The document discusses preformulation studies, which involve characterizing the physical and chemical properties of a drug substance before developing a dosage form. The goals are to generate stability-indicating parameters and select an appropriate dosage form. Key topics covered include the physical properties tested (such as solubility, polymorphism, particle size), chemical degradation pathways (such as hydrolysis, oxidation), and how these properties influence dosage form design and drug performance. Understanding a drug's preformulation behavior is critical for developing a safe, effective, and stable drug product.

1. PREFORMULATION STUDIES
UNIT I
Ms. TENY SARA THOMAS
MOUNT ZION COLLEGE OF PHARMACEUTICAL
SCIENCES AND RESEARCH, ADOOR, KERALA
ASSISTANT PROFESSOR
B.PHARM FIFTH SEMESTER
PHARMACEUTICAL QUALITY ASSURANCE

2. CONTENTS
 Introduction to Preformulation
 Goals and objectives
 Study of Physico – Chemical Characteristics
of Drug Substances
 BCS Classification of Drugs
 Application of Preformulation
Considerations and its Impact on Stability of
Dosage Forms like – solid dosage forms,
liquid dosage forms and parenterals
2

3. INTRODUCTION
Prior to development of a formulation or dosage form,
it is essential that certain properties of a drug molecule
are to be determined.
This information decides many of the subsequent
events and approaches in formulation development.
Preformulation – phase of research and development
in which the physical and chemical properties of a drug
molecule in order to develop safe, effective and stable
dosage form.
Preformulation commences when a newly synthesised
drug shows a sufficient pharmacological promise in
animal model to warrant evaluation in man.
First step in rational development of a dosage form of a
drug substance.
3

4. GOALS & OBJECTIVES
Main objective is to generate information useful to the
formulation in developing most stable and bioavailable
dosage form that can be produced.
Establish necessary physico - chemical parameters of
new drug substance that can affect the drug performance
and development of an efficacious stable and safe dosage
form.
Determine kinetic rate profile.
Establish physical characteristics.
Establish compatibility with common excipients.
Provide insights into how drug products should be
processed and stored to ensure their quality.
To develop an optimal drug delivery system.
4

5. PHYSICO-CHEMICAL CHARACTERISATION
A. Physical Properties of Drug Substances
 Organoleptic Characterisation
 Bulk Characterisation
 Solubility Profile
B. Chemical Properties of Drug Substances
 Hydrolysis
 Oxidation
 Reduction
 Racemisation
 Polymerisation 5

6. A. PHYSICAL PROPERTIES OF DRUG SUBSTANCES
The physical properties of drug molecules can
affect the structure and stability formulations and may
also alter the bioavailability of the drugs from the dosage
forms.
Hence, physical properties of drugs are important
in the dosage form design.
There are three categories of physical properties
influence dosage form design.
i) Organoleptic Characterisation
Refers to the evaluation of drug on the basis of colour,
odour, texture and taste.
Product should be good in appearance
Colour should be eye – appealing
Odour and taste should be pleasant.
Absence of impurities and should be in the purest form.
6

7. ii) Bulk Characterisation
Bulk characterisation of drug molecules involves
the characterisation of various solid – state properties
that could change during the process development.
Variability of bulk characterisations, significantly prove
subsequent events and approaches in drug development
process.
Bulk Characterisation includes :-
Crystallinity, Amorphism, and Polymorphism –
physical properties
Fine particle characterisation
Density of Drug Substances
Powder Flow Properties.
7

8. Crystallinity, Amorphism, and Polymorphism – Physical
properties
1. Crystallinity
Crystal compounds are characterised by repetitious spacing
of constituent atoms or molecules.
Crystals can be of different shapes. E.g cubic, tetragonal,
orthorhombic etc.
 The crystal habit and crystal internal structure of a drug can
affect the bulk and flow properties as well as chemical
stability.
Crystal habit – outer appearance of a crystal
Internal structure – molecular arrangement within the solid.
Degree of crystallinity affects the hardness, density,
transparency, and diffusion.
Crystallinity has a greater affect on the absorption of drugs.
Crystalline compounds may have stoichiometric or non –
stoichiometric adduct, where the non – stoichiometric adduct
is undesirable and removed.
8

