Preformulation studies

Preformulation StudiesPreformulation Studies
By L.T.M. Muungo, PhD,By L.T.M. Muungo, PhD,
Pharmaceutist,Pharmaceutist,
Department of Pharmacy, UNZA,Department of Pharmacy, UNZA,
ZambiaZambia

Outline of topicOutline of topic
 Study ofStudy of physical propertiesphysical properties of drugs like physicalof drugs like physical
form, particle size, shape, density, wetting,form, particle size, shape, density, wetting,
dielectric constant, solubility, dissolution,dielectric constant, solubility, dissolution,
organoleptic properties and their effect onorganoleptic properties and their effect on
formulation, stability and bioavailability.formulation, stability and bioavailability.
 Study ofStudy of chemical propertieschemical properties of drugs likeof drugs like
hydrolysis, oxidation – reduction, racemisation,hydrolysis, oxidation – reduction, racemisation,
polymerization and their influence on formulationpolymerization and their influence on formulation
and stability of products.and stability of products.
 Study ofStudy of prodrugsprodrugs in solving problems related toin solving problems related to
stability, bioavailability and elegancy ofstability, bioavailability and elegancy of
formulation.formulation.

IntroductionIntroduction
Preformulation:Preformulation:
• a stage of development during which thea stage of development during which the
physicochemical properties of drug substance arephysicochemical properties of drug substance are
characterized.characterized.
When???When???
• If the drug shows sufficient activity in animals & isIf the drug shows sufficient activity in animals & is
to be evaluated in humans.to be evaluated in humans.
Focus……Focus……
• On physicochemical properties of a new compoundOn physicochemical properties of a new compound
which may affect the drug performance &which may affect the drug performance &
development of efficacious dosage form.development of efficacious dosage form.

Drug Development CycleDrug Development Cycle

The Drug Development Cycle ~ AnThe Drug Development Cycle ~ An
OverviewOverview
The process of developing a new drug can take betweenThe process of developing a new drug can take between
10 and 15 years with an estimated average cost of $80010 and 15 years with an estimated average cost of $800
millionmillion
Discovery/Pre-Clinical TestingDiscovery/Pre-Clinical Testing
 Time: 6.5 YearsTime: 6.5 Years
Phase IPhase I
Phase II: Safety and EfficacyPhase II: Safety and Efficacy
 Time: 2 YearsTime: 2 Years
Phase IIIPhase III
Marketing Approval ProcessMarketing Approval Process

IntroductionIntroduction
Project team –Project team – Representative fromRepresentative from
different disciplinesdifferent disciplines
Different DisciplinesDifferent Disciplines
Medicinal Chemistry and PharmacologyMedicinal Chemistry and Pharmacology
Pre-formulation ResearchPre-formulation Research
Formulation developmentFormulation development
Process R&DProcess R&D
Analytical R&DAnalytical R&D
Toxicology and drug metabolismToxicology and drug metabolism

Development of a drugDevelopment of a drug
candidatecandidate
 DeficiencyDeficiency –– Molecular modification toMolecular modification to
improve drug propertiesimprove drug properties
Salts eg. Ephedrine HClSalts eg. Ephedrine HCl
Prodrug eg. Erythromycin EstolateProdrug eg. Erythromycin Estolate
Solvates, polymorphs etcSolvates, polymorphs etc
 SynthesisSynthesis organic media – Purityorganic media – Purity

Compound IdentityCompound Identity
StructureStructure
Formula & Mo. Wt.Formula & Mo. Wt.
Therapeutic IndicationTherapeutic Indication
•Probable Human DoseProbable Human Dose
•Desired Dosage Form(s)Desired Dosage Form(s)
•Bioavailability Model(s)Bioavailability Model(s)
•Comparative ProductsComparative Products
Potential HazardsPotential Hazards
Initial Bulk LotsInitial Bulk Lots
•Lot NumberLot Number
•Crystallization Solvent(s)Crystallization Solvent(s)
•Particle Size RangeParticle Size Range
•Melting PointMelting Point
•% Volatiles% Volatiles
•ObservationsObservations
Analytical MethodsAnalytical Methods
•HPLC AssayHPLC Assay
•TLC AssayTLC Assay
•UV/VIS SpectroscopyUV/VIS Spectroscopy
•Synthetic RouteSynthetic Route
•Probable Decay ProductsProbable Decay Products
Key DatesKey Dates
•Bulk Scale upBulk Scale up
•Toxicology Start DateToxicology Start Date
•Clinical Supplies PreparationClinical Supplies Preparation
•IND FilingIND Filing
•Phase I TestingPhase I Testing
Critical development Issue(s)Critical development Issue(s)
Essential information helpful in designing preformulation evaluation of a new drugEssential information helpful in designing preformulation evaluation of a new drug
I
II
III
V
VI
IV
VII
VIII
IX

Drug DiscoveryDrug Discovery Literature SearchLiterature Search
Preliminary DataPreliminary Data
•Stability assay
•Key Stability Data
•Key solubility Data
Molecular OptimizationMolecular Optimization
Salts & solvates
 Prodrugs
Evaluation & Selection ofEvaluation & Selection of
DrugDrug
Formulation RequestFormulation Request
PhysicalPhysical
CharacterizationCharacterization
•Bulk properties
•Solubility profile
•Stability profile
FormulationFormulation
DevelopmentDevelopment
•Compatibility & Stability
•Dissolution
•Bioavailability
Phase IPhase I
FormulationFormulation
•IND Stability
•Bioavailability
•Scale-up
Investigational New Drug (IND) ApplicationInvestigational New Drug (IND) Application
Process ResearchProcess Research
•Improve Yield
•Alternate route
•Produce bulk
Process DevelopmentProcess Development
•Bulk scale-up
AnalyticalAnalytical
ResearchResearch
•Assay development
Analytical ResearchAnalytical Research
•Bulk clearance
•Toxicity potency
•Formulation assay
•IND formulation
stability
BioavailabilityBioavailability
•In-vivo models
ToxicologyToxicology
•Acute
•Chronic

Preformulation studies are an important foundationPreformulation studies are an important foundation
tool early in the development of both API and drugtool early in the development of both API and drug
products.products.
They influence….They influence….
Selection of the drug candidate itselfSelection of the drug candidate itself
Selection of formulation componentsSelection of formulation components
API & drug product manufacturing processesAPI & drug product manufacturing processes
Determination of the most appropriate container /Determination of the most appropriate container /
closure systemclosure system
Development of analytical methodsDevelopment of analytical methods
Assignment of API retest periodsAssignment of API retest periods
The synthetic route of the APIThe synthetic route of the API
Toxicological strategic management processToxicological strategic management process
Why preformulation studies areWhy preformulation studies are
required?required?

