Pre-formulation Studies

By
Muhammad Farhan Sohail
Pre-formulation Concept
Pre-formulation commences when:
A newly synthesized drug shows sufficient
pharmacologic effects.
Pre-formulation testing is the first step in the
rational development of dosage forms of a drug
substance.
Pre-formulation is the physicochemical
characterization of the properties of the drug
prior to compounding process.
It provides the critical information for formulation
development and scale-up.

Pre-formulation Concept
Before beginning the formal preformulation
programs the preformulation scientist must
consider the following factors :-
The amount of drug available.
The physicochemical properties of the drug
already known.
Therapeutic category and anticipated dose of
compound.
The nature of information, a formulation should
have or would like to have.

Pre-formulation
It is the study of fundamental physical and
chemical properties of drug molecules & other
derived properties of drug powder that provide
information to dictate many of the subsequent
events and approaches in formulation
development.
The first learning phase of a compound is
known as pre-formulation.
Prior to development of different dosage
forms, it is essential that certain fundamental
physical and chemical properties of the drug
powder are determined.
Working Formula & Procedure
Generated from Pre-formulation
Safe handling of ingredients and equipment
Proper sequence of addition of ingredients
Optimum environmental conditions
Precautions to be observed
Expected interaction

Pre-formulation is divided into two groups
Drug Characterization
Analytical studies

Pre-formulation Drug
Characterization
TEST METHOD/FUNCTIONS

Spectroscopy simple UV assay
Solubility Aqueous, PKa, salts, solvents, dissolution
General characteristics
Organoleptic properties
Flow properties
Particle characteristics
Others

Appearance, color, odour, taste
bulk density, angle of repose,
particle size, particle shape
Specific gravity, surface tension
Stability Thermal, hydrolysis, photolysis, PH
Compression properties Tablet and capsule formation
Excipients compatibility Excipients choice

Analytical Pre-formulation
Attribute Tests
Identity NMR, UV, IR, TLC, DSC
Purity Moisture, Inorganic elements, Heavy metals, organic impurities
Assay Titration, Uvanalysis
Quality Appearance, odour, pH etc..
Pre-formulation Approaches
Pre-formulation study is performed using
following methods and techniques:
Bulk characterization
Crystallinity and polymorphism
Hygroscopicity
Particle characterization
Bulk density
Powder flow properties

Pre-formulation Approaches
Solubility analysis
Ionization constant-pKa
pH solubility profile
Common ion effect-Ksp
Thermal effects
Solubilization
Partition coefficient
Dissolution


Pre-formulation Approaches
Stability analysis
Stability in toxicological formulations
Solution stability
pH rate profile
Solid state stability
Bulk stability
Compatibility
Chemical stability

Pre-formulation Approaches
Bulk Characterization

Bulk properties for solid form such as
organoleptic properties, particle size, bulk
density and surface morphology also likely to be
changed during process development. Therefore
comprehensive characterization of all pre
formulation bulk lot is necessary to avoid
misleading predictions of stability and solubility,
which depend on a particular crystalline form.
Bulk Characterization
Organoleptic evaluation includes the
study of
Color
Odour
Taste
Appearance
Crystalline
Amorphous / powder


Organoleptic Evaluation
Compounds/
Parameter
color odor Taste Appearance
Benzoic acid White Strong odor Acidic Crystalline flakes
Camphor Colorless Characteristic
odor
Tasteless Transparent
crystals
Mefenamic acid White Odorless Pungent Amorphous
Diclofenac
sodium
White Pungent odor bitter Crystalline
Importance of Crystal
Morphology
Crystal morphology can influence many
properties of the compound such as:
Powder flow properties and compaction
Dissolution rate
Bioavailability
Stability

Bulk Characterization
Particle Size
Particle size is very important in formulation
development and defining characteristics of drug.
Methods
These include:
Sieving
Microscopy
Sedimentation
Light scattering

Bulk Characterization
Polymorphism
It is the ability of an compound to crystallize as
more than one distinct crystalline species
(polymorph).
Significance of Studying Polymorphism
Different polymorphs exhibits different Solubility,
therapeutic activity and Stability
The desired forms can be consistently manufactured.
The effects of pharmaceutical manipulations are
understood, e.g., granulation, milling and compression.
The effect of storage conditions on the dosage form can be
evaluated and predicted,
Bulk Characterization
Hygroscopicity
The phenomenon in which Substances become
moist because of affinity for moisture in the air
is known as hygroscopicity.
Importance
With most hygroscopic materials changes in
moisture level can greatly influence many
important parameters such as;
Chemical Stability of Compound
Flow ability
Compactibility