9. 2. Amorphism
Amorphous compounds are those whose atoms or
molecules are randomly placed.
Internal structure shows a major distinction whether the
solid is crystalline or amorphous.
Some drugs can exist in amorphous state. They are
typically prepared by rapid precipitation, lyophilization.
Such drugs represent highest energy state, or higher
thermodynamic energy than the crystalline state.
Amorphous form are less stable than its crystalline state.
The solubility of amorphous form is greater than its
crystalline state.
Upon storage, amorphous solids tend to revert to more
stable forms. Thermodynamic instability is a major
disadvantage for developing a dosage form.
9

10. 3. Polymorphism
When a substance exists in more than one crystalline form – the
different forms are designated as Polymorphs and the phenomenon –
Polymorphism.
Polymorphs are of two types – Enantiotropic polymorphs and
Monotropic polymorphs
Enantiotropic polymorphs – is the one which can be reversibly
changed into another form by altering the temperature or pressure.
Monotropic polymorphs – is the one which is unstable at all
temperatures and pressures.
Polymorphs differ from each other respect to their physical
properties like solubility, melting point, density etc.
Depending on the stability on e form will be more stable than the
other. Such stable forms have – lower energy state, high melting
point, least aqueous stability.
Other forms are called metastable forms with the opposite
properties.
Determined by Differential Scanning Calorimetry , X – Ray
Diffraction methods.
10

11. Fine Particle Characterisation
Bulk flow, formulation homogeneity and surface
controlled processes such as dissolution and chemical reactivity
are directly affected by size, shape, an surface morphology of drug
particles.
1. Particle Size
Size affects – drug release from dosage forms, drug absorption ,
therapeutic action, physical stability of dosage forms like
suspensions and emulsions, flow properties of powders like
interference in the flowability of the powder
Particle size generally denoted in micrometers
Determined by four different methods :-
Optical microscopy – gives number distribution
Sedimentation methods – using Andreasen Pipette method.
Conductivity methods – based on the principle of change of light
intensity using methods like – counter coulter method, light
scattering method.
11

12. 2. Particle Shape
Shape has a influence on the surface area, flow
properties, packing and compaction of the particles.
Spherical particles have minimum surface area and
better flow properties
Shape also influences rate of dissolution of drugs.
Determination of particle size – microscopy method and
light scattering method
3. Particle Surface Area
Size and surface area are inversely related to each other.
Smaller the drug particle, greater the surface area.
Maximum surface area ensures better solubility
Determination of particle surface area – adsorption
method and air – permeability method.
12

13. Density of Drug Substance
Densities of particles should be observed carefully
because sometimes particles can be hard and smooth in
one case, and rough and spongy in another.
Density is defined as weight per unit volume.
Four different types of densities are generally observed :-
1. True Density
Density of the material itself.
True density = Powder Weight / True Volume
True volume – volume obtained excluding the void
volume and intra particle pores
Measure using the gas displacement or liquid
displacement method.
13

14. 2. Granule Density
Determined for granules that are employed in the
manufacture of tablets
Granule density = Granule Weight / Granule Volume
Granule density measured using mercury displacement
method.
3. Bulk Density
Defined as the mass of the powder divided by the bulk
volume.
Bulk density = Bulk Weight / Bulk Volume
Bulk density value indicates the volume of all pores within
te powder sample.
4. Tapped Density
Ratio of the mass of the powders to the volume occupied
by powder after it has been tapped for a defined period of
time.
14

15. Flow Properties of Materials
Flow property can be affected by a number of
factors like - changes in particle size, shape, surface area,
density, frictional forces, van der waals forces etc.
Efficient flow of particles is needed for an effective
formulation. In case of liquid materials, flow properties are
measured using rheology and thixotropy.
1. Hausner’s ratio
Number that is correlated to the flowability of powder or
granular material
Hausner’s Ratio = Tapped Density / Bulk Density
2. Carr’s Compressibility Index
Ability of powder to decrease in volume under pressure
Carr’s Compressibility Index
= { [Tapped – Bulk Density] / Tapped Density } * 100
15

