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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
± 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
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
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
P ARMACEUTICAL POYDERS
± Free flowing
± Cohesive
Flow properties are significantly
affected by
± Size
± Density
± Shape
± Electrostatic charge
± Adsorbed moisture
SOLUBILITY ANALYSIS
DETERMINATIONS OF
± Pka
± Temperature dependence
± p solubility profile
± Solubility products
± Solubilization mechnanisms
± Rate of dissoution
SOLUBILITY ANALYSIS
Acidic compounds
p pþa+log (ionized)
(un-ionized
drug)
Basic compounds
p pþa+log (un-ionized)
(ionized
drug)
Absorption principles
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
Miscelles
complexation
Solubilization
Increasing the solubility of a drug by addition of a
third agent is called solubilization.
Importance
± Screening for biological activity
± Drug delivery
± Characterizing lipophilic / hydrophilic nature
of drug.
p solubility profile and common
ion effects