This document discusses preformulation in pharmaceutical research and development. It defines preformulation as characterizing the physical and chemical properties of a new drug substance to develop a stable, safe and effective dosage form. The goals are to establish the physicochemical parameters, physical characteristics, kinetic rate profile, and excipient compatibility of a new drug. The objectives are to develop elegant, stable, and safe dosage forms and have an understanding of the drug substance before dosage form development. The document outlines various physicochemical characteristics that are evaluated during preformulation including physical properties like solubility, partition coefficient, stability, and chemical properties like hydrolysis, oxidation, reduction, racemization, and polymerization.

1. PREFORMULATION
 Mr Nandakishor B Deshmukh
 Assistant Professor
 Department of Pharmaceutics
 Shraddha institute of Pharmacy, kondala zambre,
washim
1
2-Jul-23
PROF N.B.DESHMUKH

2. Definition :
 Preformulation may be defined as a stage of the research
and development process where the preformulation
studies characterizes the physical and chemical
properties of a new drug substance in order to develop
stable safe and effective dosage form.
2
2-Jul-23
PROF N.B.DESHMUKH

3. Goals and Objectives
 The goals of pre-formulation are:
 1) To establish the physicochemical parameters of a new
drug substance.
 2) To establish the physical characteristics of a new drug
substance .
 3) To establish the kinetic rate profile of a new drug
substance.
 4) To establish the compatibility of the new drug substance
with the common excipients
 5) To choose the correct dosage form of a drug substance.
3
2-Jul-23
PROF N.B.DESHMUKH

4. The objectives of Pre-formulation are:
 1) To develop elegant, stable, effective, and safe dosage
forms.
 2) It is required to have an understanding of the physical
description of a drug substance before the development
of any dosage form.
 3) Pre-formulation is the first step in rational
development of a dosage form of a drug substance
before the development of dosage form.
4
2-Jul-23
PROF N.B.DESHMUKH

5. Following are the major physicochemical characteristics of drug substances
 1) Physical properties
 i) Organoleptic Characters.
 ii) Bulk characterisation:
a) Physical form
b) Polymorphism
c) Particle size
d) Particle shape
e) Flow properties..
5
2-Jul-23
PROF N.B.DESHMUKH

6. ii) Solubility analysis:
a) Ionisation constant – pKa
b) pH solubility profile
c) Partition coefficient.
iii) Stability analysis:
a) Stability in toxicology formulations
b) Solution stability – pH rate profile
c) Solid state stability:
 Bulk stability
 Compatibility
6
2-Jul-23
PROF N.B.DESHMUKH

7. 2) Chemical properties
 Hydrolysis
 Oxidation
 Reduction
 Racemisation
 Polymerisation.
7
2-Jul-23
PROF N.B.DESHMUKH

8. 8
2-Jul-23
PROF N.B.DESHMUKH

9. ii) Bulk characterisation:
a) Physical form
Crystallinity
 Crystal habit & internal structure physicochemical property of
molecule of drug can affect bulk .
 Crystal habit is description of outer appearance of crystal.
 The internal structure is molecular arrangement within the
solid.Change with internal structure usually alters crystal habit.
 Eg. Conversion of sodium salt to its free acid form produce both
change in internal structure & crystal habit.
9
2-Jul-23
PROF N.B.DESHMUKH

10. 10
2-Jul-23
PROF N.B.DESHMUKH

11. Different shapes of crystals
Depending on internal structure compounds is classified as
1. Crystalline
2. Amorphous
 Crystalline compounds are characterized by repetitious spacing of
constituent atom or molecule in three dimensional .
 In amorphous form atom or molecule are randomly placed.
 Solubility & dissolution rate are greater for amorphous form than
crystalline, as amorphous form has higher thermodynamic energy.
 Eg. Amorphous form of Novobiocin is well absorbed where as
crystalline form results in poor absorption.
11
2-Jul-23
PROF N.B.DESHMUKH

12. Polymorphism
The ability of a substance to exist in more than one crystalline form is called as
polymorphism.
There are two types of Polymorphism.
1) Enantiotropic Polymorphism
By altering the temperature or pressure is and changed into another in a reversible manner
called as enantiotropic Polymorphism.
e.g sulphur.
2) Monotropic Polymorphism: Under all the conditions of temperature and pressure the
monotropic Polymorphism remain unstable is called monotropic Polymorphism
e.g glyceryl stearate.
12
2-Jul-23
PROF N.B.DESHMUKH