16. CORRELATION BETWEEN CARR’S INDEX, HAUSNER’S
RATIO & FLOWABILITY OF PARTICLES
16
CARR’S INDEX
HAUSNER’S
RATIO
FLOWABILITY
5-10 1.00-1.11 Excellent
11-15 1.12-1.18 Good
16-20 1.19-1.25 Fair
21-25 1.26-1.34 Passable
26-31 1.35-1.45 Poor
23-37 1.46-1.59 Very poor
>38 > 1.60 Extremely poor

17. 3. Angle of Repose
Indirect method of quantifying powder’s flowability,
because of their relationship with inter - particle cohesion.
Angle of repose = maximum angle between the surface of a
pile of a powder, and a horizontal plane. Such an angle is
calculated using,
 tan θ = height of conical heap / radius of
horizontal plane of powder
17

18. CORRELATION BETWEEN ANGLE OF REPOSE & FLOWABILITY
OF PARTICLES
18
ANGLE OF REPOSE FLOW PROPERTY
<25 Excellent
25-30 Good
30-40 Passable
>40 Very Poor
4. Moisture Content – reduces the flow property of the
particles.
5. Nature of Particles – coarse and fine particles shows a
goof low property.
6. Particle Size – particle size when smaller, flow property
is better.

19. iii) Solubility Analysis of Drug Substances
Preformulation solubility studies focus on drug –
solvent systems that could occur during the delivery of
a drug candidate.
Understanding the drugs solubility profile and
possible solubilisation mechanisms provide a basis for
formulation work.
Solubility Analysis includes :-
pKa determination
pH solubility profile
Partition Coefficient
19

20. pKa determination
As the drug needs to be introduced via a route of
administration, a dosage form should be selected.
Most of the drugs are absorbed even before the
therapeutic effect takes place.
The cell membrane acts as a barrier for most of the
drugs to be absorbed as it is a liphophilic barrier.
Charged hydrophilic heads face outwards and non
charged hydrophobic part faces to the middle part.
Uncharged layer repels the charged drug substances.
Non – ionic species diffuse readily through the cell
membrane.
Taking an example of an acid “HA”, it can dissociate
into A- the conjugate base of an acid and a hydrogen ion
H+ .
20

21.  HA <----------> H+ + A—
Ka = [A— ] [H+ ] / [HA] where, Ka is the acid
dissociation constant.
 pKa is the negative logarithm of Ka
pKa = - log Ka
Ka - function of the amount of drug that exist in the
unionised form.
pKa – gives the strength of the acid or base used.
Percentage of drug ionised can be found by the
Hendersson Hasselbach equation.
For acidic drugs,
pH = pKa + log [ionised form / unionised
form]
For basic drugs,
21

22. When the concentration of ionised and unionised form
becomes equal, pH = pKa, since log 1 = 0.
Lower the pKa, higher the acidic strength.
pKa value can be determined by analytical methods
like, UV – Visible spectroscopy, potentiometric
titrations etc.
GIT has an entire range pH of 1-8. stomach is said to
have a pH range of 1-3 and the intestine is said to have a
ph range of 5-8.
pH solubility profile
pH is the negative logarithm of H+ ion.
Solubility of many compounds depend strongly on the
pH of the solution.
Changing the pH, can make a difference in the
solubility of the acidic or basic drugs.
22

23. INFLUENCE OF DRUG PKA & PH ON DRUG ABSORPTION
23
Drugs pKa pH/ Site of Absorption
Very weak acid > 8.0
Unionised at all pH/ absorption
throughout GIT
Moderately weak
acid
2.5-7.5
Unionised in gastric pH, ionised
in intestinal pH / absorption site -
stomach
Strong acid <2.5 Ionised at all pH / poor absorption
Very weak base <5.0
Unionised at all pH/ absorption
through the GIT
Moderately weak
base
5.0-11.0
Ionised in gastric pH, unionised in
intestinal pH / absorption site -
intestine
Strong base >11.0 Ionised at all pH / poor absorption

24. Partition Coefficient
P.C is the ratio of the concentration of solute in two immiscible or
slightly miscible liquids, when it is in equilibrium across the interface
between them.
Generally refers to the concentration ratio of un-ionised species of a
compound.
Po/aq = (conc. of drug in organic phase)/ (conc. of drug in aqeous
phase)
Partition coefficient measures how hydrophilic or hydrophobic a
drug substance is.
Estimates the distribution of drugs in the body.
Hydrophobic drugs distribute in the hydrophobic areas such as lipid
bilayers of the cells.
Hydrophilic drugs are found in the hydrophilic areas such as blood
serum.
Determined experimentally by shake flask method, high
performance liquid chromatography.
24