Preformulation CharacterizationPreformulation Characterization
Bulk propertiesBulk properties
 OrganolepticOrganoleptic
 crystallinity and polymorphismcrystallinity and polymorphism
 water adsorptionwater adsorption
 particle size, shape, andparticle size, shape, and
surface areasurface area
 bulk densitybulk density
 AdhesionAdhesion
 powder flowpowder flow
 compressibilitycompressibility
Physico-chemical propertiesPhysico-chemical properties
 solubility analysissolubility analysis
 IonizationIonization
 partition coefficientspartition coefficients
 dissolutiondissolution
StabilityStability
•solid state (RH, oxygen, light, compatibility)solid state (RH, oxygen, light, compatibility)
•solution (pH, buffers, solvent, temperature)solution (pH, buffers, solvent, temperature)
•compatibility with excipients (other additives)compatibility with excipients (other additives)
Biopharmaceutical propertiesBiopharmaceutical properties
•absorption (route, rate, extent, mechanism,absorption (route, rate, extent, mechanism,
absorption windows, food effects)absorption windows, food effects)
•metabolism (first pass metabolism, enzymemetabolism (first pass metabolism, enzyme
induction, metabolism in GIT)induction, metabolism in GIT)
•duration of action (dosing, controlled release)duration of action (dosing, controlled release)
•dosedose

Investigative Procedures on
Pre-formulation Characteristic
contents as Examples

ObjectiveObjective
 Quantitation of physical chemicalQuantitation of physical chemical
properties that will assist in developing aproperties that will assist in developing a
stable, safe and effective formulation withstable, safe and effective formulation with
maximum bioavailabilitymaximum bioavailability

Principal areas ofPrincipal areas of
Pre-formulationsPre-formulations
 Bulk CharacterizationBulk Characterization
 Solubility AnalysisSolubility Analysis
 Stability AnalysisStability Analysis

Principal areas of PreformulationsPrincipal areas of Preformulations
 Bulk CharacterizationBulk Characterization
Crystallinity and polymorphismCrystallinity and polymorphism
HygroscopicityHygroscopicity
Fine particle characterizationFine particle characterization
Bulk densityBulk density
Powder flow propertiesPowder flow properties

Bulk CharacterizationBulk Characterization
 Synthetic process simultaneously developedSynthetic process simultaneously developed
 A drug candidateA drug candidate – Solid form not identified –– Solid form not identified –
emerge of new polymorphsemerge of new polymorphs
 Solid formSolid form – particle size, bulk density and– particle size, bulk density and
surface morphology – Process developmentsurface morphology – Process development
 Comprehensive characterizationComprehensive characterization – To avoid– To avoid
misleading predictions of stability or solubility,misleading predictions of stability or solubility,
which depends on a particular crystalline formwhich depends on a particular crystalline form

Crystallinity and polymorphismCrystallinity and polymorphism
Crystal habit and the internal structureCrystal habit and the internal structure
affects the bulk and physiochemicalaffects the bulk and physiochemical
propertiesproperties
Flowability to chemical stabilityFlowability to chemical stability
HabitHabit – Description of the outer– Description of the outer
appearance of a crystalappearance of a crystal
Eg: Acicular or needle, platy, massive,Eg: Acicular or needle, platy, massive,
tabular etctabular etc
Internal structure :Internal structure : MolecularMolecular
arrangement within the solidarrangement within the solid

 Changes in internal structure for a compound – AlterChanges in internal structure for a compound – Alter
change in the crystal habit.change in the crystal habit.
 Characterisation Involves –Characterisation Involves –
 Verifying the solid is the expected chemical compoundVerifying the solid is the expected chemical compound
 Characterization the internal structureCharacterization the internal structure
 Describing the habit of the crystalDescribing the habit of the crystal
Prismatic
Bladed

Habit and Crystal chemistry of aHabit and Crystal chemistry of a
compoundcompound
Chemical CompoundChemical Compound
HabitHabit Internal structureInternal structure
AmorphousAmorphousCrystallineCrystalline
Single entitySingle entity
PolymorphsPolymorphs
Molecular AdductsMolecular Adducts
Non Stoichiometric inclusionNon Stoichiometric inclusion
compoundscompounds
StoichiometricStoichiometric
SolvatesSolvates
(Hydrates),(Hydrates),
LayerLayer Channel
CageCage
(Clathrate)(Clathrate)

 CrystalsCrystals
 Repetitious spacingRepetitious spacing of constituent atoms or moleculesof constituent atoms or molecules
in 3 dimensional arrayin 3 dimensional array
 AmorphousAmorphous
Have atoms or moleculesHave atoms or molecules randomly placedrandomly placed, prepared by, prepared by
Rapid precipitationRapid precipitation
LyophilizationLyophilization
Rapid cooling of liquid meltsRapid cooling of liquid melts
 Amorphous – Higher thermodynamic energy,Amorphous – Higher thermodynamic energy,
solubilites and dissolutions is also high.solubilites and dissolutions is also high.
Upon storage – Tends to revert more stable formsUpon storage – Tends to revert more stable forms
Disadv.: Thermodynamic instabilityDisadv.: Thermodynamic instability

 Crystalline –Crystalline –
 Nonstoichiometric adducts – entrapped solvents withinNonstoichiometric adducts – entrapped solvents within
crystals. Eg.: Inclusionscrystals. Eg.: Inclusions
Undesirable, Lack of reproducibility – AvoidedUndesirable, Lack of reproducibility – Avoided
Stoichiometric adducts – As a solvate, is a molecularStoichiometric adducts – As a solvate, is a molecular
complex that has incorporated the crystalline solventcomplex that has incorporated the crystalline solvent
molecules into specific sites within crystal latticemolecules into specific sites within crystal lattice
Eg.: water ( hydrate- monohydrate)Eg.: water ( hydrate- monohydrate)
Aq. Solubilities, Eg AmpicillinAq. Solubilities, Eg Ampicillin
Dissolution - bioavailabilityDissolution - bioavailability

CrystallinityCrystallinity
Conversion of an anhydrous compound to a hydrateConversion of an anhydrous compound to a hydrate
within the dosage form may reduce the dissolutionwithin the dosage form may reduce the dissolution
rate & extent of drug absorption.rate & extent of drug absorption.

PolymorphismPolymorphism
 Ability of a compound or element to crystallize as moreAbility of a compound or element to crystallize as more
than one distinct crystalline species withthan one distinct crystalline species with different internaldifferent internal
lattices.lattices.
 Chemical stability and solubility – Drug’s bioavailabilityChemical stability and solubility – Drug’s bioavailability
 Physicochemical parameter that alterPhysicochemical parameter that alter
 Melting pointMelting point
 DensityDensity
 Hardness, crystal shape, optical propertiesHardness, crystal shape, optical properties
 Eg.: Chloramphenicol PalmitateEg.: Chloramphenicol Palmitate
 3 crystalline polymorphic forms, A,B,C and amorphous3 crystalline polymorphic forms, A,B,C and amorphous
formform
 Physicochemical properties vary : MP, Density,Physicochemical properties vary : MP, Density,
hardness, optical properties etchardness, optical properties etc

 Chemical stability & solubility changesChemical stability & solubility changes
due to polymorphism can have an impactdue to polymorphism can have an impact
on drug’s bioavailability & its developmenton drug’s bioavailability & its development
program.program.
 e.g. Chloramphenicol Palmitate exist in 3e.g. Chloramphenicol Palmitate exist in 3
crystalline polymorphic forms (A, B & C),crystalline polymorphic forms (A, B & C),
“peak” serum levels increased substantially as“peak” serum levels increased substantially as
a function of the % of form B polymorph, thea function of the % of form B polymorph, the
more soluble polymorph.more soluble polymorph.
 Characterization of polymorphic &Characterization of polymorphic &
solvated forms involves quantitativesolvated forms involves quantitative
analysis of these differinganalysis of these differing
physicochemical properties.physicochemical properties.
% of Form B