13. METHODS TO IDENTIFY POLYMORPHISM
1. Optical crystallography
2. Hot 0stage microscopy
3. X-Ray Diffraction method
4. NMR technique
5. FTIR technique.
6. Microcalorimetry
7. Thermal methods
8. Melting point determination
13
2-Jul-23
PROF N.B.DESHMUKH

14. c) Particle size
Particle size is characterized using these terms:
Very coarse, Coarse, Moderately coarse, Fine,Very fine.
• Particle size can influence variety of important factors-
i. Dissolution rate
ii. Suspendability
iii. Uniform distribution
iv. Penetrability-
v. Lack of grittiness
14
2-Jul-23
PROF N.B.DESHMUKH

15. Methods to Determine Particle Size
a. Sieving (5u-150µ)
b. Microscopy(0.2μ-100μ)
c. Sedimentation rate method(1μ-200μ)
d. Light energy diffraction(0.5μ-500μ)
e. Laser holography(1.4u-100µ)
15
2-Jul-23
PROF N.B.DESHMUKH

16. Particle Shape
The term particle shape is used to express the geometrical shape and surface
regularity of the material particle shape affects the surface area flow packing
properties of the particles.
Equant
Acicular
Flake
Plate
Columnar
Lath
16
2-Jul-23
PROF N.B.DESHMUKH

17. Flow Properties
The flow properties of powders are critical for an efficient
tablet operation.
 During the preformulation evaluation of the drug
substance, therefore its flow ability characteristic
should be studied especially when the anticipated dose
of the drug is large.
 Flow properties are affected by changes in particle size,
density, shape, electrostatic charges, and adsorbed
moisture.
17
2-Jul-23
PROF N.B.DESHMUKH

18. It is characterized by
Angle Of Repose
Carr‟s Index
Hausner Ratio
Rheology
Thixotropy
18
2-Jul-23
PROF N.B.DESHMUKH

19. 19
2-Jul-23
PROF N.B.DESHMUKH

20. 20
2-Jul-23
PROF N.B.DESHMUKH

21. 21
2-Jul-23
PROF N.B.DESHMUKH

22. 22
2-Jul-23
PROF N.B.DESHMUKH

23. Solubility analysis
Ionization Constant (PKA) Many drugs are either weakly acidic or basic
compounds and, in solution, depending on the pH value, exist as ionized or un-
ionized species. The un- ionized species are more lipid soluble and hence more
readily absorbed.
The factors that are important in
[Un- ionized form]
pH = pKa + log ----------------------------- ----------------------for bases
[ionized form]
[Ionized form]
pH = pKa + log ---------------------------------------- for acids
[un ionized form
23
2-Jul-23
PROF N.B.DESHMUKH

24. Determination of pka
 Potentiometric titration
 Spectrophotometric determination
 Dissolution rate method
Liquid-Liquid partition method
24
2-Jul-23
PROF N.B.DESHMUKH

25. b) Partition coefficient
The lipophilicity of an organic compound is usually
described in terms of a partition coefficient log P which can
be defined as the ratio of the concentration of the unionized
compound at equilibrium between organic and aqueous
phases This ratio is known as the partition coefficient or
distribution coefficient and is essentially independent of
concentration of dilute solutions of a given solute species.
Log P = 0 means that the absorption of weakly acidic and
basic compounds are the pH at the sit e of absorption
25
2-Jul-23
PROF N.B.DESHMUKH

26. Methods of finding Partition coefficient:
1) Shake-flask method
2) Chromatographic method.
3) Counter current and filter probe method.
4) Tomlinson‟s filter probe method.
5) Microelectrometrictitratation method
6) Automated instrument is now available
26
2-Jul-23
PROF N.B.DESHMUKH

27. Applications of partition coefficient
a) Measure of Lipophilic character of Drugs molecules.
b) Recovery of antibiotics from fermentation.
c) Extraction of drug from biological fluid for therapeutic
monitoring.
d) Absorption of drug from dosage forms. (Ointments,
Suppositories, Transdermal patches).
e) Study of distribution of flavoring oil between oil & water
in emulsion
27
2-Jul-23
PROF N.B.DESHMUKH

