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 counterion. 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 agent

Compound modified

Modificatio n Solubility Toxicity Organolept ic properties Reduced pains on injection

Acetyl Doxacyclin aminoacetic acid Embonic acid Kanamycin Probencid Morpholine Pivampicillin Cephalosporins

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 c r y s t a llin e s in g le e n t ity p o ly m o r p h s m o le c u la r a d d u c ts s t o c h io m e tr ic s o lv a t e s (h y d ra te s ) n o n s t o c h i o m e t r ic in c lu s io n c o m p o u n d s channel cage ( c la t h r a t e ) la y e r in t e r n a l s t ru c t u re a m o rp h o u s

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-tobatch 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 cosolvents 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

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