''Preformulation Studies'' || Industrial Pharmacy _1

This document provides a information about introduction to preformulation, goals and objectives, study of physiochemical characteristics of drug substances are abstracted.

1. Presented by: Hina Tousif
Presented by: Hina tousif

2. CONTENTS
.
•Introduction to preformulation
.
•Goals and objectives
•
.
•Study of physicochemical
characteristics of drug substances
•

3. Introduction

❖ Preformulation is defined as the phase
of research and development. It also
studies characterize physical and
chemical properties of a drug molecule
in order to develop safe, and stable
dosage form.

4. OBJECTIVES
➢ To generate useful data needed in
developing stable and safe dosage
forms.
➢ It also shortness the time of drug
development process.
➢ To improved bioavailability and
targeted delivery.

5. Goals of preformulation
To establish the physicochemical
parameters of a candidate drug molecule.
To determine the kinetic rate profile of drug
substances.
To establish the compartibility of a
candidate drug molecule with common
excipients.

6. PHYSICO-CHEMICAL PROPERTIES OF DRUG
 Definition:
Physicochemical properties of drugs are the
chemical and physical properties that combine to form the
characteristics of a drug molecule.
1)Physical Properties:
➢Physical properties of drug is responsible for its action.

2)Chemical Properties:
➢ The drug react extracellularly according to simple
chemical reactions like neutralization, chelation, oxidation
etc.

7. Various physico-chemical properties
a).Physical properties of drug substances;
▪ Physical form (crystal & amorphous)
▪ Particle size
▪ Shape
▪ Flow properties
▪ Solubility profile(pKa, pH, partition coefficient)
▪ Polymorphism
b).Chemical properties of drug substances;
▪ Hydrolysis
▪ Oxidation
▪ Reduction
▪ Racemisation
▪ Polymerization

8. a).Physical properties of drug substances
Physical form(crystal & amorphus):
❖Crystal (or) solid form are preffered for the
formulation, because they can be easily converted
into tablet and capsule.
❖While in amorphous form atoms (or) molecules are
randomly placed as in the liquid, they do not have
any fixed internal structure.
❖ Solubility & dissolution rate are randomly placed as
amorphous form than crystalline. Because
amorphous form has higher “thermodynamics
energy”.

9. Crystalline
➢Crystals are made up of atoms (or) ions that are
arranged in a repeating, three – dimensional pattern
called a space lattice.
Eg: cubic, tetragonal .
➢ Crystalline has a greater affect on absorption of
drugs.
➢ Crystals can have many types of bonds, including
metallic, covalence, and ionic bonds.
➢ Crystals can be cleaved along a definite plane,
resulting in clean cleavage.

10. Amorphous
➢ Amorphous solids are made up of atoms &
molecules that are not organized in a definite lattice
pattern.
Eg: Glasses, plastics, and polymers.
➢ Amorphous forms are less stable than its crystalline
state.
➢ The solubility of amorphous form is greater than its
crystalline state.
➢ Upon storage, amorphous solids tend to revert to
more stable forms.

11. Particle size
➢ Particle size represents the dimensions of solid
powders, liquid particles, and gases bubbles.
➢ Particle size generally denoted in “micrometers”.
➢ Particle size mainly influence dissolution rate.
➢ Absortption rate of poorly soluble drug can be
improved by reducing the particle size and thus
enhances the bioavailability of drugs.
➢ Particle size affects drug release from dosage
forms, drug absorption, therapeutic action etc,.

12. Particle shape
➢ Apart from particle shape plays an important role
during preformulation phase, as the shape of
particle may influence surface area, flow
properties, and compaction force.
➢ It also influences rate of dissolution of drugs.
➢ A drug particle may exist in different forms like
spherical, angular, acicular , oval, (or) rough.

13. Flow properties
Flow property can be affected by a
number of factors particle– changes in particle size,
shape, surface area, density, frictional forces, and van
der waals forces etc.
➢Efficient flow of particles is needed for an effective
formulation.
➢ Flow property is determined by bulk density, angle of
repose, hausner ratio and shear cell testing.