Bulk Characterization
Angle Of Repose
The angle which the sides of a heap form with
horizontal axis is known as angle of repose.
Sr. No. Flow Property Angle
01 Excellent 25-30
02 Good 31-35
03 Fair 36-40
04 Passable (may hang up) 41-45
05 Poor (must agitate) 46-55
06 Very Poor 56-65
07 Very Very Poor
65
Bulk Characterization
Compressibility Index:
Compressibility index is an indirect measure of
bulk properties, shape, size, surface area,
moisture content and cohesiveness of the
material because all these parameters can effect
observed compressibility index.
Sr. No. Flow Property C.I %
01 Excellent 1-10
02 Good 11-15
03 Fair 16-20
04 Passable (may hang up) 21-25
05 Poor (must agitate) 26-31
06 Very Poor 32-37
07 Very Very Poor
38
Bulk Characterization
Hausners ratio:
It is calculated by using formula:
tapped density/bulk density


Sr. No. Flow Property H.R
01 Excellent 1.0-1.11
02 Good 1.12-1.18
03 Fair 1.19-1.25
04 Passable (may hang up) 1.26-1.34
05 Poor (must agitate) 1.35-1.45
06 Very Poor 1.46-1.59
07 Very Very Poor
1.60
Bulk Characterization
True density
Bulk density
Tapped Density

Bulk Characterization
Surface Tension
It is the force acting parallel to the surface at right angle to a
line of 1m length anywhere in the surface.
force acting perpendicular to the surface divided by the length
of the surface
= F / 2l

Specific Gravity
Ratio of mass of a substance to mass of an equal volume of
another substance taken as the standard.
Specific gravity= Ws / Ww
Ws= weight of substance
Ww= weight of water


Solubility Studies
Solubility

It is defined in quantitative terms as the concentration of
solute in a saturated solution at a certain temperature,
and in qualitative way, it may be defined as the
spontaneous interaction of two or more substances to
form a homogenous molecular dispersion.

Solubility Studies
The solubility of drug is an important physicochemical
property because it affects the bioavailability of the drug, the
rate of drug release into the dissolution medium, and
consequently, the therapeutic efficacy of the pharmaceutical
product.
The solubility of a molecule in various solvents is determined
as a first step.
This information is valuable in developing a formulation.
Solubility is usually determined in a variety of commonly
used solvents and some oils if the molecule is lipophilic.

Expression for approximate
solubility
Descriptive Terms Relative amount of solvent to dissolve
1 part of solute
Very soluble Less than 1
Freely soluble 1-10
Soluble 10-30
Sparingly soluble 30-100
Slightly soluble 100-1000
Very slightly soluble 1000-10000
Insoluble or practically insouble More than 10,000
Biopharmaceutical Classification
System (BCS) Classification
BCS Class Permeability Solubility
I High High
II High Low
III Low High
IV Low Low
Class Boundaries

Highly soluble: the highest does is soluble in <250 ml water over a pH range of 1
to 7.5
Highly permeable: >90% dose absorbed in humans
Rapidly dissolving: >85% of labeled amount of drug substance dissolves within
30 minutes
Solubility Studies
Pre-formulation solubility studies focus on
drug-solvent systems that could occur during
the delivery of a drug candidate.
Pre-formulation solubility studies include
Determination of pka
pH-solubility profile
Common ion effect
Thermal effects
Solubilization
Partition coefficient
Dissolution

Solubility Determination
The solubility of a material is usually determined by
the equilibrium solubility method, which employs a
saturated solution of the material, obtained by stirring
an excess of material in the solvent for a prolonged
period until equilibrium is achieved.
The solubility should ideally be measured at two
temperature.
4C to ensure physical stability and entered short term storage and chemical
stability unit more definitive data are available. The minimum density of water
occurs at 4C. This leads to a minimum aqueous solubility.
37C to support biopharmaceutral evaluation .
Common solvents used for solubility determination
are selected through ICH guidelines which categories
solutions into following 4 groups:
ICH guide lines
Class 1 solvents: Solvents to be avoided
Known human carcinogens, strongly suspected human
carcinogens, and environmental hazards.
Hexane
Methanol
Toluene
Class 2 solvents: Solvents to be limited
Non-genotoxic animal carcinogens or possible causative
agents of other irreversible toxicity such as neurotoxicity
or teratogenicity.
Solvents suspected of other significant but reversible
toxicities.
Benzene
Carbon tetrachloride
ICH guide lines
Class 3 solvents: Solvents with low toxic potential
Solvents with low toxic potential to man; no health-
based exposure limit is needed. Class 3 solvents have
PDEs of 50 mg or more per day.
Acetone
Isopropyl acetate
butanol
Class 4 solvents: Solvents with no adequate data
may also be of interest to manufacturers of
excipients, drug substances, or drug products.
However, no adequate toxicological data is available.
Isopropyl ether
Petrolium ether

Solubility Studies
pH Solubility Profile
Solubility at various pH
Solubility in various solvents
Factors Studied In Relation
To Solubility Analysis
Temperature
pH
Ionic strength
Buffer type and concentration
Common solvent for solubility
Water
Polyethylene Glycols
Propylene Glycol
Glycerin
Sorbitol
Ethyl Alcohol
Methanol
Benzyl Alcohol
Isopropyl Alcohol
Castor Oil
Peanut Oil
Sesame Oil
Buffers at various pHs
SGF & SIF
pKa Determination
pKa
pKa values are used to express the pH at which
acidic and basic groups attached to molecules
are 50% ionized and 50% unionized in aqueous
solution.