Classification-Classification-
1.1. Monotropic polymorphs -Monotropic polymorphs - one stable crystal form andone stable crystal form and
one meta stable regardless of temperature changeone meta stable regardless of temperature change
OROR
Only one polymorph is stable at all reasonable Temp.Only one polymorph is stable at all reasonable Temp.
 Eg. Glyceryl stearates, metalazoneEg. Glyceryl stearates, metalazone
2. Enantiotropic polymorphs2. Enantiotropic polymorphs - One polymorph is stable- One polymorph is stable
over one temperature range, another polymorph isover one temperature range, another polymorph is
stable over a different temperature rangestable over a different temperature range
 E.g. carbamazepine and acetazolamine,SulfurE.g. carbamazepine and acetazolamine,Sulfur

 Preformulation study-Preformulation study-
 - identifies polymorph stable at room- identifies polymorph stable at room
temptemp
 - stability of polymorph in dosage form- stability of polymorph in dosage form
Analytical Method Material
req.
Microscopy
Fusion Method
DSC
IR
X-ray powder diffraction
SEM
TGA
Dissolution/ solubility analysis
1mg
1mg
2-5 mg
2-20 mg
500 mg
2 mg
10 mg
Mg to gm

Analytical method forAnalytical method for
characterization of polymorphcharacterization of polymorph
1.1. Microscopy-Microscopy-

Hot stage microscopyHot stage microscopy
Micrographs taken at a heating rate of 10Micrographs taken at a heating rate of 1088C/minC/min
(a) 30.0(a) 30.088C, (b) 156.5C, (b) 156.588C, (c) 162.5C, (c) 162.588C, (d) 166.2C, (d) 166.288C,C,
(e) 168.5(e) 168.588C and (f) 170.5C and (f) 170.588C.C.

Thermal AnalysisThermal Analysis
1. DSC-1. DSC- measures Heat Loss/ Gain resultingmeasures Heat Loss/ Gain resulting
from chemical or physical changesfrom chemical or physical changes
2. TGA-2. TGA- measures changes in samplemeasures changes in sample
weight as a function of time/ tempweight as a function of time/ temp
Eg. Endothermic reaction-Eg. Endothermic reaction-
Exothermic reactions-Exothermic reactions-
Eg. Anhydrous, Dihydrate formEg. Anhydrous, Dihydrate form

3. X-ray diffraction3. X-ray diffraction
 When X-rays interact with aWhen X-rays interact with a crystallinecrystalline
substance (Phase), one gets a diffractionsubstance (Phase), one gets a diffraction
pattern.pattern. The X-ray diffraction pattern of aThe X-ray diffraction pattern of a
pure substance is, therefore, like a fingerprintpure substance is, therefore, like a fingerprint
of the substance.of the substance.
4. Additional techniques used are- NMR, SEM,4. Additional techniques used are- NMR, SEM,
IRIR

Scanning electron microscopyScanning electron microscopy
(SEM)(SEM)

HygroscopicityHygroscopicity
 FactorsFactors
 Adsorption & equilibrium moisture content depends uponAdsorption & equilibrium moisture content depends upon
 Atmospheric humidityAtmospheric humidity
 TemperatureTemperature
 Surface AreaSurface Area
 Exposure & mechanism for moisture uptakeExposure & mechanism for moisture uptake
 TypesTypes
 DeliquescentDeliquescent:: adsorbs sufficiently water to dissolves completelyadsorbs sufficiently water to dissolves completely
 HygroscopicHygroscopic: adsorb water and forms hydrate: adsorb water and forms hydrate
 Changes in moisture level affectsChanges in moisture level affects
 Chemical stabilityChemical stability
 Flow abilityFlow ability
 CompactibilityCompactibility

HygroscopicityHygroscopicity
 Normalized or percentage weight gain data fromNormalized or percentage weight gain data from
these hygroscopic studies are plotted againstthese hygroscopic studies are plotted against
time to predict stability studies.time to predict stability studies.
 Karl Fischer titration, gas chromatography, TGAKarl Fischer titration, gas chromatography, TGA
 Based on data, Specific handling duringBased on data, Specific handling during
manufacturing (Humidity control) / specialmanufacturing (Humidity control) / special
storage (Dessicant)can be recommended.storage (Dessicant)can be recommended.

Fine Particle CharacterizationFine Particle Characterization
Bulk flow, formulation homogeneity and surface areaBulk flow, formulation homogeneity and surface area
controlled processes such as dissolution.controlled processes such as dissolution.
MicroscopyMicroscopy
Coulter counterCoulter counter
Sieve methodSieve method
BET method (Surface area)BET method (Surface area)
SEM methodSEM method

Coulter counterCoulter counter
 A Coulter counter is an apparatus for counting and
sizing particles suspended in electrolytes.
 A typical Coulter counter has one or more
microchannels that separate two chambers containing
electrolyte solutions.
 As fluid containing particles or cells is drawn through
each microchannel, each particle causes a brief change
to the electrical resistance of the liquid.
The counter detects these changes in electrical

BET methodBET method
 Braunner, Emmett and Teller methodBraunner, Emmett and Teller method
 Layer of nitrogen is adsorbed on theLayer of nitrogen is adsorbed on the
sample surface at -196°C (until surfacesample surface at -196°C (until surface
adsorption reach equillibrium)adsorption reach equillibrium)
 Sample is heated to room temperature-Sample is heated to room temperature-
N2 desorbs and its volume is measuredN2 desorbs and its volume is measured
and converted to no. of adsorbedand converted to no. of adsorbed
molecule via ideal gas law (PV=nRT)molecule via ideal gas law (PV=nRT)
 Each N2- 16AEach N2- 16A22

Bulk DensityBulk Density
 Bulk density :Bulk density :
Varies with Method of crystallization, milling orVaries with Method of crystallization, milling or
formulationformulation
High dose – Size of capsulesHigh dose – Size of capsules
Low dose - homogeneityLow dose - homogeneity
Drug and excipientsDrug and excipients
 Tapped densityTapped density
 True densityTrue density

Powder Flow propertiesPowder Flow properties
Powder Flow properties: Free flowing or
cohesive
Factors affecting are-
particle size, density, shape, moisture
content, electrostatic charge
-Flow rates (g/sec)
-Compressibility Index
-Angle of repose

Way to improve flow properties
-Granulation
-Slugging/ compaction
-Glident

Principal areas of Pre-formulations-Principal areas of Pre-formulations-
Solubility AnalysisSolubility Analysis
 Ionization constant –pKaIonization constant –pKa
 pH solubility profilepH solubility profile
 Common ion effect – KspCommon ion effect – Ksp
 Thermal effectsThermal effects
 SolubilizationSolubilization
 Partition co-efficientPartition co-efficient
 DissolutionDissolution

 What is solubility??What is solubility??
 Factors affecting solubilityFactors affecting solubility
 Saturation solubilitySaturation solubility
 What is Dissolution??What is Dissolution??