25. B. CHEMICAL PROPERTIES OF DRUG SUBSTANCES
A chemical property is a drugs property that
becomes evident after a chemical reaction. Chemical
properties are determined by the investigation of the
chemical property.
Major chemical properties that are studies in
preformulation are:-
Hydrolysis
Oxidation and Reduction
Racemisation
Polymerisation
25

26. I) HYDROLYSIS
Hydrolysis means the reaction of a drug
molecule with water resulting in the cleavage of
chemical bond. this leads to degradation of substance.
Esters, amides, lactums are most prone to hydrolysis.
Hydrolysis are of two types:-
Acid based hydrolysis
Base based hydrolysis
Water can act as both acid and base.
26

27. Acid based hydrolysis
In case of acid based hydrolysis, Water acts as a base.
Water becomes H3O+
ion – Hydronium ion.
Taking an example of acetic acid
CH3COOH + H2O  H3O+ + CH3COO -
Base based hydrolysis
In case of base based hydrolysis, Water acts as a acid.
Water becomes proton donor, to be a Hydroxide ion (OH-
).
Taking an example of pyridine.
27

28. Hydrolysis can be prevented by :-
Addition of buffers, addictives, surfactants –
suppresses hydrolysis
Modification of chemical structure
Replacing aqueous solvents with non aqueous
solvent – reduces hydrolysis
Reduce exposure to water
Conversion of some drugs into dry powder for
reconstitution
Examples of drugs that undergo hydrolysis – aspirin ,
penicillin, diamorphine, etc. 28

29. II) OXIDATION AND REDUCTION
Oxidation and reduction are the common
pathway for drug degradation in solid and liquid
formulations. Oxidation and reduction involve the
transfer of electrons, between the reactants. These two
processes are together called Redox reactions.
Oxidation – loss of electrons
Reduction – gain of electrons
Generally, in pharmaceutical formulations,
oxidation is mediated by the reaction with atmospheric
oxygen.
Oxidation occurs in two ways:-
Auto – oxidation
Free radical chain process
29

30. Auto oxidation
Defined as reaction of substance with molecular
oxygen, which produces free radical, by homolytic bond
fission of a covalent bond.
Free radical chain process
Occurs as 3 step process – initiation , propagation and
termination
During initiation, compound is converted to a free
radical.
In propagation step, free radical combines with oxygen
to form peroxy radical.
The peroxy radical further combines with hydrogen to
form hydroperoxide and new radical is formed in the
termination step.
Some radicals combine to form inactive products.
30

31. Such a degeneration can be prevented by :-
Use of antioxidants and chelating agent
Contact of drugs with heavy metals must be avoided
Reducing agents can be used to prevent oxidation
pH adjustment can be done to prevent oxidation and
reduction
Oxygen in containers can be replaced with nitrogen
or carbon dioxide
Store in dark and cool containers.
31

32. III) RACEMISATION
- a process of conversion of optically active
compound into an optically inactive compound.
Half of the compound becomes its mirror images
Rate of racemisation depends on the presence of
catalytic hydrogen, hydroxyl ion, heat, light,
temperature and solvent.
Interconversion can alter the pharmacokinetic
properties, pharmacological properties, and toxological
properties
This conversion can make the drug inert or dangerous.
Eg. l- epinephrine is 15-20 times active than the d-
form
32

33. IV) POLYMERISATION
- form of chemical degradation where two or more
identical molecules combine to form large complex molecules
known as polymers.
It can also be defined as a process in which simple monomer
molecules combined to form large complex.
Polymerisation can be of mainly two types:-
Addictive polymerisation - monomers with double or triple
bond combine to form polymers, and the reaction does not give
by products
Condensation polymerisation – monomers combine to form
polymers along with the formation of by products like water,
ammonia, hydrochloric acid etc.
Eg. – shellac on aging undergoes polymerisation which
disintegration and dissolution time
Glucose solution darkens due to polymerisation
Formaldehyde solution, on standing, leads to formation of white
deposit.
33

