This document discusses preformulation studies for parenteral products. Preformulation testing provides important information for developing dosage forms and involves determining the physical and chemical properties of drug molecules. Key aspects of preformulation studies discussed include bulk characterization of properties like crystallinity and polymorphism. Solubility analysis looks at aqueous solubility, drug ionization, and partition coefficient. Stability studies evaluate stability in formulations, of solutions, and in the solid state under various temperature and humidity conditions. Additional analytical techniques discussed that are useful in preformulation include spectroscopy, microscopy, and chromatography. Thorough preformulation work lays the foundation for developing efficacious and stable dosage forms.

1. P
REFORMULATION OF
P
ARENTRAL P
RODUCT
BY,
11/03/13
Joan Vijetha.R
M.Pharm(pharmacutices)
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2. CONTENT
 Introduction.
 Definition.
 Pre-formulation
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studies
Bulk characterisation.
Solubility analysis.
Stability analysis.
Spectroscopy.
Microscopy.
Chromatography .
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3. INTRODUCTION
 Pre-formulation
testing is the first step in the
rational development of dosage forms.
 Pre-formulation study is done mainly to
develop efficient dosage form.
 Gives information for design of dosage form.
 Used to identify molecular structure,
formula, molecular weight, etc.
 Therapeutic identification.
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4. Definition
refers injectable route of
administration. It derived from Greek words
Para (Outside) and enter on (Intestine). So it
is a route of administration other than the
oral route.
 Parenteral
is done prior to
development of dosage form, it is essential
that certain fundamental physical and
chemical properties of the drug molecule and
other derivative properties of the drug is
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determined.
 Per-formulation

5. Bulk characterisation
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.
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6. Crystallinity

Crystal habit and internal structure of a drug
can affect bulk and physicochemical
properties, which range form flow ability to
chemical stability.

The crystal habit describes the outer
appearance of crystals( plate, equate, needle,
bladed, etc.) and internal structure
arrangement.
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7. 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
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stability, compatibility, etc.


8. Particle size





Study of particle size give an information about
solubility, dissolution rate, absorption, etc.
Fine particle characterization very important
property and here smallest particle should be tested
to facilitate homogeneous sample preparation.
Counter current Technique-To check particle size
and particle volume
BET (Brunauer, Emmet, Teller) Nitrogen
Adsorption Apparatus -Measurement of surface area
SEM( Scanning Electron Microscopy)- to check
surface morphology .
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9. 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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10. HYGROSCOPICITY
 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
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temperature.

11. SOLUBILITY ANALYSIS
 Aqueous
Solubility
 Drug Pka / Ionization At Physiological
Ph
 Partition Coefficient
 Thermal effect
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12. Aqueous Solubility

Solubilisation is increased by addition of cosolvent

E.g.-
propylene
molecules
by
glycol
disrupting
solubilize
the
drug
hydrophobic
interactions of water.
More non polar the solute
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greater is the solubilisation
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13. Drug pKa / Ionization at
physiological pH

pKa is the dissociation constant of a
drug.

The non ionized substances is lipid
soluble thus dissolve in lipid material
of the membrane and transported by
passive diffusion.
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
Where as, the ionized substances is 13

14. 
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)

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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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15. 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, C o -organic phase concentration
C w -aqueous phase concentration
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16. THERMAL/HEAT
EFFECTS
Drugs which are unstable to heat requires refrigerate
storage or lyophilisation (these products must be used
within short periods)
 If it is endothermic ---> ∆H is +ve
increase in temp ---> increase in drug solubility
 If it is exothermic ---> ∆H is – ve
increase in temp ---> decrease in drug solubility
 For determining ∆H
ln S= - ∆H /RT + C
S=molar solubility at temperature,
T=temperature in Kelvin,
R= gas constant

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17. Stability analysis
 Stability
in toxicology formulation.
 Solution stability.
 Solid state stability.
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18. Stability in toxicology
formulation
 Toxicology
studies typically commence
early in development, it is often
advisable to evaluate samples of the
toxicology preparation for stability and
potential homogeneity problems.
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19. Solution stability
 The
primary objective of this phase of
pre-formulation research is
identification of condition necessary to
form a stable solution.
 This
study include-effect of pH, ionic
strength, light, temperature and oxygen
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20. Solid state stability
• Solid phase stability depends on several
factors like temperature, pH, humidity,
hydrolysis, oxidation, etc
• For a new drug compound
Weighed sample are place in open screw cap
vials and are exposed directly to light, temp,
humidity for 12weeks.
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21. STORAGE
CONDITION
4WEEKS
8WEEKS
12WEEKS
5o C-REFRIGERATOR
22OC- ROOM TEMP
37OC-AMBIENT
HUMIDITY
50OC-AMBIENT
HUMIDITY
70OC-AMBIENT
HUMIDITY
90OC-AMBIENT
HUMIDITY
37OC/75%R.H
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22. Hydrolysis
 Important
factor in drug stability.
 Hydrolytic reaction involves
nucleophilic attack.
 The condition catalysis the brake down
as follows
•
•
•
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Presence of OH.
Presence of divalent metal ion.
Presence of light and heat.
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23. Oxidation and
Reduction
 Oxidation
is controlled by
environment(i.e.) light, oxygen &
oxidizing agent.
 Reduction is based on redox reaction
where there is mutual change in
electrons.
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24. 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.
 IR Spectrophotometer: The study of the
interaction of electromagnetic radiation with
vibrational and rotational resonances within a
molecular structure is termed as IR
Spectroscopy.
 X-Ray Diffraction: When a beam of non
homogenous x-rays is allowed to pass through 24
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

25. 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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26. Chromatography
In the pre-formulation studies,
chromatographic techniques such as TLC,
HPLC,GC carrying a major role.
 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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27. SUMMARY
 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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28. REFERENCE




Remington, The Science And Practice Of Pharmacy,
20th Edition,pg.940-42.
Leon Lachman, Herbert Al, Joseph Lk., The
Theory And Practice Of Industrial Pharmacy, 3rd
Ed.Pg. 171- 196.
Bhatt Bhavik R, A SEMINAR ON
PREFORMULATION
STUDIES:PHYSICOCHEMICAL
CHARACTERIZATION OF NEW DRUG
MOLECULES.
Manjul Pratap Singh & Anita Singh, Parenteral
Products.
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29. THANK You...
THANK
You...
THANK
THANK You...
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