Very soluble less than 1 part
Freely soluble from 1 to 10 parts
Soluble from 10 to 30 parts
Sparingly soluble from 30 to 100 parts
Slightly soluble from 100 to 1000 parts
Very slightly soluble from 1000 to 10,000 parts
Practically insoluble more than 10,000 parts

 Solubility study done in various solventsSolubility study done in various solvents
-Aqueous solvent-Aqueous solvent
- water, buffers- water, buffers
-Nonaqueous solvents-Nonaqueous solvents
- Organic solvents- Organic solvents
- Glycerol, PEG- Glycerol, PEG

 Focus on drug-solvent system that couldFocus on drug-solvent system that could
occur during the delivery of the drugoccur during the delivery of the drug
candidatecandidate
 Provides basis for formulation work.Provides basis for formulation work.
 Determination ofDetermination of
pKapKa
Temperature dependenceTemperature dependence
pH solubility profilepH solubility profile
Solubility productsSolubility products
Solubilization mechanismsSolubilization mechanisms
Rate of dissolutionRate of dissolution

 Analytical methods useful includeAnalytical methods useful include
HPLCHPLC
UV SpectroscopyUV Spectroscopy
Fluoroscence SpectroscopyFluoroscence Spectroscopy
Reverse Phase gas chromatographyReverse Phase gas chromatography
 Factors to be defined for solubility andFactors to be defined for solubility and
Dissolution study -Dissolution study -
pHpH
TemperatureTemperature
Buffer concentrationsBuffer concentrations

pKapKa DeterminationDetermination
 Dissociation constant is capability of drugDissociation constant is capability of drug
to ionize within pH range of 1 to 10to ionize within pH range of 1 to 10
 Solubility & absorption alteredSolubility & absorption altered
 Henderson-Hasselbalch equationHenderson-Hasselbalch equation
 Acidic compoundsAcidic compounds
 Basic CompoundsBasic Compounds

contd..contd..
 Absorption PrinciplesAbsorption Principles
 Weakly acidic drug pka > 3, unionized form in theWeakly acidic drug pka > 3, unionized form in the
stomach , Drug is ionized predominantly instomach , Drug is ionized predominantly in
intestine.intestine.
 Basic drug pka=8-10, ionized form predominantlyBasic drug pka=8-10, ionized form predominantly
in stomach & intestinein stomach & intestine
Eg. ErythromycinEg. Erythromycin
- Other factors like lipid solubility, dissolution rate,- Other factors like lipid solubility, dissolution rate,
common ion effects, metabolism also affectscommon ion effects, metabolism also affects

contd..contd.. Determination of pKaDetermination of pKa
 Analytical methodsAnalytical methods
Determination of spectral shifts by UV or Visible spectroscopyDetermination of spectral shifts by UV or Visible spectroscopy
(Dilute aq. Solution can be analyzed directly)(Dilute aq. Solution can be analyzed directly)
 Potentiometric TitrationPotentiometric Titration
(pKa range of 3-10)(pKa range of 3-10)
 Factors affecting pKaFactors affecting pKa
 BufferBuffer
 TemperatureTemperature
 Ionic StrengthIonic Strength
 Co-solventCo-solvent

Effect of TemperatureEffect of Temperature
 Solution ProcessSolution Process
 EndothermicEndothermic
 Heat of solution is positiveHeat of solution is positive
 ExothermicExothermic
 Heat of solution is negative ( lithium salts)Heat of solution is negative ( lithium salts)
 Non-electrolytes & ionized formsNon-electrolytes & ionized forms ΔΔH between 4 to 8 kcal/molH between 4 to 8 kcal/mol
 Salt forms of drugs -2 to 2 kcal/mole (less sensitive to temp.)Salt forms of drugs -2 to 2 kcal/mole (less sensitive to temp.)
 Effect solution dosage form design & storage condition.Effect solution dosage form design & storage condition.
 Solvent systems including co-solvents.Solvent systems including co-solvents.
 MicellesMicelles
 ComplexationComplexation

 Heat of solution – solubility values for saturatedHeat of solution – solubility values for saturated
solutions equilibrated at controlled temperaturesolutions equilibrated at controlled temperature
 Range: 5°C, 25°C, 37°C, 50°CRange: 5°C, 25°C, 37°C, 50°C
 lnS = -lnS = -∆Hs/R (1/T)+C∆Hs/R (1/T)+C
Where S = molar solubility at temperature T kelvinWhere S = molar solubility at temperature T kelvin
R = gas constantR = gas constant
ΔΔHHss = Heat of solution= Heat of solution
 Semi log plot solubility vs reciprocal temperatureSemi log plot solubility vs reciprocal temperature
 ΔΔHHss obtained from slopeobtained from slope
 Salt forms of drugs – less sensitiveSalt forms of drugs – less sensitive ΔΔHHss : -2 to +2kcal/mol: -2 to +2kcal/mol
 Unionized form of weak acids/ bases dissolved in waterUnionized form of weak acids/ bases dissolved in water
ΔΔHHss : 4-8kcal/mole: 4-8kcal/mole

SolubilizationSolubilization
 Increasing the solubility ofIncreasing the solubility of
a drug by addition of thirda drug by addition of third
agent (solubilizing agent) isagent (solubilizing agent) is
called as solubilizationcalled as solubilization
 Addition of co-solvent toAddition of co-solvent to
the aqueous system likethe aqueous system like
ethanol, propylene glycol, &ethanol, propylene glycol, &
glyceringlycerin
 Act by disrupting theAct by disrupting the
hydrophobic interactions athydrophobic interactions at
the nonpolar solute/waterthe nonpolar solute/water
interface.interface. Fig: Solubility of hydrocortisone & hydrocortisone 21-Fig: Solubility of hydrocortisone & hydrocortisone 21-
heptonoate in propylene glycol-water mixturesheptonoate in propylene glycol-water mixtures

Partition CoefficientPartition Coefficient
 Ratio of unionized drug distributedRatio of unionized drug distributed
between the organic & inorganic aqueousbetween the organic & inorganic aqueous
phase at equilibrium.phase at equilibrium.
 ImportanceImportance
Screening for biological activityScreening for biological activity
Drug deliveryDrug delivery
 System used areSystem used are
Octanol/water and Chloroform/waterOctanol/water and Chloroform/water

pH Solubility Profile & Common IonpH Solubility Profile & Common Ion
EffectsEffects
 Solubility of an acidic or basic drugSolubility of an acidic or basic drug
depends ondepends on
pKa of the ionizing functional group &pKa of the ionizing functional group &
intrinsic solubilities for both the ionized &intrinsic solubilities for both the ionized &
unionized forms.unionized forms.
 Experimental determination of a solubilityExperimental determination of a solubility
product should include measurement ofproduct should include measurement of
pH as well as assays of both drug &pH as well as assays of both drug &
counter ion concentrations.counter ion concentrations.

