PREFORMULATION STUDY:

FOR SOLIDS

Presented By:Mr. BHANDARI UMESH M.

1st yr M - Pharm.
Department of Pharmaceutics.
RCPIPER, SHIPUR
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CONTENTS

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INTRODUCTION
OBJECTIVES
PREFORMULATION STUDIES
PHYSICOCHEMICAL
CHARACTERISATIONS
ANALYTICAL MEASURES
CONCLUSION
REFERENCES
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INTRODUCTION

Preformulation testing is the first step in the rational development of dosage forms.

If an organic compound shows sufficient desirable pharmacological activity, next step is

to incorporate the compound in dosage form.

Preformulation may be defined as phase of research and development where the

preformulation scientific charecterises the physical, chemical , mechanical and
medicinal properties of a new drug subject to in order to develop ,safer , and effective
dosage
form.
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OBJECTIVES
To develop the most stable , safe and effective dosage form
with maximum bioavailability.
To confirms absence of barrier for the development of
compound into safe and marketable drug
To study the physicochemical characterization of drug
To select the most suitable excipients.
Establish its compatibility with common excipients
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WHY PREFORMULATION IS IMPORTANT ?

It describes the process of optimizing the delivery of drug

thorough determination of physical, chemical properties of new
drug molecule that affect drug performance and development of
an efficacious stable and safe dosage form.
Preformulation studies on a new drug molecule provide useful
information for subsequent formulation of a physicochemically
stable and Biopharmaceutically suitable dosage form.

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PHYSICOCHEMICAL PROPERTIES
1. BULK CHARACTERIZATION :
Bulk properties of the solid form such as
crystallinity, polymorphism, particle size, powder flow
property, and surface characteristics are likely to
change during process development.
Crystallinity
The crystal habit and internal structure of drug can
affect the bulk and physicochemical properties, but
sometime same internal structure but different habit.
Compounds have several different habits ( platy,
equant, needle, bladed, and prismic etc.)
eg. Novobiosin (antibiotic)
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POLYMORPHISM
When a substance exist in more than one crystaline
species with a different internal structure thus various
forms called as polymorphism
Formation of different polymorphs depends on
solvents, temperature, pressure, rate of cooling, etc.
Polymorphic transitions can also occur during milling,
granulating, drying and compressing operations
Two types of polymer
Enantiotropic eg. Sulphur
Monotropic
eg. Glyceryl sterate
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Pseudopolymorphism

The molecular complex is incorporated in

crystallizing solvents molecules, at specific site
with in crystaline lattice and has steriometric
number of solvent molecule complex

Two types
Hydrates incorporated solvent is water
Solvates incorporated solvent other than water

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Particle size
Study of particle size give an information about
solubility, dissolution rate, absorption etc.
Smaller the particle size and greater surface area
and faster the dissolution rate better will be the
absorption rate and get higher bioavability of drug
eg.
1. Hydrophilic drug : Griseofulvin and
spironolactone
2. Hydrophobic drug : Aspirin

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Powder flow property

The flow properties of a powder will determine
the nature and quantity of excipients needed to
prepare a compressed or a powder dosage
form.
Most flow property significantly affected by
change in partical size, density, shape ,
electrostatic charge and adsorbed moisture.
Flow property of powder is not good then
weight variation hardness and thickness
variation occur
Method for measurement of flow property
Angle of repose
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Bulk density

ANGLE OF REPOSE
Angle of repose of the granules was determined by the
height cone method.
A funnel was fixed to a desired height and granules
were filled in it. They were allowed to flow down on a
graph paper fixed on a horizontal surface
Angle of repose
<20
20-30
30-34
>40

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Flow property
Excellent
Good
Passable
Very poor

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Bulk density
A. Carrs Index :
Carrs index = ( tapped density poured
density)
poured density

X 100

B. Hausners Ratio :

Hausners Ratio =
density

tapped

X 100

poured density

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HYGROSCOPICITY
Many pharmaceutical materials have the
tendency to adsorb atmospheric moisture
(specially water soluble salt ) they called as
hygroscopic and this phenomenon know as
hygroscopicity
Hygroscopicity determine by

Thermo gravimetric analysis

Gas chromatography
Karl Fischer titration
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SOLUBILITY ANALYSIS
1. INTRINSIC SOLUBILITY
It is equilibrium solubility of the free acids or
free bases form of an ionisable compound at a pH
where it fully unionised
Orally administered drug must dissolve in the
aqueous fluid of the GIT prior to absorption.
Solubility can be improved by addition of
cosolvents.
It can be determine by adding excess amount of
drug to fixed volume of a solvent till saturation ,14
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2. Drug pKa / Ionization at

physiological pH
pKa is the dissociation constant of a drug.
The nonionized substances is lipid soluble thus
dissolve in lipid material of the membrane and
transported by passive diffusion.
Where as, the ionized substances is a lipid insoluble
therefore permeation is slow.

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The percentage of ionization can be calculated

by Henderson Hasselbalch equation
For Acidic compounds:
pH = pKa + log(ionized
drug/unionized drug)

For Basic compounds:

pH = pKa + log(unionized drug/ionized

drug)

Degree of ionization depends up on the pH.

for acidic drugs pKa ranges from 3-7.5.
for basic drugs pKa ranges from 7-11.
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3. PARTITION COEFFICIENT
Partition coefficient is a ratio of equilibrium
concentration of drug in oil phase to
equilibrium concentration of drug in aqueous
phase .
K=Co/Cw
where,
Co-organic phase concentration
Cw-aqueous phase concentration
It useful for the measuring liphophilic

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 various organic solvents used

Eg. n- octanol
Chloroform
Ether etc.