28. c) Solubilization
Solubility is defined as amount of solute that can be dispersed
molecularly in the given amount of solvent under standard
conditions of temperature pressure and pH.
Terms Expression of solubility
Part by volume of solvent required to
dissolve 1 part by weight of solute
Very soluble Less than 1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 to 1000
Very slightly soluble From 1000 to 10,000
28
2-Jul-23
PROF N.B.DESHMUKH

29. Methods for increasing solubility
1. pH Adjustments
2. Co-solvency
3. Complexation
4. Surface active agent / Solubilization by Surfactant
5. Solid Solutions.
6. Chemical Modification of drug.
29
2-Jul-23
PROF N.B.DESHMUKH

30. Chemical properties
Chemical stability study includes the ways that cause instability of drug through
chemical reactions resulting in a reduction of potency.
The following chemical properties should be evaluated during a pre-formulation
research:
1) Hydrolysis
2) Oxidation
3) Reduction
4) Racemisation
5) Polymerisation.
30
2-Jul-23
PROF N.B.DESHMUKH

31. HYDROLYSIS
Hydrolysis is the most common degradation pathway since water plays an important role in
many processes especially in solution and also in solids (in which water may be present in low
concentrations).
Preventive Measures against Hydrolysis
Hydrolysis reactions occurring due to the presence of moisture and catalytic species H + and
OH– ions can be prevented as follows:
1) Buffer: It is used for product stabilisation.
2) Complexing Agent: It forms a complex with drug, prevents its hydrolysis and thus prolongs
the shelf-life.
3) Suppression of Solubility: Less solubility reduces the drug concentration in solution phase
and also reduces the hydrolysis rate.
4) Removal of Water: Presence of water should be avoided by storing the drug in dry form
and by using water immiscible vehicle
31
2-Jul-23
PROF N.B.DESHMUKH

32. 1.Oxidation
The environmental phenomenon of oxidation requires
oxygen If molecular oxygen is involved the reaction is
rapid and termed auto-oxidation.
Chemically oxidation involves loss of electrons which
requires an electron acceptor or an oxidising agent for
Anti-oxidising agent, light and trace metals that can
used catalyse the reaction.
example iron converting from ferric (Fe3+) to ferrous
(Fe2+)].
32
2-Jul-23
PROF N.B.DESHMUKH

33. Preventive Measures against oxidation
Oxidation reaction occurs due to the presence of moisture, oxygen, trace metals,
H + and OH− ions.
Oxidation can be prevented by:
1) Using antioxidants (e.g. tocopherol)
2) chelating agents
3) Buffers
4) Preventing light exposure
5) Maintaining oxygen free environment
6) Storing the product at a low temperature.
33
2-Jul-23
PROF N.B.DESHMUKH

34. Reduction
Reduction is a relatively common pathway of drug metabolic process.
Hepatic microsomes catalyse diverse reductive chemical reactions
with the use of NADPH.
Cytochrome P450 catalyses the azo and nitro reduction reaction.
The enzyme alcohol dehydrogenase catalyses the reduction of chloral
hydrate into trichloroethanol (its active metabolite).
Prednisolone and cortisone reduces to hydrocortisone (their active
metabolites).
The intestinal flora reduces the azo dyes (used as colouring agents in
pharmaceutical or food products) into amines in the liver.
34
2-Jul-23
PROF N.B.DESHMUKH

35. Racemisation
Racemisation involves the conversion of one
enantiomer of a compound such as an L -
amino acid into the other enantiomer.
The compound then alternates between each
form while the ratio between the (+) and ( –)
groups approach es the ratio 1:1, at which it
becomes optically inactive.
35
2-Jul-23
PROF N.B.DESHMUKH

36. Polymerization
Polymerisation is a continuous reaction occurring
between molecules.
A polymer is formed by the reaction between more
than one monomer.
For example glucose solution darkens due to
polymerisation of the breakdown product [5 -
(hydroxyl methyl) furfural]
36
2-Jul-23
PROF N.B.DESHMUKH

37. 37
2-Jul-23
PROF N.B.DESHMUKH