A le

ct u
re o Savitribai Phule Pune University
n B.PHARM
Semester- V

PREFORMULATION
INDUSTRIAL
PHARMACY-I

By
B. S. BHANAGE
Assistant Professor
Pharmaceutics Department
Unit Outcome

• On completion of this unit students will able to

understand the concept of preformulation
studies.

• Also they will able to understand the various

aspects of preformulation.

• Students will get clear idea about role of

preformulation in the development of new
stable dosage form.

• They will learn about the concept of stability.

Contents

• Introduction (Drug discovery and development)

• Concept of preformulation

• Aspects of Preformulation

• Analytical Techniques
Drug Discovery to
developmet
New Chemical Preclinic
Entity: al
1. By Organic Studies:
Synthesis Phharma
2. Molecular cology
Modificatio ADME
n Toxicolo
3. Isolation of gy
Plants

Formulatio Preformulation
n
Developm
ent
What is preformulation?
• Preformulation involves the study of
physicochemical properties of new compound
which could affect on the drug performance
and which will helps to develop a stable and
efficacious dosage form.
• It confirms that there is no any significant
barrier to the drug development process.
Aspects of Preformulation
1.Bulk Characterization:
Crystellinity and Polymorphism
Hygroscopicity
Fine Particle Characterization
Powder flow Properties

2. Solubility Analysis
Ionization Constant pka
Ph solubility Profile
Common Ion Effect
Thermal Effect
Solubilization
Partition Coefficient
Dissolution

3. Stability Analysis:
Stability in Toxicology Formulation
Solution Stability
Solid State Stability
Bulk Characterization:
Crystallinity:
How crystallinity will affect on Drug?
• Crystal habit or its internal structure of the
drug may affect on the physicochemical
properties such as flowability, hygroscopicity
chemical stability etc.

(Habit- is the outer structure of the cryatal and

Internal structure is the arrangement of
molecules within the solid)
How crystallinity will affect on Drug?
• Crystal habit or its internal structure of the
drug may affect on the physicochemical
properties such as flowability, hygroscopicity
chemical stability etc.

(Habit- is the outer structure of the cryatal and

Internal structure is the arrangement of
molecules within the solid)
 Internal
structure of
chemical comp.

crystalline
Amorphuos

Molecular
Single Entity Adducts
• Continued…..

Molecular Adducts

Nonstoichiometric Stoichiometric
inclusion solvates
compound (hydrates)

layer
channel
 Crystallinity Affect on Drug
Development
Amorphous form of crystal Having high solubility high
Dissolution but
thermodynamically unstable

Nonstoichiometric Adducts Solvent molecule entrapment

within crystal lattice, should be
avoided for development. (Lack
of reproducibility)

Stoichiometric Adducts Conversion of anhydrous comp.

to hydrates within the dosage
form may reduce the dissolution
rate and extent of drug
absorption.
Polymorphism:
Polymorphism
• It is the ability of a compound to cryastallize in
more than one form with different internal
structure.
• Polymorphism affects on the solubility and
chemical stability of the drug molecules, which
can have a big impact on the bioavailability
and its development process.
• While performimg Preformulation, it is
important to identify the polymorph which is
stable at room temperature and to determine
that whether the polymorphic conditions are
possible within the temperature range used for
stability studies and processing
Hygroscopicity:
• Water soluble salt forms are having
tendency to absorb water. And generally
it depends on the atmospheric humidity,
temperature, surface area, exposure etc.
• And this moisture absorption will
generally influence on chemical stability,
flowablity, compactibility.
• (Test for moisture content: samples are placed
in open containers by making thin powder bed
for achieving more more exposure to atm.
Moisture. Then the samples are exposed to
range of relative humidities prepared with
saturated aq. Salt solutions. )
• Moisture uptake can be checked at time
points of 0-24 hrs and storage of 0-12
weeks.
• Analytical methods: TGA, Gravimetry,
karl Fischer Apparatus.
Fine particle characterization:
It should be tested during preformulation
because, it is required to produce
homogeneous dosage form and to
maximise the surface area for internal
actions.
 •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.
Powder flow properties
•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.
Solubility Analysis
•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
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.
 Percent ionisation can be calculatedas

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.
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
 •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.
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
 Particular dissolution
Stability studies
• 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…
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.
Analytical Methods
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
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
UV Spectrometry
• 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.
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.
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.
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 existant and stability of
solvated drug molecule.
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.
Thank You!!