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PREFORMULATION

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

Preformulation is the study of the physical and chemical properties of the drug prior to the compounding process.

GOALS OF PREFORMULATION STUDIES
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
PREFORMULATION RESEARCH

I.

Solubility Studies

pKa determinations pH solubility profile Common ion effect Solubilisation Partition Coefficient

Dissolution

PRINCIPLE AREAS OF

PREFORMULATION RESEARCH
PREFORMULATION RESEARCH

II.

Bulk characterization

Crystallinity and Polymorphism Hygroscopicity Micromeritic Properties Particle Characterization Density and Porosity

Powder flow properties

PRINCIPLE AREAS OF

PREFORMULATION RESEARCH
PREFORMULATION RESEARCH

III. Stability Analysis Solution Stability Solid State Stability Drug-Excipient Compatibility

SOLUBILITY STUDIES

pKa Determination
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
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)

Henderson Hasselbalch equation • This provides an estimation of the ionized and unionized drug concentration at

For acidic compounds, pH=pKa+log(Unionized drug\Ionized

drug)

Methods for the determination of pKa 1. Potentiometric titration.
Methods for the determination of
pKa
1.
Potentiometric titration.

2.

3.

4.

5.

6.

UV spectroscopy.

Solubility measurement.

HPLC techniques.

Capillary zone electrophoresis.

Foaming activity.

pH solubility profile
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

Common ion effect is the decrease in the degree of dissociation of the salt by

addition of common ion.

PARTITION COEFFICIENT
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
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
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
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

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
DISSOLUTION TEST APPARATUS

DISSOLUTION TEST APPARATUS

PADDLE TYPE
PADDLE TYPE

BULK CHARACTERIZATION

CRYSTALLINITY
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

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
HYGROSCOPICITY
HYGROSCOPICITY
MICROMERITIC PROPERTIES
MICROMERITIC PROPERTIES

Particle characterization

Density

Porosity

Powder flow properties

DENSITY
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
Porosity

The porosity or voids E, of the powder is

Porosity or voids =

void volume bulk volume

POWDER FLOW PROPERTIES
POWDER FLOW PROPERTIES

Angle of repose

FIXED FUNNEL METHOD

FIXED FUNNEL METHOD ANGLE OF REPOSE FIXED CONE METHOD
ANGLE OF REPOSE
ANGLE OF REPOSE

FIXED CONE METHOD

FIXED FUNNEL METHOD ANGLE OF REPOSE FIXED CONE METHOD
FLOW PROPERTIES
FLOW PROPERTIES

Carr’s index

FLOW PROPERTIES Carr’s index

STABILITY ANALYSIS

STABILITY ANALYSIS
STABILITY ANALYSIS

Solution stability

Solid stability

Drug excipient compatibility

STABILITY ANALYSIS
STABILITY ANALYSIS

SOLUTION STABILITY

  • 1. Hydrolysis

  • 2. Oxidation

  • 3. Photolysis

  • 4. Recemization

HYDROLYSIS
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
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
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
RECEMISATION

Optical active substance losses its optical activity.

DRUG EXCIPIENT COMPATIBILITY
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
COMPATIBLE EXCIPIENTS

THANK YOU

ALL THE BEST
ALL THE BEST