PREFORMULATIO

N
 WHEN

If the drug shows

sufficient activity in
animals and is to be
evaluated in man
 FOCUS

On physicochemical properties
of a new compound which
may effect the drug
performance and development
of efficacious dosage form.
Essential information

Compound identity
Structure
Formula and molecular
weight
Therapeutic indications
– Probable human doses
– Desired dosage form(s)
– Bioavailability model(s)
– Competitive products
Initial bulk lots
– Lot number
– Crystallizationsolvents
– Particle size range
– Meltingpoint
– %volatiles
– Observations
Analytical methods
– HPLC,TLC,UV/VIS,Synthetic
route,Probable decay
routes
Key dates
– Bulk scale up, toxicology start
date,clinical supplies
preparation,IND filing,Phase-I
testing.
Critical development issues
PRELIMINARY EVALUATION
AND MOLECULAR
OPTIMIZATION
Stability and solubility problems
adversely effects drug
performance.
This helps in identifying problem
in each suspected area.
Molecular modifications can be
done that would most likely
improve the drug’sproperties
MODIFICATION APPROACHES

Two approaches are most

common

– Salt formation

– Prodrug development
 SALT FORMATION
Either by addition or removal
of proton to form an ionized
drug molecule
Neutralized with a counter-
ion.
e.g.ephedrine
hydrochloride
ephedrine + H+ to the
secondary
nitrogen atom
Organic salts are more
water soluble
Increased dissolution
rates and improved
bioavailability
 DISADVANTAGES FOR SALT
FORMATION

Salt formation is limited to

molecules
with ionizable groups
PRODRUG FORMATION

Prodrugs are synthetic

derivatives
(esters or amides) of drug
molecules that
may have intrinsic activity but
usually
undergo some transformation in
vivo to
liberate the active drug molecule
FACTORS THAT CAN BE
ALTERED BY PRODRUG
FORMATION
Increased lipophilicity and
increased water solubility
Increased duration of activity
Increased distribution
Pharmaceutical improvements
– Stability
– Solubility
– Taste
– Odor
– Crystallinity
– Reduced pain on injection
 ERYTHROMYCIN
ESTOLATE
In aqueous solution
protonated erythromycin is
– Water soluble
– Has bitter taste
– Rapidly hydrolysed in gastric
acid
Lauryl sulfate salt of
propionate ester prodrug
(estolate) has improved
Salt forming Compound Modificatio
agent modified n
Acetyl Doxacyclin Solubility
aminoacetic
acid
Embonic acid Kanamycin Toxicity

Probencid Pivampicillin Organolept

ic
properties
Morpholine Cephalosporins Reduced
pains on
injection
 MAJOR AREAS OF
PREFORMULATION RESEARCH

BULK CHARACTERIZATION
– Crystallinity and polymorphism
– Hygroscopicity
– Fine particle characterisation
– Bulk density
– Powder flow properties
 MAJOR AREAS OF
PREFORMULATION RESEARCH
SOLUBILITY ANALYSIS
– Ionisation constant(Pka)
– PH solubility profile
– Common ion effect(Ksp)
– Thermal effects
– Solubilization
– Partition coefficient
– Dissolution
 MAJOR AREAS OF
PREFORMULATION RESEARCH
STABILITY ANALYSIS

– Stability in toxicology

– Solution stability
• PH rate profile

– Solid state stability

• Bulk stability
• Compatibility
BULK CHARACTERIZATIION
Great potential for many
polymorphic forms to emerge
Bulk properties
– Particle size
– Bulk density
– Surface morphology
Avoid misleading predictions
of stability or solubility which
depend on particular
crystalline form.
 CRYSTALLINITY AND
POLYMORPHISM

Habit is the description of the

outer appearance of a crystal
Internal structure is the
molecular arrangement within
the solid.
 OUTLINE OF DIFFERENTIATING
HABIT AND CRYSTAL CHEMISTRY
OF A COMPOUND

c h e m ic a l c o m p o u n d

h a b it in t e r n a l s t ru c t u re

c r y s t a llin e a m o rp h o u s

s in g le e n t ity m o le c u la r a d d u c ts

p o ly m o r p h s s t o c h io m e tr ic s o lv a t e s n o n s t o c h i o m e t r ic
(h y d ra te s ) in c lu s io n c o m p o u n d s

channel la y e r

cage
( c la t h r a t e )
MICROSCOPY

THERMAL ANALYSIS

POLYMORPHISM
 MICROSCOPY
ISOTROPIC
– Do not transmit light with
polarized filters and appear
black
– Only one refractive index
ANISOTROPIC
– Transmits light and appear
bright with brilliant colors
– Have more than one refractive
index
– Two refractive indices are
uniaxial
 USES

Investigating polymorphism
Melting points
Transition temperatures
THERMAL ANALYSIS

Differential scanning calorimetry

(DSC) and differential thermal
analysis(DTA)

– Measure the heat loss or gain from a

chemical or physical change as a
function of temperature
– Crystallization and degradation are
exothermic
– Fusion,boiling,sublimation etc are
endothermic.
 USES
Quantitative measurement is
a direct function for
polymorphism,purity,solvatio
n,degradation and excipient
compatibility.
For characterizing crystals
DSC curves can be used.
TGA and DSC can be used to
quantitate the presence of a
solvated species within a
X-Ray-diffraction
Establishing the batch-to-
batch reproducibility of a
crystalline form.

