PREFORMULATION

RAGHUL H
B PHARMACY 2014-2018
NANDHA COLLEGE OF PHARMACY
ERODE
 PREFORMULATION

• Preformulation is the study of the physical and

chemical properties of the drug prior to the
compounding process.
 GOALS OF PREFORMULATION STUDIES

• To establish the physico-chemical parameters of

a new drug
• To determine its kinetics and stability.
• To establish its compatiblity with common
excipients.
PRINCIPLE AREAS OF
PREFORMULATION RESEARCH
I. Solubility Studies
• pKa determinations
• pH solubility profile
• Common ion effect
• Solubilisation
• Partition Coefficient
• Dissolution
PRINCIPLE AREAS OF
PREFORMULATION RESEARCH
II. Bulk characterization
• Crystallinity and Polymorphism
• Hygroscopicity
• Micromeritic Properties
• Particle Characterization
• Density and Porosity
• Powder flow properties
PRINCIPLE AREAS OF
PREFORMULATION RESEARCH
III. Stability Analysis
• Solution Stability
• Solid State Stability
• Drug-Excipient Compatibility
SOLUBILITY STUDIES
 pKa Determination
• Determination of the dissociation
constant for a drug capable of ionization
within a pH range of 1-10 is important
since solubility and consequently
absorption can be altered by orders of
magnitude with changing pH.
 Henderson Hasselbalch equation
• This provides an estimation of the ionized
and unionized drug concentration at a
particular pH.
• For basic compounds,
pH=pKb+log (Ionized drug\Unionized
drug)
• For acidic compounds,
pH=pKa+log(Unionized drug\Ionized
drug)
Methods for the determination of
pKa
1. Potentiometric titration.
2. UV spectroscopy.
3. Solubility measurement.
4. HPLC techniques.
5. Capillary zone electrophoresis.
6. Foaming activity.
 pH solubility profile
• The solubility of an acidic or basic drug
depends on the pKa of the ionizing
functional group and the intrinsic solubilities
for both the ionized and unionized forms
 COMMON ION EFFECT
• Common ion effect is the decrease in the
degree of dissociation of the salt by
addition of common ion.
 PARTITION COEFFICIENT
• A measurement of a drug’s lipophilicity and
an indication of its ability to cross cell
membranes is the oil/water partition
coefficient.
• logP is the ratio of unionized drug
distributed between the organic and
aqueous phase at equilibrium.
 PARTITION COEFFICIENT
• Po/w=(Coil/Cwater)equilibrium
• If the compound has a
• Log P= 0 equally soluble in water and in the
partitioning solvent.
• Log P= -2 it is 100 times more soluble in
water
• Log P= 5,it is 1,00,000 times more soluble in
partitioning solvent.
PARTITION COEFFICIENT
SHAKE FLASK METHOD
 PARTITION COEFFICIENT
• The drug is likely to have poor permeablity
or poor oral absorption if a drug exceeds
two or more of the following limits:
• Lop P is greater than 5
• The molecular weight is greater than 500
• There are more than 5 hydrogen bond
donors
• There are more than 10 hydrogen bond
acceptors
SOLUBILIZATION
• The solubility of the drug is increased by the
addition of the cosolvent to the aqueous
system.
• The solubility of the poorly soluble non
electrolyte can be improved by using cosolvents
such as ethanol, propylene glycol, and glycerin.
• By disrupting the hydrophobic interactions of
water at the non polar solute\water
interaction.
• Solubilisation due to the addition of cosolvent
is depends on the chemical structure of the
drug.
 DISSOLUTION
• Dissolution of the drug particle is
controlled by several physicochemical
properties including
 Chemical form
 Crystal habit
 Particle size
 Solubility
 Surface area
 Wetting Property
DISSOLUTION TEST APPARATUS
DISSOLUTION TEST APPARATUS
PADDLE TYPE
BULK CHARACTERIZATION
 CRYSTALLINITY
• Crystal habit and the internal structure of a
drug can affect bulk and physicochemical
properties. which range from flowability to
the drug stability.
• Characterization of a solid form involves:
 Verifying the solid is the expected chemical
compound.
 Characterizing the internal structure.
 Describing the habit of the crystal.
POLYMORPHISM
• Polymorphism is the ability of a compound
to crystallize as more than one crystalline
form with different internal lattices.
• Chemical stability and solubility changes
due to the polymorphism can have an
impact on a drug’s bioavailability and its
development program.
• These are of two types:
1. Enantiotropic.
2. Monotropic.
HYGROSCOPICITY
 MICROMERITIC PROPERTIES
• Particle characterization
• Density
• Porosity
• Powder flow properties
 DENSITY

• Density is derived from the information on particle

size distribution, particle shape, and surface area.
• Density is defined as the ratio of the mass to its
volume
HELIUM PYCNOMETER
Porosity
• The porosity or voids E, of the
powder is
Porosity or voids = void volume
bulk volume
 POWDER FLOW PROPERTIES
Angle of repose
 ANGLE OF REPOSE
FIXED FUNNEL METHOD FIXED CONE METHOD
 FLOW PROPERTIES

Carr’s index
STABILITY ANALYSIS
STABILITY ANALYSIS
• Solution stability
• Solid stability
• Drug excipient compatibility
 STABILITY ANALYSIS

SOLUTION STABILITY
1. Hydrolysis
2. Oxidation
3. Photolysis
4. Recemization
 HYDROLYSIS

Many pharmaceuticals contain ester or amide

functional group, which undergo hydrolysis in
solution
Ex: anaesthetic, antibiotics, vitamins and
barbiturates.
1) Ester hydrolysis cleaved to produce acid and alcohol.
2) Amide hydrolysis cleaved to produce acid and amine.
 OXIDATION

• The most common form of oxidative decomposition

occuring in pharmaceutical preparation is
autooxidation
• Reaction of any molecule with the molecular oxygen.
• Free radicals are produced by reaction of homolytic
bond fission of a covalent bond.
 PHOTOLYSIS

• Decomposition of the pharmaceutical compounds

resulting from the absorption of radiant energy in the
form of light.
• Oxidative reduction, ring rearrangement,
polymerisation occurs
 RECEMISATION

• Optical active substance losses its optical activity.

DRUG EXCIPIENT COMPATIBILITY
An incompatibility in the dosage form can
result in any of the following changes:
1. Changes in organoleptic properties.
2. Changes in dissolution performance
3. Physical form conversion.
4. An increase in potency.
5. An increase in degradation products.
SCHEME TO IDENTIFY CHEMICALLY
COMPATIBLE EXCIPIENTS
THANK YOU

ALL THE BEST