DissolutionDissolution
 Release of drug from a dosage form involves diverse factorsRelease of drug from a dosage form involves diverse factors
as:as:
 A drug is expected to be release from the solid dosage formsA drug is expected to be release from the solid dosage forms
(granules, tablets, capsules etc) & immediately go into(granules, tablets, capsules etc) & immediately go into
molecular solutionmolecular solution. This process is called. This process is called dissolutiondissolution..
 Dissolution (Dissolution (molecular dispersionmolecular dispersion) is a prerequisite for the) is a prerequisite for the
drug absorption.drug absorption.
 APPLICATIONAPPLICATION
 The dissolution test is used as aThe dissolution test is used as a quality control toolquality control tool to monitorto monitor
routinely the uniformity & reproducibility of production batches.routinely the uniformity & reproducibility of production batches.
 The test is utilized as aThe test is utilized as a research toolresearch tool for optimizing the parametersfor optimizing the parameters
& ingredients in new formulations.& ingredients in new formulations.
 WheneverWhenever in vitroin vitro && in vivoin vivo correlationcorrelation are observed, the dissolutionare observed, the dissolution
studies are used as tools to substitute the frequent studies ofstudies are used as tools to substitute the frequent studies of
bioabsorption.bioabsorption.

DissolutionDissolution contd…contd…
 Dissolution is expressed in terms ofDissolution is expressed in terms of a rate processa rate process..
 Greater the rate, faster the dissolution.Greater the rate, faster the dissolution.
 Dissolution rate may be defined as “Dissolution rate may be defined as “the amount of drugthe amount of drug
substance that goes into solution per unit time undersubstance that goes into solution per unit time under
standardized conditions of liquid/solid interface,standardized conditions of liquid/solid interface,
temperature & solvent compositiontemperature & solvent composition”.”.
 Noyes-Whitney’s equationNoyes-Whitney’s equation is useful for estimating theis useful for estimating the
rate of dissolution.rate of dissolution.
dC / dt = DA/ hV (CdC / dt = DA/ hV (Css -C)-C)
DISSOLUTION TESTING CONDITIONSDISSOLUTION TESTING CONDITIONS
 ApparatusApparatus
 Dissolution MediumDissolution Medium
 AgitationAgitation
 ValidationValidation

DISSOLUTION APPARATUSDISSOLUTION APPARATUS
The most commonly employed dissolution test methods
are (1) the basket method (Apparatus 1)
(2) the paddle method (Apparatus 2)
The basket and the paddle methods are simple, robust,
well standardized, and used worldwide. These methods
are flexible enough to allow dissolution testing for a variety
of drug products.
Apparatus 1 and Apparatus 2 should be used unless
shown to be unsatisfactory.
The in vitro dissolution procedures, such as
(3) the reciprocating cylinder (Apparatus 3) and
(4) a flow-through cell system (Apparatus 4)
described in the USP, may be considered if
needed.
These methodologies or other alternatives/modifications
should be considered on the basis of their proven
superiority for a particular product.

DissolutionDissolution
basket methodbasket method
(Apparatus 1)(Apparatus 1)
Paddle methodPaddle method
reciprocating cylinderreciprocating cylinder
flow-through cellflow-through cell
system (Apparatus 4)system (Apparatus 4)

 Stability AnalysisStability Analysis
Stability in toxicology formulationsStability in toxicology formulations
Solubility stabilitySolubility stability
pH rate profilepH rate profile
Solid state stabilitySolid state stability
Bulk stabilityBulk stability
CompatibilityCompatibility

Stability AnalysisStability Analysis
Stability Analysis requirementStability Analysis requirement
Stability in toxicology formulationsStability in toxicology formulations
Solution stabilitySolution stability
pH rate profilepH rate profile
Solid state stabilitySolid state stability
Bulk stabilityBulk stability
CompatibilityCompatibility

Stability AnalysisStability Analysis
 Preformulation studies give firstPreformulation studies give first quantitativequantitative
assessmentassessment of chemical stability of a new drug.of chemical stability of a new drug.
Solution State SolidSolution State Solid
StateState
Handling, formulation, storage and administration ofHandling, formulation, storage and administration of
a drug candidatea drug candidate
 Test protocols & experimental methodsTest protocols & experimental methods
 Assay – intact drug and degraded productAssay – intact drug and degraded product
Evaluation – HPLC, Gas ChromatographyEvaluation – HPLC, Gas Chromatography

StabilityStability in toxicologyin toxicology
formulationsformulations Since toxicological studies typically commence early in drugSince toxicological studies typically commence early in drug
development, it is often advisable to evaluate samples ofdevelopment, it is often advisable to evaluate samples of
toxicology preparations for Stability and potentialtoxicology preparations for Stability and potential
homogeneity problemshomogeneity problems
 Drug administered – Feed or oral gavage of solution orDrug administered – Feed or oral gavage of solution or
suspension of drug in an aqueous vehiclesuspension of drug in an aqueous vehicle
 Minerals, vitamins, enzymes , a multitude of functionalMinerals, vitamins, enzymes , a multitude of functional
groups present in feed – reduces shelf life of druggroups present in feed – reduces shelf life of drug
 Fresh sample of feed to be usedFresh sample of feed to be used
 Solution or suspension – Checked for ease of manufactureSolution or suspension – Checked for ease of manufacture
Stored in a flame sealed ampoules at various temperaturesStored in a flame sealed ampoules at various temperatures
Occasionaly shaking – DispersabilityOccasionaly shaking – Dispersability

SolutionSolution StabilityStability
 Aim-Aim-Identification of conditions necessary to form a stableIdentification of conditions necessary to form a stable
solutionsolution
 Study Includes – effects of pH, Ionic strength, Co-solvent, light ,Study Includes – effects of pH, Ionic strength, Co-solvent, light ,
temperature and oxygentemperature and oxygen
 Probing experiments at extremes conditions of pH andProbing experiments at extremes conditions of pH and
temperature (0.01N HCl , water ,0.01N, NaOH all at 90°C).temperature (0.01N HCl , water ,0.01N, NaOH all at 90°C).
 Assay specificity and Maximum rates of degradationAssay specificity and Maximum rates of degradation
 Complete pH rate profile – pH of max stability.Complete pH rate profile – pH of max stability.
 Aq. Buffers are used to provide wide range with constant levels ofAq. Buffers are used to provide wide range with constant levels of
drug, co solvent and ionic strengthdrug, co solvent and ionic strength
 Compatible with physiological mediaCompatible with physiological media
 Eg.: Ionic strength ( µ) of 0.9% NaCl is 0.15Eg.: Ionic strength ( µ) of 0.9% NaCl is 0.15
 Equation: µ = ½ ∑mEquation: µ = ½ ∑miiZZii
22
 mmi =i = molar conc. of the ion, with valence Zimolar conc. of the ion, with valence Zi

