition:

❖ Pre-formulation is the stage of development during which the

physicochemical properties of the drug substance are characterised and
established. Knowledge of the relevant physiochemical and
biopharmaceutical properties determines the appropriate formulation and
delivery method for Pre-Clinical and Phase 1 studies.

❖ Pre-formulation study is a phase which is initiated once the new molecule is

seeded. In a broader way, it deals with studies of physical, chemical,
analytical, and pharmaceutical properties related to molecule and provides
idea about suitable modification in molecule to show a better performance.

Goals of pre-formulation studies:

The objectives of pre-formulation studies are -
▪ To choose the correct form of drug substance
▪ To evaluate its physical properties
▪ To generate a thorough understanding of the material’s stability under
various conditions, leading to the optimal drug delivery system.
▪ To establish the physicochemical parameters of drug molecules for its
stability for any desired dosage form.
▪ Preparation of safe, effective, and stable form with better therapeutic
values.
▪ Pre-formulation studies on a new drug molecule provide useful information
for subsequent formulation of a physicochemically stable and
biopharmaceutically suitable dosage form.
▪ Pre-formulation work is the foundation of developing efficacious and
economical formulations.
 PRINCIPAL AREAS OF PRE-FORMULATION:

Principal areas

Physical-Chemical Solubility Analysis Stability Analysis

Bulk Characterization
Properties

Crystallinity & Ionisation constant pKa Stability in toxicology

Organoleptic Properties
polimorphism formulation
pH solubility profile Solution stability
Particle size & shape Hygroscopicity

Common ion effect (pH stability profile)

Particle size
Purity charactarization Solid state stability
Thermal effect
Bulk stability
Surface area Powder flow properties
Solubilization
Compatibility

Volatilization

Partition Co-efficient

Dissolution

Pre-formulation studies can be devided into-

1. Physical considerations
1. Organoleptic
2. Microscopic
3. Particle size and shape
4. PKa
5. Solubility
 6. Dissolution
7. Polymorphism
8. Physical form
9. Flow properties
2. Chemical considerations
1. Hydrolysis
2. Oxidation
3. Reduction
4. Racemization
5. Polymerization
6. Isomerisation
7. Photostability

Physical Considerations-
1. Physical form:-
Drug may exist in crystal or amorphous form.
▪ Crystal form:-
It is characterized by repeated arrangements of atoms in
three-dimensional array.
▪ Amorphous form:-
It has atoms or molecule randomly placed and does not
have any defined structure or molecular arrangement.
2. Polymorphism:-

When a substance exists in more than one crystalline form, the

various forms are called polymorphs and the phenomenon
polymorphism. It is the ability of a solid material to exist in more than
one form of crystal structure.
Polymorphs may divided in to two types-

▪ Enantiotropic: reversibly change into another form at varying in

temperature& pressure.

Example- acetazolamide, carbamazepine.

 ▪ Monotropic :- Unstable at all temperature & pressure.

Example-flufenamic acid.
3. Particle size:-
Particle size can influence variety of important factors: Dissolution
rate, Suspendability, uniform distribution, penetrability, lack of
grittiness. Particle diameter is also important consideration in the
pre-formulation studies.
4. Particle shape:-
Particles may exist in various shape. Like- spherical, ova, rod-shaped
etc. Particle shape also important consideration in pre-formulation
studies.
5. Solubility profile:-
In solubility profile following parameters are considered.
▪ Partition co-efficient:-
“It is the ratio of drug amount dissolved in oil phase to the drug amount
dissolved in aqueous phase”
Xo
Partition co-efficient (p) =
Xw
▪ pKa:- it is also called dissociation constant. This parameter gives
information about drug ionization at any physiological PH condition.

▪ pH:-it is the measurement unit of acidity or alkalinity of any chemical

compound.

Chemical considerations
1. Hydrolysis :-
It is the chemically breakdown reaction of any compound in the
presence of water.
2. Oxidation –Reduction reaction:-
 An oxidation –reduction (redox) reaction is a type of chemical
reaction that involves-
▪ Oxidation is the gain of oxygen.
▪ Reduction is the loss of oxygen
▪ Oxidation is the loss of hydrogen
▪ Reduction is the gain of hydrogen
▪ Oxidation is loss of electrons
▪ Reduction is gain of electrons.
3. Racemization;-

It is the formation of racemic mixture from any optically active

compound. Racemic mixture is the equimolar mixture of enantiomers
and it is optically inactive.
4. Polymerization:-
It is a continuous reaction between molecules , more than one
monomer reacts together to form a polymer.

Bulk Properties:
Bulk properties of the solid form such as crystallinity, polymorphism, particle size,
powder flow property, and surface characteristic are likely to change during
process development.
Crystalinity:
The crystal habit describes the outer appearance of crystals (platy, equant,
needle, bladed, etc.) and internal structure arrangement. Compounds have
several different habits, depending on the environment for growing crystals.
Hygroscopicity:
The tendency of a solid to take up water form the atmosphere, as it is subjected
to a controlled RH program under isothermal condition i.e. hygroscopicity.
Classified based on the amount of rate of water uptake when a solid is exposed to
controlled RH value at specified temperature.
Bulk characterization:
Bulk characterization of drug molecules involves the characterization of various
solid-state properties that could change during process development.
Microscopy:
Material with more than one refractive index are anisotropic and appear bright
with brilliant colors against black polarized background. The color intensity
depends upon crystal thickness. Isotropic material have single refractive index
and this substance do not transmit light with crossed polarizing filter and appear
black.

Different between amorphous solids and crystalline solids:

Amorphous Crystalline
Melt over a wide range of temperature Sharp melting point
Haven’t definite geometrical shape Characteristic geometrical shape
Physical properties are same in Physical properties are different in
different direction different direction
Unsymetrical Symetrical
Don’t brake at fixed cleavage plans Cleavage along particular direction

Solubility analysis
▪ The solubility of event new drug must be determined as a function of pH
over the physiological pH range of 1-8 .
Thermal analysis:

Differential scanning calorimetry (DSC) & Differential thermal analysis ( DTA) are
particularly useful in the investigation of polymorphism. It measures the heat loss
or gain resulting from physical or chemical changes within a sample as a function
of temperature.

Pre-formulation studies include-

▪ pKa determination
▪ pH solubility
▪ Temperature dependence
▪ Solubility products
▪ Solubilization mechanisms
▪ Rate of dissolution.

pKa DETERMINATION
pKa is the dissociation constant of a drug
The un-ionized drug is lipid soluble thus permeates through lipid membrane. It is
determined by uv spectroscopy, potentiometric titration etc.

It can be calculated by –

Henderson-Hasselbalch equation:
⁡[ionized]
For basic compounds- pH= pKa +
[unionized]

[unionized]
For acidic compounds- pH= pKa +
[ionized]
 DETERMINATION OF SOLUBILITY

Solvent (fixed volume)

Vigorously shaking

Examine visually

Undissolved solute
particles?

Yes No

Total amount added Adding solute in small

up incremental amount

Estimated solubility
 EFFECT OF TEMPERATURE:
▪ The solubility of a solute in a solvent is dependent on temperature, nature
of solute and nature of solvent.
▪ Heat of solution represents the heat released or absorbed when a mole of
solute is dissolved in a large quantity of solvent.
▪ Most of the substance are endothermic, absorbing heat in process of
dissolution.

pH Solubility Profile

Excess drug Stir in beaker Continuous

power with distilled stirring of
water suspension

Measure pH Add
Determine the
of suspension acid/base
concentration
of drug in the
filtrate

Solubility pH