PREFORMULATION
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