Solution StabilitySolution Stability
 Procedure-Procedure-
Stability solutions : Flint glass ampoules, flame sealed –Stability solutions : Flint glass ampoules, flame sealed –
prevent evaporation, Stored at temperature not exceedingprevent evaporation, Stored at temperature not exceeding
its Boiling Point (if organic co-solvents are used).its Boiling Point (if organic co-solvents are used).
 Varied temp-Varied temp- Activation energyActivation energy
 Light stabilityLight stability – protective packing– protective packing
 Amber – yellow –green glass containersAmber – yellow –green glass containers
 Wrapped in aluminium foil or cardboard packagesWrapped in aluminium foil or cardboard packages
 Potential for oxidation:Potential for oxidation:
 Excessive headspace of OExcessive headspace of O22
 Excessive headspace with inert gasExcessive headspace with inert gas
 Inorganic antioxidant – Sodium metabisulfiteInorganic antioxidant – Sodium metabisulfite
 Organic antioxidant – Butylated hydroxytoluene BHTOrganic antioxidant – Butylated hydroxytoluene BHT

Solution StabilitySolution Stability
 pH rate profilepH rate profile
Stability data at each pH and temperatureStability data at each pH and temperature
Analyzed kinetically – apparent decay constantAnalyzed kinetically – apparent decay constant
Arrhenius plot – log of apaprent decay rate constant VsArrhenius plot – log of apaprent decay rate constant Vs
reciprocal of absolute temperaturereciprocal of absolute temperature
Energy of activationEnergy of activation

Solid state stabilitySolid state stability
Aim: Identifications of stable storageAim: Identifications of stable storage
conditions for drug in the solid state andconditions for drug in the solid state and
identification of compatible excipients foridentification of compatible excipients for
a formulations.a formulations.
 Affected by change in purity and crystallinityAffected by change in purity and crystallinity
 Initial bulk lots and newer lots– to be studiedInitial bulk lots and newer lots– to be studied
 Solid state is slower and difficult to interpret than solutionSolid state is slower and difficult to interpret than solution
statestate
 TLC, UV-Vis, fluorescenceTLC, UV-Vis, fluorescence
 Polymorphic changes – DSC, IR or appearance changes likePolymorphic changes – DSC, IR or appearance changes like
oxidation – surface discolorationoxidation – surface discoloration
Procedure:Procedure: Open screw cap vials – Exposed to variousOpen screw cap vials – Exposed to various
conditions Temp., Humidity and light upto 12weeksconditions Temp., Humidity and light upto 12weeks

Solid State StabilitySolid State Stability
Storage conditionsStorage conditions
1.1. Refrigerator- 5°CRefrigerator- 5°C
2.2. Room temp.- 22°CRoom temp.- 22°C
3.3. Ambient humidity, 70% RH, 90%RHAmbient humidity, 70% RH, 90%RH
4.4. 25°C/60% RH, 40°C/75% RH,25°C/60% RH, 40°C/75% RH,
5.5. Light- Clear, Amber, yellow-green glass, controlLight- Clear, Amber, yellow-green glass, control
samplesample
6.6. Ambient humidity- O2 headspace, N2 headspaceAmbient humidity- O2 headspace, N2 headspace

Elevated temperature studiesElevated temperature studies
 The elevated temperatures commonly used areThe elevated temperatures commonly used are 40, 50, and40, 50, and
60 degree centigrade with ambient humidity.60 degree centigrade with ambient humidity.
 The samples stored at highest temperature are observedThe samples stored at highest temperature are observed
weekly for physical and chemical changesweekly for physical and chemical changes and compared toand compared to
an appropriate control .an appropriate control .
 If a substantial change is seen, samples stored at lowerIf a substantial change is seen, samples stored at lower
temperature are examined .temperature are examined .
 If no changes is seen after 30 days at 60°C , the stabilityIf no changes is seen after 30 days at 60°C , the stability
prognosis is excellent.prognosis is excellent.

Stability under high humidityStability under high humidity
conditionsconditions
 Solid drug samples can be exposed toSolid drug samples can be exposed to differentdifferent
relative humidity conditionsrelative humidity conditions by keeping them inby keeping them in
laboratory desiccators containing saturatedlaboratory desiccators containing saturated
solutions of various salts.solutions of various salts.
 TheThe closed desiccatorsclosed desiccators in turn are kept in oven toin turn are kept in oven to
provide constant temperature.provide constant temperature.
 The preformulation data of this nature are useful inThe preformulation data of this nature are useful in
determining if the material should be protected anddetermining if the material should be protected and
stored in controlledstored in controlled low humidity environmentlow humidity environment or ifor if
non aqueous solventnon aqueous solvent be used during formulation.be used during formulation.

Photolytic stabilityPhotolytic stability
 Many drugs fade or dorpen on exposure light.Many drugs fade or dorpen on exposure light.
 Increased Impurity levelIncreased Impurity level
 Samples should be exposed to light providing an overallSamples should be exposed to light providing an overall
illumination ofillumination of not less than 1.2 million lux hoursnot less than 1.2 million lux hours
and an integrated near ultraviolet energy of not less thanand an integrated near ultraviolet energy of not less than
200 watt hours/square meter200 watt hours/square meter
 IfIf protected samplesprotected samples (e.g., wrapped in aluminum foil) are(e.g., wrapped in aluminum foil) are
used as dark controls to evaluate the contribution ofused as dark controls to evaluate the contribution of
thermally induced change to the total observed change,thermally induced change to the total observed change,
these should be placed alongside the authentic sample.these should be placed alongside the authentic sample.
 Resulting data may be useful in determining if an amberResulting data may be useful in determining if an amber
colored container is required or if color masking bye shouldcolored container is required or if color masking bye should
be used in the formulationbe used in the formulation

Stability to OxidationStability to Oxidation
 Drug’s sensitivity to oxidation can be examined byDrug’s sensitivity to oxidation can be examined by
exposing it to atmosphere of high oxygen tension.exposing it to atmosphere of high oxygen tension.
 Usually a 40% oxygen atmosphere allows for rapidUsually a 40% oxygen atmosphere allows for rapid
evaluation.evaluation.
 Samples are kept in desiccators equipped with three-waySamples are kept in desiccators equipped with three-way
stop cocks, which are alternatively evacuated andstop cocks, which are alternatively evacuated and
flooded with desired atmosphere.flooded with desired atmosphere.
 The process is repeated 3 or 4 times to ensure 100%The process is repeated 3 or 4 times to ensure 100%
desired atmosphere.desired atmosphere.
 Results may be useful in predicting if an antioxidant isResults may be useful in predicting if an antioxidant is
required in the formulation or if the final productrequired in the formulation or if the final product

Compatibility studiesCompatibility studies
 The knowledge ofThe knowledge of drug excipients interactiondrug excipients interaction
is useful for the formulation to select appropriateis useful for the formulation to select appropriate
excipients.excipients.
 The described preformulation screening of drugThe described preformulation screening of drug
excipients interaction requires only 5mg of drug inexcipients interaction requires only 5mg of drug in
a 50% mixture with the excipients to maximize thea 50% mixture with the excipients to maximize the
likelihood of obscuring an interaction .likelihood of obscuring an interaction .
 Mixtures should be examined for physicochemicalMixtures should be examined for physicochemical
properties like appearance, Assay and degradationproperties like appearance, Assay and degradation

Formulation RecommendationFormulation Recommendation
 Upon the completion of preformulation evaluationUpon the completion of preformulation evaluation
of a new drug candidate, it is recommended that aof a new drug candidate, it is recommended that a
comprehensive reportcomprehensive report to be preparedto be prepared
highlighting the pharmaceutical problems associatedhighlighting the pharmaceutical problems associated
with this molecule.with this molecule.
 This report should conclude with recommendationsThis report should conclude with recommendations
for developingfor developing phase I formulationsphase I formulations..
 These reports are extremely important in preparingThese reports are extremely important in preparing
regulatory documents & aid in developingregulatory documents & aid in developing
subsequent drug candidates.subsequent drug candidates.

