3. INTRODUCTION
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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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4. OBJECTIVES
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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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5. 4/21/2016 5
WHY PREFORMULATION IS IMPORTANT ?
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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.
6. 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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PHYSICOCHEMICAL PROPERTIES
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7. 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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8. Pseudo-polymorphism
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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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9. 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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10. 10
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
•Bulk density
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11. ANGLE OF REPOSE
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Angle of repose Flow property
<20
20-30
30-34
>40
Excellent
Good
Passable
Very poor
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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’
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Bulk density
Carr’s index = ( tapped density – poured density)
poured density
Hausner’s Ratio = tapped density
poured density
A. Carr’s Index :
B. Hausner’s Ratio :
X 100
X 100
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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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14. 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 , and then filter then
determine the concentration of drug
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SOLUBILITY ANALYSIS
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15. 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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16. The percentage of ionization can be calculated by
Henderson Hasselbalch equation …
For Acidic compounds:
For Basic compounds:
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.
pH = pKa + log(unionized drug/ionized drug)
pH = pKa + log(ionized drug/unionized drug)
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17. 3. PARTITION COEFFICIENT
Partition coefficient is a ratio of equilibrium
concentration of drug in oil phase to equilibrium
concentration of drug in aqueous phase .
where,
Co-organic phase concentration
Cw-aqueous phase concentration
It useful for the measuring liphophilic charecter of drug.
K=Co/Cw
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• Eg. n- octanol
• Chloroform
• Ether etc.
various organic solvents used
4. SOLUBILITY ENHANCEMENT
solubility of poorly water soluble drug can be
enhanced by one of the following method.
• 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.
=
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dc DA
dt = h (Cs – C)
20. 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…
STABILITYANALYSIS
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21. 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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23. 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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24. 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
TEM
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25. 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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26. 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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27. 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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28. 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 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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30. 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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31. 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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32. 32
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, Aulton’s pharmaceutics, 3rd ed Elsevier
Ltd 2007, page no. 336-370
REFERENCES
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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
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