PREFORMULATION

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 identityStructureFormula and molecular weightTherapeutic 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– 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

Ephedrine H+ cl- cl- + ephedrine - H+

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 solubilityIncreased duration of activity Increased distribution Pharmaceutical improvements – Stability– Solubility– Taste– Odor– Crystallinity– Reduced pain on injection

ERYTHROMYCIN ESTOLATEIn 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 pharmaceutical properties with enhanced bioavailability.

Salt forming agent Compound modified Modification

Acetyl aminoacetic acid

Doxacyclin Solubility

Embonic acid Kanamycin Toxicity

Probencid Pivampicillin Organoleptic 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 CHARACTERIZATIIONGreat potential for many polymorphic forms to emergeBulk 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 crystalInternal structure is the molecular arrangement within the solid.

OUTLINE OF DIFFERENTIATING HABIT AND CRYSTAL CHEMISTRY OF A COMPOUND

h a b it

p o lym o rp hs

s in g le e n tity

s to ch io m e tric so lva tes(h yd ra te s)

ch a nn e l la ye r

ca ge(c la th ra te )

n o n s to ch iom e tricin c lus io n co m p ou n ds

m o lecu la r a dd u c ts

c rys ta llin e a m orp ho us

in te rna l s tru c tu re

ch e m ica l com p ou nd

MICROSCOPY

THERMAL ANALYSIS

POLYMORPHISM

MICROSCOPYISOTROPIC – 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– Three refractive indices are biaxial.

Most drugs are biaxial with orthorhombic or monoclinic or triclinic crystal system

USES

Investigating polymorphismMelting pointsTransition 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.

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.

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 analytical forms can be analyzed.

Single crystal analysis provides precise identification and description of a crystalline substance.

POLYMORPHISMIs 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 solubilityEffects drug’s bioavailability and its development programPhysicochemical parameters that alter– Melting point– Density– Hardness– Crystal shape– Optical properties– Vapor pressure

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 site. Eg:Histamine,Ach

HYGROSCOPICITYChanges 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 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 observed by scanning

electron microscopy.

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– 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– 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 pKaSolubility and absorption altered

Henderson – Hasselbach equation Acidic compounds pH=pKa+log (ionized) (un-ionized drug)Basic compoundspH=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

In general unionized species absorbed more

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

Extent of solubilization depends on chemical structure of drug compound.

PARTITION COEFFICIENTRatio 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.

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