Outline of topicOutline of topic
 Study of chemical properties of drugs likeStudy of chemical properties of drugs like
hydrolysis, oxidation – reduction,hydrolysis, oxidation – reduction,
racemisation, polymerization and theirracemisation, polymerization and their
influence on formulation and stability ofinfluence on formulation and stability of
products.products.

Study of chemical properties ofStudy of chemical properties of
drugs likedrugs like
 HydrolysisHydrolysis
 Oxidation – ReductionOxidation – Reduction
 PhotolysisPhotolysis
 RacemisationRacemisation
 PolymerizationPolymerization
Mechanisms of degradation and their influence onMechanisms of degradation and their influence on

OBJECTIVEOBJECTIVE
 Initial investigationInitial investigation on chemical propertieson chemical properties
 Knowledge about theKnowledge about the chemical and physicalchemical and physical
stabilitystability of a candidate drug in the solid andof a candidate drug in the solid and
liquid state – drug developmentliquid state – drug development
 Stability of formulation –Stability of formulation – shelf lifeshelf life of marketedof marketed
productproduct
 Chemical properties ,Chemical properties , path of degradation ,path of degradation ,
Rate of degradationRate of degradation
 Stability with temperature ,pH, light and oxygen , aStability with temperature ,pH, light and oxygen , a
number of experiments need to be performednumber of experiments need to be performed

Hydrolysis:Hydrolysis: (drug) molecules interact with water(drug) molecules interact with water
molecule to yield breakdown product.molecule to yield breakdown product.
 Susceptible to the hydrolytic process: esters, substitutedSusceptible to the hydrolytic process: esters, substituted
amides, lactones, and lactams.amides, lactones, and lactams.
Eg: Anestheics, antibiotics , vitamins and barbituratesEg: Anestheics, antibiotics , vitamins and barbiturates
1. Ester hydrolysis:1. Ester hydrolysis:
EsterEster Acid + Alcohol (involves rupture of aAcid + Alcohol (involves rupture of a
covalent linkage between a carbon atom and an oxygencovalent linkage between a carbon atom and an oxygen
atom).atom).
Catalysts – polar nature such as mineral acids, alkalies orCatalysts – polar nature such as mineral acids, alkalies or
certain enzymes – capable of supplying Hcertain enzymes – capable of supplying H++
and OHand OH--
ionsions
Acid or alkali catalysed hydrolysisAcid or alkali catalysed hydrolysis
Degradation
Pathway
Hydrolysis

Kinetic study of hydrolysis of Aspirin was done
in various buffer solutions. It was observed that Aspirin is
most stable at 2.4, at pH 5 to 7 degradation is pH independent
and above pH 10 stability decreases with increase in pH.

Factors to be considered in Hydrolysis
 pH
 Type of solvent : solvent lower dielectric constant
 Eg.: ethanol,glycols, mannitol etc.
 Complexation : steric or polar effects. Eg.: caffeine with
benzocaine – electronic influence of complexing agent –
alters affinity
 Surfactants: nonionic , cationic , anionic stabilizes drug
against base catalysis. Eg: 5% SLS – 18folds increase in
t1/2 of benzocaine
 Modification of chemical structure
 Salts and esters

Amide hydrolysisAmide hydrolysis
 Hydrolytic reaction results :Hydrolytic reaction results :
Amide Acid +AmineAmide Acid +Amine
Eg.: ChloramphenicolEg.: Chloramphenicol
NiacinamidesNiacinamides
 Ring alterations: hydrolysis proceed as a result ofRing alterations: hydrolysis proceed as a result of
ring cleavage.ring cleavage.
Eg. PilocarpineEg. Pilocarpine

Oxidation - reductionOxidation - reduction
Second most common way.Second most common way.
Eg.: steroids, vitamins ,antibiotics etcEg.: steroids, vitamins ,antibiotics etc
Mediated by free radicals or by molecular oxygenMediated by free radicals or by molecular oxygen
Complex oxidative processesComplex oxidative processes
Sensitive towards trace metal and other impuritiesSensitive towards trace metal and other impurities
Redox reactions involve eitherRedox reactions involve either transfer of oxygentransfer of oxygen
oror hydrogen atomshydrogen atoms or transfer ofor transfer of electronselectrons

 Oxidation – presence of oxygenOxidation – presence of oxygen
Initiated by heat ,light or trace metal ions thatInitiated by heat ,light or trace metal ions that
produce organicproduce organic free radicalsfree radicals
These radicals propagate the oxidation reaction ,These radicals propagate the oxidation reaction ,
which proceeds until inhibitors destroy thewhich proceeds until inhibitors destroy the
radicals or until side reactions eventually breakradicals or until side reactions eventually break
the chainthe chain
Eg. DopamineEg. Dopamine

 Substance is oxidized when :Substance is oxidized when :
If electrons are removed from itIf electrons are removed from it
Gains electronegative atoms or radicals or losesGains electronegative atoms or radicals or loses
electropositive atoms or radicalselectropositive atoms or radicals
Addition of oxygen and removal of hydrogenAddition of oxygen and removal of hydrogen
 Most common : autoxidation (free radical chainMost common : autoxidation (free radical chain
process)process)
 Involves homolytic bond fission of a covalent bondInvolves homolytic bond fission of a covalent bond
– each atom retains one of the electrons of original– each atom retains one of the electrons of original
covalent bond:covalent bond:

AutoxidationAutoxidation
 Initiation: RHInitiation: RH R. + H.R. + H.
 Propagation:Propagation:
 R. + OR. + O 22 RORO 22
 RORO 22. + RH. + RH ROOH + R.ROOH + R.
 Hydroperoxide decompositionHydroperoxide decomposition
 ROOHROOH RO. + .OHRO. + .OH
 TerminationTermination
 RO2. +XRO2. +X Inactive productsInactive products
 (X converts to peroxides group)(X converts to peroxides group)
 RO2 +RO2RO2 +RO2 Inactive productsInactive products
 Rate of prednisolone : presence of aerobic and anaerobicRate of prednisolone : presence of aerobic and anaerobic
conditionsconditions
 Rancidity – oils and fatsRancidity – oils and fats
 Oxygen content and AntioxidantsOxygen content and Antioxidants
Light, heat
Activation

PhotolysisPhotolysis
 PhotochemicalPhotochemical
 PhotosensitizerPhotosensitizer
 UV- violet portions – more active ( shortetUV- violet portions – more active ( shortet
wavelength ,more energy)wavelength ,more energy)

RacemizationRacemization
 Racemization – compound changes optical activityRacemization – compound changes optical activity
without changing the chemical composition.without changing the chemical composition.
 Levo and dextro formLevo and dextro form
Eg: l-adrenaline is 15-20times more active thanEg: l-adrenaline is 15-20times more active than
dextro formdextro form
Racemic mixtureRacemic mixture
 Stability and therapeutic activityStability and therapeutic activity

