PREFORMULATION

WHENIf the drug shows sufficient activity in animals and is to be evaluated in man

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

Essential informationCompound 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 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 OPTIMIZATIONStability 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 drugsproperties

MODIFICATION APPROACHESTwo approaches are most common Salt formation Prodrug development

SALT FORMATIONEither 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+ clcl- + 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 FORMATIONProdrugs 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 FORMATIONIncreased 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 pharmaceutical properties with enhanced bioavailability.

Salt forming agent Acetyl aminoacetic acid Embonic acid Probencid Morpholine

Compound modified Doxacyclin Kanamycin Pivampicillin Cephalosporins

Modification Solubility Toxicity Organoleptic properties Reduced pains on injection

MAJOR AREAS OF PREFORMULATION RESEARCHBULK CHARACTERIZATION Crystallinity and polymorphism Hygroscopicity Fine particle characterisation Bulk density Powder flow properties

MAJOR AREAS OF PREFORMULATION RESEARCHSOLUBILITY ANALYSIS Ionisation constant(Pka) PH solubility profile Common ion effect(Ksp) Thermal effects Solubilization Partition coefficient Dissolution

MAJOR AREAS OF PREFORMULATION RESEARCHSTABILITY ANALYSIS Stability in toxicology Solution stability PH rate profile

Solid state stability Bulk stability Compatibility

BULK CHARACTERIZATIIONGreat 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 POLYMORPHISMHabit 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 COMPOUNDchemical compound

habit crystalline single entity polymorphs molecular adducts stochiometric solvates (hydrates)

internal structure amorphous

nonstochiometric inclusion compounds channel layer

cage (clathrate)

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

USESInvestigating polymorphism Melting points Transition temperatures

THERMAL ANALYSISDifferential 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.

USESQuantitative 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-diffractionEstablishing 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.

USESMixtures 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 solubility Effects drugs bioavailability and its development program Physicochemical 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

HYGROSCOPICITYFACTORS 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 CHARACTERISATIONDissolution 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 DENSITYFACTORS EFFECTING Method of crystallization Milling Formulation

Can be corrected by Milling Slugging Formulation

Method to determine bulk density.

POWDER FLOW PROPERTIESPHARMACEUTICAL POWDERS Free flowing Cohesive

Flow properties are significantly affected by Size Density Shape Electrostatic charge Adsorbed moisture

SOLUBILITY ANALYSISFocus on drug-solvent system that could occur during the delivery of the drug candidate. Provides basis for formulation work.

SOLUBILITY ANALYSISDETERMINATIONS OF Pka Temperature dependence pH solubility profile Solubility products Solubilization mechnanisms Rate of dissoution

SOLUBILITY ANALYSISAnalytical methods useful include HPLC UV spectroscopy Fluorescence spectroscopy Reverse phase gas chromatography

Dissociation constant pKaSolubility and absorption altered Henderson Hasselbach equationAcidic compounds pH=pKa+log (ionized) (un-ionized drug) Basic compounds pH=pKa+log (un-ionized) (ionized drug)

Absorption principlesWeakly 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 PkaANALYTICAL 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 pKaBuffer Temperature Ionic strength Co solvent

EFFECT OF TEMPERATURESOLUTION 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 TEMPERATUREEffect solution dosage form design and storage condition Solvent systems including co-solvents Miscelles complexation

SolubilizationIncreasing 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 effectsSolubility of an acidic or basic depends on pKa of the ionizing functional group intrinsic solubilities for both the ionised and unionised forms