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PREFORMULATION

STUDIES:
PHYSICOCHEMICAL
CHARACTERIZATION
Muhammad Dzakwan OF
APIS

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CONTENTS

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.

It can be defined as an investigation of physical and chemical


property of a drug substance alone and when combined with
excipients.

Physiochemical properties are those that can be determined


from in vitro experiments.

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OBJECTIVES

The main objective is to generate information


useful to the formulation in developing most
stable and bioavailable dosage form that mass
can be produced.

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Why is Preformulation 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,
quality, 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 PROPERTIES
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 describes the outer appearance of crystals
( platy, equant, needle, bladed, etc.) and internal structure
arrangement.

Compounds have several different habits, depending on the


environment for growing crystals.

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Polymorphism
polymorphism is the ability of the compound to crystallize as
more than one distinct crystalline species with different internal
structure.

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

Different polymorphs vary in physical properties such as


dissolution, solid-state stability, compatibility, etc

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Particle size
Study of particle size give an information about solubility,
dissolution rate, absorption, etc.

particle size and surface area of a solid drug are inversely related
to each other.
eg: Griseofulvin

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.

This refers mainly to factors such as the ability to process the


powder through machines.
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HYGROSCOCITY
The tendency of a solid to take up water from the
atmosphere, as it is subjected to a controlled RH program
under isothermal condition i.e. hygroscopicity.

Classified based on the amount of rate of water uptake when


a solid is exposed to controlled RH value at a specified
temperature.

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SOLUBILITY ANALYSIS

1. AQUEOUS SOLUBILITY
Important goal of the preformulation effort is to devise a
method for making solutions of the drug

Orally administered drug must dissolve in the aqueous fluid of


the GIT prior to absorption.
Solubility can be improved by addition of cosolvents.

Solubilities cannot be determined by precipitative methods.

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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 as

For Acidic compounds:

% ionized = 100/ 1+ antilog (pKa pH)

For Basic compounds:

% ionized = 100/ 1+ antilog (pH pKa)

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 influence permeation of a drug
across biological membrane.

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
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Following administration, the drug must travel
through a variety of membranes to gain access to the
target area.

Drug with extremely high partition co-efficient


(i.e. very oil-soluble ) readily penetrate the
membranes.

While drugs with excessive aqueous solubility i.e.


low oil/water partition co-efficient cannot penetrate
the membrane.
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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.

Intrinsic dissolution
Paricular dissolution

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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.

solution phase stability: The effect of pH on stability is important


in the development of both oral and Parenteral dosage forms

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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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

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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.

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B. SPECTROSCOPY
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.

Spectrophotometry can be used to study to enzyme reaction


and to evalute the effect of drug on enzyme.

UV study of compounds gives information regarding


unsaturation of compounds.
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IR Spectroscopy

The study of the interaction of electromagnetic radiation with


vibrational and rotational resonances within a molecular structure
is termed as IR Spectroscopy.

IR has the ability to differentiate isomers groups such as Cis-


trans double bond compound.

Gives an information regarding functional group present in new


drug molecule.

FT-IR use for both qualitative and quqntitative analysis of sample.

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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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Thermal Analysis
Differential scanning calorimetry (DSC) and differential
thermal analysis(DTA) are particularly useful in
preformulation studies including purity, polymorphism,
solvation, degradation, and excipient compatibility.

It measures physical or chemical changes of drug


molecules.

Thermigravimetric analysis
Used to detect the existange and stability of solvated
drug molecule.
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C. CHROMATOGRAPHY

In the preformulation studies, chromatographic


techniques such as TLC, HPLC,GC carrying a major role.

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.

Analytical data from TLC may be required to precisely


determine the kinetics of decomposition.

HPLC and GC are useful for solubility measurements.


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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 efficacious and economical formulations.

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REFERENCES
1) Banker GS, Rhodes CT., Modern pharmaceutics, 4th ed. New
York: Marcel Dekker; 2002. p.167-184

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


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

3) Remington, The Science and Practice of Pharmacy, 20th


Edition, B.I Publication Pvt Ltd.p.940-42

4) Leon Lachman, Herbert AL, Joseph LK., The theory and


practice of industrial pharmacy, 3rd ed. Bombay: Varghese
publishing house; 1990. p. 171- 196

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KARAKTERISASI STUDI PREFORMULASI
No Uji Metode, fungsi dan karakterisasi

1 Kelarutan
Larutan Fase kelarutan, kemurnian, kelarutan intrinsik
pKa Efek pH, kontrol kelarutan
Garam Pembentukan garam
Pelarut Stabilitas, ekstra
Koefisien partisi (log P) Lipofilisitas, struktur aktivitas
Disolusi Biofarmasetika
2 Titik leleh DSC, polimorfisme, hidrat, solvate
3. Metode Analisi UV, TLC, HPLC, FTIR, Raman Spek
4. Stabilitas
Larutan Hidrolisis, oksidasi, fotolisis, pH, pengaruh ion
Padatan DSC, DTA, TGA,

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No Uji Metode, fungsi dan karakterisasi

5. Mikroskopis
Morfologi Mikroskop, karakterisasi fisik
Ukuran partikel Mikroskop, ayakan, sedimentasi, LD, PCS
Bentuk SEM, TEM,
Luas permukaan BET, permeabilitas udara
6. Kristal dan Polimorf
Kristal DSC, PXRD, kristanilitas, kelarutan
Polimorfi DSC, PXRD, metastabil, stabilitas padatan
7. Sifat Fisik-Mekanis
Densitas partikel Bj ruahan, Bj mampat, Bj sejati, true density
Sudut diam Tipe aliran
Kompresibilitas CI carrs, Hausner Ratio

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No Uji Metode, fungsi dan karakterisasi

8. Sifat Kompresi Index Carrs, Hausner Ratio, pemilihan eksipien


9. Kompatibilitas DSC, FTIR, Raman Spektroskopi, SEM, TEM,
eksipien TLC, pemilihan eksipien

10. Rancangan Drug Jenis bentuk sediaan yang akan dibuat


Delivery System
11. Referensi Jurnal, buku ajar, kompendial, FDA, ICH, EMEA
FI, USP, BP, JP, NP

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Matur
Nuhun .
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