4. SOLUBILITY ENHANCEMENT
solubility of poorly water soluble
drug can be enhanced by one of the following
method.

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Co-solvency
eg. Ethanol, PEG, glycerin
Solubilisation eg. Tween, SLS

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5. DISSOLUTION
To know the gastrointestinal absorption & other
physicochemical properties.
The intrinsic dissolution rate is determined by the rotating disc
method.
The dissolution rate is described by Noyes-Whiteny equation.
dc
dt =

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DA
(Csh C)

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STABILITY ANALYSIS
DRUG STABILITY
In this study includes both solutions and solid-state
experiments under various conditions for handling,
formulation, storage, and in vivo administration.
Stability is important part of drug development
program
Acid sensitive drugs protected from highly acidic
environment of the stomach by coating it with
suitable polymers.
Solid phase stability depends on several factors
like temperature, pH, humidity, hydrolysis, oxidation,
etc
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COMPATIBILITY
Compatibility test play a very important role
in the preformulation studies of oral dosage
forms.
Problems arise because of the interaction
with other drug substances and with
preservatives, stabilizers, dyes, and flavors.
It is important for the formulator of a new
drug substance to know with which excipients
he can work and which he cannot.
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DRUG- EXCIPIENT COMPATIBILITY STUDY

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ANALYTICAL MEASURES
Various analytical techniques are available for
the
investigation of the physicochemical properties
and determination of impurity of new drug
molecules.
These includes:
1. Microscopy
2. Spectroscopy
3. Chromatography
4. Thermal method
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A. MICROSCOPY
In this technique substances are examined
under the microscope. It gives information
about shape, thickness, particle size, etc. of
drug molecules.
By this method we can study crystal
morphology, difference between polymorphic
character of molecule.
Following microscopic tech
Electron microscope
Optical microscope
SEM
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TEM

B. SPECTROSCOPY
1.UV and Visible Spectrophotometry
When organic molecules in solution, or as liquid,
are
exposed to light in the visible and ultraviolet light
regions of spectrum, they absorb light of particular
wavelengths depending on the type of electronic
transition that is associated with the absorption.
The electronic transitions depends on the electron
bonding with in the molecule.
Detection of impurity.
UV study of compounds gives information
regarding unsaturation of compounds.
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2. IR Spectroscopy
The study of the interaction of electromagnetic
radiation with vibrational and rotational resonances
within a molecular structure is termed as IR
Spectroscopy.
Gives an information regarding functional group
present in new drug molecule.
FT-IR use for both qualitative and quantitative
analysis of sample.
IR has the ability to differentiate isomers groups such
as Cis-trans double bond compound.
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3. X-RAY DIFFRACTION
When a beam of non homogenous x-rays is allowed to pass through a
sample the x-ray beam is diffracted & it is recorded by means of
photographic plates .
Single Crystal X-ray provides the most complete information about the
solid state.
It is used to differentiate the amophous and crystalline forms.
This method is tedious, time consuming & hence unsuitable for routine
use.

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C. CHROMATOGRAPHY
In the preformulation studies,
chromatographic techniques such as
TLC
HPTLC
HPLC
GC
FLASH CHROMATOGRAPH
The major advantages are direct analysis of
aqueous samples, high sensitivity, and
specific determination of drug
concentration, separation of drug from
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impurities or degradation products.
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Analytical data from TLC may be required

to precisely determine the kinetics of
decomposition.
HPLC and GC are useful for solubility
measurements.
GC has strong separation power.

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D. THERMAL ANALYSIS
In the preformulation studies, Thermal analysis
techniques such AS
DTA
DSC
TGA
These following method are particularly useful
in preformulation studies including purity,
polymorphism, solvation, degradation, and
excipient compatibility.
It measures physical or chemical changes of
drug molecule
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CONCLUSION
Preformulation studies on a new drug molecule
provide useful information for subsequent formulation
of a Physicochemically stable and
Biopharmaceutically suitable dosage form.
Thorough Preformulation work is the foundation of
developing effective and economical formulations.

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REFERENCES
1)

Leon Lachman, Herbert A.L, The theory and practice

of industrial pharmacy, special Indian edition 2009:
CBS publishers and distributors. Pg no.. 171- 196

2)

Banker GS, Rhodes CT., Modern pharmaceutics, 4th

ed. New York: Marcel Dekker; 2002. p.167-184

3)

Alfred Martin., Physical pharmacy. 4th ed. New York:

Lippincott Williams & Wilkins; 2001. p. 77-100

4)

Michael E. Aulton, Aultons pharmaceutics, 3rd ed

Elsevier Ltd 2007, page no. 336-370
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5) D.A. Skoog, F.J Holler, S.R. Crouch, Instrumental

analysis Indian edition New Delhi, 2011, page
no.191,836,865-867,893-896,976-988
6) A.H. Nathani, Ready retrive, Pharmaceutical
formulation, 1st ed Carrier publication Nashik,
page no. 1-22
7) Chatwal G.R, Anand S.K, Instrumental method of
chemical analysis, 5th ed Himalaya publication,
Mumbai 2013, page no. 2.177,

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Email. : umesh.m.b143@gmail.com

Thank you
Thank you
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