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PREFORMULATION

Y EN

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
Potential hazards
Initial bulk lots
± Lot number
± Crystallizationsolvents
± Particle size range
± Meltingpoint
± %volatiles
± Observations
Analytical methods
± PLC,TLC,UV/VIS,Synthetic
route,Probable decay routes
þey 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 APPROAC ES

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 + + to the secondary
nitrogen atom

Ephedrine + cl- cl- + ephedrine - +


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 T AT 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
ERYT ROMYCIN ESTOLATE
In aqueous solution protonated
erythromycin is
± Yater soluble
± as bitter taste
± Rapidly hydrolysed in gastric acid
Lauryl sulfate salt of propionate ester
prodrug (estolate) has improved
pharmaceutical properties with
enhanced bioavailability.
Salt forming agent Compound modified Modification

Acetyl aminoacetic Doxacyclin Solubility


acid

Embonic acid þanamycin Toxicity

Probencid Pivampicillin Organoleptic


properties
Morpholine Cephalosporins Reduced pains
on injection
MAJOR AREAS OF PREFORMULATION
RESEARC

BULþ C ARACTERIZATION
± Crystallinity and polymorphism
± ygroscopicity
± Fine particle characterisation
± Bulk density
± Powder flow properties
MAJOR AREAS OF PREFORMULATION
RESEARC
SOLUBILITY ANALYSIS
± Ionisation constant(Pka)
± P solubility profile
± Common ion effect(þsp)
± Thermal effects
± Solubilization
± Partition coefficient
± Dissolution
MAJOR AREAS OF PREFORMULATION
RESEARC
STABILITY ANALYSIS

± Stability in toxicology

± Solution stability
‡ P rate profile

± Solid state stability


‡ Bulk stability
‡ Compatibility
BULþ C ARACTERIZATIION
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 POLYMORP ISM

abit is the description of the outer


appearance of a crystal
Internal structure is the molecular
arrangement within the solid.
OUTLINE OF DIFFERENTIATING ABIT AND
CRYSTAL C EMISTRY OF A COMPOUND

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MICROSCOPY

T ERMAL ANALYSIS

POLYMORP ISM
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
± ave more than one refractive index
± Two refractive indices are uniaxial
± Three refractive indices are biaxial.
Most drugs are biaxial with orthorhombic or
monoclinic or triclinic crystal system
USES

Investigating polymorphism
Melting points
Transition temperatures
T ERMAL 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.

Thermogravimetric analysis (TGA) measures


changes in sample weight as a function of time
(isothermal ) or temperature.
USES
Quantitative measurement is a direct function
for polymorphism,purity,solvation,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 bulk
sample.
ß-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 analytical forms can be
analyzed.

Single crystal analysis provides precise


identification and description of a crystalline
substance.
POLYMORP ISM
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
± ardness
± Crystal shape
± Optical properties
± Vapor pressure
Polymorphs can be classified as
± Enantiotropic
± Monotropic

Stability during process and at different


temperatures has to be studied
YGROSCOPICITY
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
± ygroscopic : forms hydrate addition of water at
specific site. Eg: istamine,Ach
YGROSCOPICITY
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 justify special handling
procedures kinetically
FINE PARTICLE
C ARACTERISATION
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 observed by scanning
electron microscopy.
BULþ DENSITY
FACTORS EFFECTING
± Method of crystallization
± Milling
± Formulation
Can be corrected by
± Milling
± Slugging
± Formulation
Method to determine bulk density.
POYDER FLOY PROPERTIES

P ARMACEUTICAL POYDERS
± Free flowing
± Cohesive
Flow properties are significantly
affected by
± Size
± Density
± Shape
± Electrostatic charge
± Adsorbed moisture
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
± p solubility profile
± Solubility products
± Solubilization mechnanisms
± Rate of dissoution
SOLUBILITY ANALYSIS

Analytical methods useful include


± PLC
± UV spectroscopy
± Fluorescence spectroscopy
± Reverse phase gas chromatography
Dissociation constant pþa
Solubility and absorption altered

enderson ± asselbach equation

Acidic compounds
p pþa+log (ionized)
(un-ionized
drug)
Basic compounds
p pþa+log (un-ionized)
(ionized
drug)
Absorption principles

Yeakly acidic drug ± pþa > 3 , unionised form in the


stomach

Drug is ionised predominantly in intestine

Basic drug pþa  8-10,ionised form predominantly in


stomach and intestine

In general unionized species absorbed more


DETERMINATION OF Pka

ANALYTICAL MET ODS


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

± Potentiometric titration (pþa range of 3-10)


FACTORS AFFECTING pþa

Buffer
Temperature
Ionic strength
Co solvent
EFFECT OF TEMPERATURE

SOLUTION PROCESS
± ENDOT ERMIC
‡ EAT OF SOLUTION IS POSITIVE
± EßOT ERMIC
‡ EAT OF SOLUTION IS NEGATIVE
Non-electrolytes and ionized forms delta
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

Extent of solubilization depends on chemical


structure of drug compound.
PARTITION COEFFICIENT
Ratio of unionised drugs distributed
between organic and inorganic aqueous
phase at equilibrium

Importance
± Screening for biological activity
± Drug delivery
± Characterizing lipophilic / hydrophilic nature
of drug.
p solubility profile and common
ion effects

Solubility of an acidic or basic depends on


± pþa of the ionizing functional group
± intrinsic solubilities for both the ionised and
unionised forms

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