14. Solubility profile
➢ Solubility profile is essential for the successful
development of pharmaceutical formulations,
impacting drug delivery, efficacy, and safety.
➢Solubility Analysis includes:-
.pKa determination
.pH solubility profile
.Partition Coefficient

15. pKa determination
➢ pKa determination at the preformulation stage is
important because,
Based on the pKa value, particular pH can
be selected to obtain optimum solubility and suitable salt
form to get improved bioavailability, permeability, drug
interaction,and stability.
➢ Methods of pKa determination:
1.Potentiometric Titration
2.UV-Spectroscopy
3.Conductometric Titration

16. pH solubility profile
➢ pH is the negative logarithm of H
+
ion.
➢ Solubility of many compounds depend strongly on
the pH of the solution.
➢ Changing the pH, can make a difference in the
solubility of the acidic or basic drugs.
➢ The preferred pH range for evaluation is 1-14, but
1-8 is adequate and provides insight into
gastrointestinal behaviour.

17. Partition Coefficient
➢ A partition coefficient is a ratio that compares the
concentrations of a compound into two immiscible
solvents at equilibrium. Its also known as a
distribution coefficient.
➢Partition coefficient=(conc. Of drug in organic
phase) / (conc. Of drug in aqeous phase).
➢ Log P, is a key measurment that indicates a drug`s
lipophilicity and ability to cross cell membranes.
➢Estimates the distribution of drugs in the body.

18. Partition Coefficient
continuation;
➢ Hydrophobic drugs are found in the hydrophobic
areas such as lipid bilayers of the cells.
➢ Hydrophillic drugs are found in the hydrophillic areas
such as blood serum.
➢ Determined experimentally by shake flask method
and high performance liquid chromatography.

19. Polymorphism
➢ When a substance exists in more than one crystalline form – the
different forms are designated as polymorphs and the phenomenon
is known as polymorphism.
➢ Polymorphs are two types: Enantiotropic and Monotropic
polymorphs.
➢ The polymorph which can be changed from one form into another by
varying temp or pressure is called as “Enantiotropic polymorph”.
E.g: Sulphur.
➢ One polymorph which is unstable at all temp, & pressure is called as
“Monotropic polymorph”.
E.g:Glyceryl stearate.
➢ Polymorphism influences drug efficacy, bioavailability and toxicity.
➢ Determined by X-Ray diffraction , Differential scanning calorimetry
methods.

20. b). Chemical properties of drug substances
1.Hydrolysis
Hydrolysis means the reaction of a drug molecule
with water resulting in the cleavage of chemical bond , this
leads to degradation of substance. Esters , amides, lactums
are most prone to hydrolysis.
 Acid based hydrolysis
 Base based hydrolysis
Water can act as both acid and base.
➢Examples of drugs that undergo hydrolysis- Aspirin,
pencillin, diamorphine, etc.

21. 2).Oxidation
➢ It is a very common pathway for drug degradation in
liqiud & solid formulation.
E.g:Codeine, Dopamine.
➢ Oxidation is gain of oxygen and loss of electrons.
➢ Oxidation occurs in two ways:-
1.Auto oxidation
2.Free radical chain process.
The prevention of oxidative
degradation can be controlled by addition of
antioxidants, metals, peroxides or scavengers.

22. 3).Reduction
➢ Reduction is a relatively more common pathway of
drugs metabolic process.
➢ Reduction –Gain of electrons.
➢Hepatic microsomes catalyze diverse reduction use of
NADPH.
➢ Cytochrome P450 catalyze the azo & nitro reduction
reaction.
➢ Prednisolone & cortisone reduces to hydrocortisone.

23. 4).RACEMISATION
A process of “conversion of optically active
compound into an optically inactive compound”.
➢ Rate of racemisation depends on the presence of
catalytic hydrogen, hydroxyl ion, heat, light ,
temperature and solvent.
➢ Interconversion can alter the pharmacokinetic properties,
pharmacological and toxological properties.
➢ This convertion can make the drug inert or dangerous.
E.g: l –form of epinephrine is 15-20 times
active than the d-form.

24. 5).Polymerisation
➢ It is defined as a process in which simple monomer molecules
combined to form large complex.

➢ It is a continous reaction between molecules.
➢ Polymerisation can be of mainly two types:-
1.Addictive polymerisation
2.Condensation polymerisation
➢ Formaldehyde solution on standing, leads to formation of white
deposit.
E.g:Glucose solution darkness due to
polymerisation.

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