It is determined by analytical methods
Spectroscopy (preferred)
Potentiometery
Conductivity

Solubility Studies
Importance
Since most drugs are ionizable, the pKa value(s) provides
information regarding its interaction with charges
biological membranes and receptor sites. In addition, it is
possible to establish the pH range over which a drug
molecule is neutral in charge (and therefore more
lipophilic and easily absorbed).
It gives valuable information regarding where in the
digestive tract an orally available drug may be absorbed.
Analysis of pKa also provides information on solubility
since the solubility of unionized species is lower that of
ionized species.
Handerson Hasselbalch
Equation
It provides an estimate of the ionized and un-
ionized drug concentration at a particular pH.
For acidic compounds:
pH= pKa + log [ionized drug]/[un-ionized drug]
For basic compounds:
pH= pKa+ log [un-ionized drug]/[ionized drug]

Above equations are used
To determine pKa by following changes in solubility.
To predict solubility at any pH, provided intrinsic solubility and pKa are
known.
To facilitate the selection of suitable salt forming compounds and predict the
solubility and pH properties of salt
Common Ion Effects
The common-ion effect is a term used to
describe the effect on a solution of two
dissolved solutes that contain the same ion.
The presence of a common ion suppresses
the ionization of a weak acid or a weak base.
Common-ion effect, decrease in solubility of
an ionic salt, i.e., one that dissociates in
solution into its ions, caused by the presence
in solution of another solute that contains
one of the same ions as the salt. The
common-ion effect is an example of
chemical equilibrium.
Analytical Methods For
Solubility Analysis
HPLC
UV SPECTROSCOPY
FLUORESCENCE SPECTROSCOPY
GC
POTENTIOMETERY
Solubilization
Solubilization is defined as the process of preparing a
visually clear solution of a substance that is only
slightly soluble in solvent.
A general method of increasing solubility is the
addition of a co-solvent to the aqueous system .the
extent of solubilization depends on the chemical
structure of the drug.
The more non-polar the solute ,the greater is the
solubilization achieved by cosolvent addition
These cosolvents solubilize drug molecules by
disrupting hydrophobic interaction at the non polar
solute-water interface.

Importance
For drugs with either poor solubility or
insufficient solubility in projected dosage
forms
Preformulation studies must include some
experiments to identify possible mechanism
for solubilization.
Partition co-efficient
Partition co efficient is defined as the ratio of
unionized drug distributed between the
organic and aqueous phases at equilibrium.

P
o/w
= C oil
C water


Drug will go through a series of partitioning
steps
1. Leaving the aqueous extracellular fluids
2. Passing through lipid membranes
3. Entering other aqueous environment
before reaching the receptor
Parti ti on co-ef f i ci ent
Procedure for obtaining partition
coefficient
The basic procedure for obtaining a partition
coefficient is to shake a weighed amount of chemical
in a flask containing a weighed amount of water
saturated octanol and octanol saturated water. Many
times the aqueous phase will be buffered with a
phosphate buffer at ph 7.4 to reflect physiological
pH. The amount of chemical is determined by proper
analytical technique and partition coefficient is
calculated by using formula already discussed.
n octanol/water partitioning system seems to mimic
the lipid membrane/water system found in body.


Dissolution
The process of dissolution occur in two steps
1. Solvation of the solute molecules by the solvent
molecules.
2. Transfer of these molecules from the interface into
the bulk medium by convection or diffusion.
The various factors affecting dissolution are:
Chemical nature of solute
Crystal habit
Particle size
Surface area
Wetting properties


Partition coefficient and SAR
In homologous series of compounds in which the
change in structure only involves an increase in
length of carbon chain , gradation in intensity of
action have been observed.
Increasing the non polar portion increases the
partition coefficient and the solubility in water
decreases.
Increase in length of carbon chain results
increases activity until it reaches a maximum.
The increase in activity roughly parallels the
decrease in water solubility
Dissolution rate
Noyes whitney equation
dC =DA (Cs-C)
dt hV
D=diffusion coefficient
H=thickness of diffusion layer at solid liquid interface
A=surface area
V=volume of medicine
Cs=concentration of a saturated solution of solute in dissolution
media at the experiment temperature
C=concentration at time t
Dc/dt= dissolution rate

Chemical Stability
In SGF and SIF
pH-stability profile
Solid state stability
Effect of moisture
Effect of solid state form amorphous vs. crystalline
Excipient compatibility
Effect of moisture
Effect of processing
Degradation mechanism
Hydrolysis
Oxidation potential
Effect of temperature

References
Pharmaceutics,the science of dosage form
design by M.E.Aulton
The theory and practice of industrial pharmacy
by Leon Lachman, Herbert A. Lieberman and
Joseph L.Kanig
Physical pharmacy by Martin
Text book of Organic Medicinal and
pharmaceutical Chemistry by Charles
O.Wilson, Ole Gisvold and Robert F.Doerge
Pharmaceutical Dosage forms and drug
delivery system by Ansel.