34. BIOPHARMACEUTICAL CLASSIFICATION
SYSTEM [BCS] OF DRUGS
BCS of drugs is a system to
differentiate drugs on the basis of :-
Solubility
Permeability
Dissolution
Scientific framework for
classifying drug substances based on
their aqueous solubility and intestinal
permeability
34

35. A theoretical basis for correlating in-vitro
drug dissolution with in-vivo bioavailability
was developed.
The classification of drugs is based on
Fick’s first law :-
Fick’s first law states,
JW = PW * CW
JW = drug flux across the gut wall
PW = permeability of the membrane
CW = drug concentration at GI membrane 35

36. SOLUBILITY
- maximum amount of solute dissolved in a given solvent under
standard conditions of temperature, pressure, and pH :- measured to determine
solubility.
- solubility is the ability of the drug to be in solution after dissolution.
PERMEABILITY
- Ability of drug to pass the biological membrane which is lipophilic.
- permeability of drug is indirectly based on the extent of absorption of
a drug substance
- determined using the in – situ method :- rat intestinal perfusion
method.
36

37. DISSOLUTION
- is a process in which solid substance
solubilises in a solvent.
- dtermined using UPS Apparatus I @ 100rpm or
Apparatus II @ 50rpm
- dissolution media :- 900ml – 0.1 N HCl, pH
4.5 or 6.8 buffer, simulated intestinal fluid.
37
APPARATUS 1 APPARATUS 2

38. 38
CLASS SOLUBILITY PERMEABILITY EXAMPLES
CLASS I HIGH HIGH
METAPROLOL
PROPRANOLOL
CLASS
II
LOW HIGH
NIFEDIPINE
NAPROXEN
CLASS
III
HIGH LOW
CIMETIDINE
METFORMIN
CLASS
IV
LOW LOW
TAXOL
CHLORTHIAZOL

39. CLASS I
Drug dissolves rapidly and absorbs rapidly
Gives therapeutic action, shows excellent
property
Ideal for oral route of administration
CLASS II
Drugs dissolve slowly and absorb rapidly
Optimum for controlled release drugs via oral
or intravenous route of administration
Dissolution is rate controlled. 39

40. CLASS III
Drug dissolves rapidly but absorption is
limited
Bioavailability is incomplete.
Permeability is rate controlled
CLASS IV
Low dissolution rate and low permeability
Slow therapeutic action
Oral administration is not preferred
Intravenous and other routes of administration
is preferred. 40

41. APPLICATIONS of BCS of DRUGS
Valuable tool for formulation scientist for
selection of design of dosage form
Reduce cost and time for scale-up and post-
approval changes
Applicable in clinical and pre-clinical testing
Eliminates the need of human subjects to
unnecessary drug exposure
Helps in maintaining high public standard of
therapeutic equivalence
41

42. APPROACHES TO BE MADE IN EACH
CLASS OF BCS
CLASS I – Simple oral dosage form
CLASS II – techniques to increase surface
area, change solvents or surfactants
CLASS III – incorporate permeability
enhancers
CLASS IV – combine approaches of class I &
II
42

43. APPLICATION OF PREFORMULATION IN
DIFFERENT DOSAGE FORMS AND IMPACT IN ITS
STABILITY
SOLID DOSAGE FORMS
Physicochemical properties and chemical
properties are studied to determine the exact drug
substance, excipients, manufacturing process etc
to be used in the formulation.
Instability problem – change in therapeutic
effect, release of drug from dosage form,
manufacturing problems 43

44. LIQUID DOSAGE FORMS
Physicochemical properties like pH, colour,
clarity, viscosity etc
Chemical problems – assay, degradation
product analysis, microbial properties
determination
Instability problems – loss of flavour,
interaction with plastic bottles, settling, caking,
and crystal growth, creaming, coalescence,
breaking, flocculation, phase inversion
44

45. PARENTRAL DOSAGE FORMS
Physicochemical properties like bulk
characterisation and solubility analysis
Chemical problems – spectroscopical studies
and chromatographic studies
Instability problems – discolouration due to
oxidation and photochemical reaction, presence
of precipitate, formation of clouds due to
chemical reactions, presence of crystals called
whiskers at the tip of the container.
45