Each diffraction pattern is

characteristic of a specific
crystalline lattice.

Amorphous form does not

produce a pattern.
 USES
Mixtures of different analytica
forms can be analyzed.

Single crystal analysis

provides precise identification
and description of a crystalline
substance.
 POLYMORPHISM
Is the ability of a compound (or
element ) to crystallise as more than
one distinct crystalline species with
different internal lattices.
Changes in chemical stability and
solubility
Effects drug’s bioavailability and its
development program
Physicochemical parameters that
alter
– Melting point
– Density
– Hardness
Polymorphs can be classified as
– Enantiotropic
– Monotropic

Stability during process and at

different temperatures has to be
studied
 HYGROSCOPICITY
FACTORS
– Adsorption and equilibrium
moisture content depends upon
– Atmospheric humidity
– Temperature
– Surface area
– Exposure and mechanism for
moisture uptake
TYPES
– Deliquescent :Adsorb sufficietly
water to dissolve completely
– Hygroscopic : forms hydrate
addition of water at specific
 HYGROSCOPICITY
Changes in moisture level
effects
– Chemical stability
– Flow ability
– Compactibility

Normalised or percentage
weight gain data from these
hygroscopic studies are
plotted against time to
 FINE PARTICLE
CHARACTERISATION
Dissolution and chemical
reactivity are directly effected
by
– Size
– Shape
– Surface morphology of drug
molecules
Can be done using
– Light microscope
– Stream counting devices such as
coulter counter technique.
– Surface morphology can be
 BULK DENSITY
FACTORS EFFECTING
– Method of crystallization
– Milling
– Formulation
Can be corrected by
– Milling
– Slugging
– Formulation
Method to determine bulk
density.
 POWDER FLOW
PROPERTIES
PHARMACEUTICAL
POWDERS
– Free flowing
– Cohesive
Flow properties are
significantly affected by
– Size
– Density
– Shape
– Electrostatic charge
SOLUBILITY ANALYSIS

Focus on drug-solvent
system that could occur
during the delivery of the
drug candidate.

Provides basis for formulation

work.
SOLUBILITY ANALYSIS

DETERMINATIONS OF
– Pka
– Temperature dependence
– pH solubility profile
– Solubility products
– Solubilization mechnanisms
– Rate of dissoution
SOLUBILITY ANALYSIS

Analytical methods useful

include
– HPLC
– UV spectroscopy
– Fluorescence spectroscopy
– Reverse phase gas
chromatography
Dissociation constant pKa
Solubility and absorption altered

Henderson – Hasselbach equation

Acidic compounds
pH=pKa+log (ionized)
(un-ionized
drug)
Basic compounds
pH=pKa+log (un-ionized)
(ionized
drug)
Absorption principles

Weakly acidic drug – pKa > 3 ,

unionised form in the stomach

Drug is ionised predominantly in

intestine

Basic drug pKa = 8-10,ionised

form predominantly in stomach
and intestine
DETERMINATION OF Pka

ANALYTICAL METHODS
– Determination of spectral
shifts by UV or visible
spectroscopy(dilute
aq.solutions can be
analyzed directly).

– Potentiometric titration
(pKa range of 3-10)
FACTORS AFFECTING pKa

Buffer
Temperature
Ionic strength
Co solvent
 EFFECT OF
TEMPERATURE
SOLUTION PROCESS
– ENDOTHERMIC
• HEAT OF SOLUTION IS POSITIVE
– EXOTHERMIC
• HEAT OF SOLUTION IS NEGATIVE

Non-electrolytes and ionized

forms delta H between 4 to 8
kcal/mole
Salt forms of drugs –2 to 2
kcal/mole(less sensitive to
temperature)
EFFECT OF TEMPERATURE

Effect solution dosage form

design and storage condition

Solvent systems including co-

solvents

Miscelles

complexation
 Solubilization
Increasing the solubility of a drug by
addition of a third agent is called
solubilization.

Addition of cosolvent to the aqueous

system like ethanol,propylene glycol
and glycerine.

act by disrupting the hydrophobic

interactions at the nonpolar solute/
water interface
PARTITION COEFFICIENT
Ratio of unionised drugs
distributed between
organic and inorganic
aqueous phase at
equilibrium

Importance
– Screening for biological
activity
– Drug delivery
pH solubility profile and
common ion effects

Solubility of an acidic or basic

depends on
– pKa of the ionizing functional
group
– intrinsic solubilities for both
the ionised and unionised forms