Kinetics of degradation:Kinetics of degradation:
K = rate of reactionK = rate of reaction
Drug – ProductDrug – Product
Zero ,first , second order reactions, half life etc.Zero ,first , second order reactions, half life etc.
Effect of temperature : logk = log A – Ea/2.303RTEffect of temperature : logk = log A – Ea/2.303RT
Depends on functional group of assymetrical carbonDepends on functional group of assymetrical carbon
atom,aromatic grp tends to accelerate racemizationatom,aromatic grp tends to accelerate racemization

ProdrugsProdrugs
 Study of prodrugs in solving problems related toStudy of prodrugs in solving problems related to
Stability,Stability,
Bioavailability andBioavailability and
Elegancy of formulationElegancy of formulation

Prodrugs- IntoductionProdrugs- Intoduction
 Drugs – Undesirable physicochemical andDrugs – Undesirable physicochemical and
biological propertiesbiological properties
 How do one improve therapeutic efficacy?How do one improve therapeutic efficacy?
Biological, Physical and Chemical meansBiological, Physical and Chemical means
 Biological approachBiological approach –– Alters the ROAAlters the ROA – may or– may or
may not be acceptable by the patientmay not be acceptable by the patient
 Physical approachPhysical approach –– Modify the design of theModify the design of the
dosage formdosage form Eg.: CDDSEg.: CDDS
 Chemical ApproachChemical Approach – Best to– Best to enhance the drugenhance the drug
selectivity by minimizing the toxicityselectivity by minimizing the toxicity

ProdrugProdrug
 3 Chemical means –3 Chemical means – To optimize the drugTo optimize the drug
therapeuticstherapeutics
1. Design and development of new drugs with1. Design and development of new drugs with
desirable featuresdesirable features
Screening of chemicals for biological activity-Screening of chemicals for biological activity-
Clinically usefulClinically useful
2. Design of2. Design of hard and soft drugshard and soft drugs with desirablewith desirable
characterisitcscharacterisitcs
3. Design of3. Design of prodrugsprodrugs

ProdrugProdrug
 Hard drugsHard drugs :Resistant to biotransformation - Long:Resistant to biotransformation - Long
biological half life, no toxic metabolite formation.biological half life, no toxic metabolite formation.
Disadv.: AccumulationDisadv.: Accumulation
 Soft drugs:Soft drugs: A biologically active drug compound i.e
biotransformed in vivo in a rapid and predictable
manner into non- toxic moieties. Relatively inert
metabolites
Disadv.:Disadv.: Short Duration Of Action
Ex. Insulin, adrenaline
Replacement of alkyl chain of drug – ester group –
readily hydrolysed in vivo

ProdrugProdrug
A prodrug is chemically modified inert drugA prodrug is chemically modified inert drug
precursor which upon biotransformationprecursor which upon biotransformation
liberates the pharmacologically active parentliberates the pharmacologically active parent
compoundcompound
Pro-agent, bioreversible derivative or latentiated drugPro-agent, bioreversible derivative or latentiated drug
Design approach –Design approach – Drug latentiationDrug latentiation
ClassificationClassification
Depends on constitution, lipophilicity and method ofDepends on constitution, lipophilicity and method of
bioactivation and catalysts involved in bioactivationbioactivation and catalysts involved in bioactivation
1. Carrier linked prodrugs1. Carrier linked prodrugs
2. B2. Bioprecursorsioprecursors

Carrier linked prodrugsCarrier linked prodrugs
Simple prodrugsSimple prodrugs
Are ones where the active drug is covalentlyAre ones where the active drug is covalently
linked to an inert carrier or transport moietylinked to an inert carrier or transport moiety
Esters or amidesEsters or amides
Greatly modified lipophilicity due to theGreatly modified lipophilicity due to the
attached carrierattached carrier
Active drug released byActive drug released by hydrolytic cleavagehydrolytic cleavage
either chemically or enzymaticallyeither chemically or enzymatically

BioprecursorsBioprecursors
Known as Metabolic precursorsKnown as Metabolic precursors
Are inert molecules obtained by chemicalAre inert molecules obtained by chemical
modifications of active drug but do notmodifications of active drug but do not
contain a carriercontain a carrier
Moiety has same lipophilicity as the parentMoiety has same lipophilicity as the parent
drugdrug
Bioactivated by redox biotransformation onlyBioactivated by redox biotransformation only
enzymaticallyenzymatically
Eg.: Arylacetic acid NSAID – fenbufen fromEg.: Arylacetic acid NSAID – fenbufen from
aroylpropionic acid precursors.aroylpropionic acid precursors.

Pro-ProdrugPro-Prodrug
Few cases of carrier type prodrugs to be fFew cases of carrier type prodrugs to be formulated asormulated as
ophthalmic, parenteral or oral liquid preparations, theophthalmic, parenteral or oral liquid preparations, the
conversion to active drug –- Chemically ( nonconversion to active drug –- Chemically ( non
enzymatically) triggered by change in pH –- Stabilityenzymatically) triggered by change in pH –- Stability
problemsproblems
Overcome by :Overcome by :
Double prodrug or pro-prodrug conceptDouble prodrug or pro-prodrug concept
Further derivatized in a fashion – OnlyFurther derivatized in a fashion – Only
enzymatically conversion of prodrug is possibleenzymatically conversion of prodrug is possible
before the latter can cleave to release the active drugbefore the latter can cleave to release the active drug
Eg.: diesters of pilocarpic acidEg.: diesters of pilocarpic acid

Mutual ProdrugMutual Prodrug
 In contrast to simple prodrugs where the carrierIn contrast to simple prodrugs where the carrier
used is biologically inert,used is biologically inert,
 Prodrug comprises of 2 pharmacological activeProdrug comprises of 2 pharmacological active
agents coupled together to form a single moleculeagents coupled together to form a single molecule
that each acts as carrier for the otherthat each acts as carrier for the other
 Prodrugs of two active compounds are called asProdrugs of two active compounds are called as
mutual prodrugsmutual prodrugs
Eg.: Benorylate : For NSAID’s of aspirin andEg.: Benorylate : For NSAID’s of aspirin and
paracetamolparacetamol

Examples of ProdrugExamples of Prodrug
Aspirin – Produg of salicylic acid- decreaseAspirin – Produg of salicylic acid- decrease
GI irritationGI irritation
Hexamine – Excreted in urine is converted toHexamine – Excreted in urine is converted to
formaldehyde in the acidic urine pH -formaldehyde in the acidic urine pH -
Urinary tract antibacterialUrinary tract antibacterial

Ideal characteristics of ProdrugIdeal characteristics of Prodrug
 Shouldn’t have intrinsic pharmacologicalShouldn’t have intrinsic pharmacological
activity-activity- InertInert
 Rapidly transformRapidly transform, chemically or enzymatically, chemically or enzymatically
into the active form where desiredinto the active form where desired
 The metabolic fragments, apart from the activeThe metabolic fragments, apart from the active
drug should bedrug should be nontoxicnontoxic

Applications - ProdrugApplications - Prodrug
 Pharmaceutical Applications:Pharmaceutical Applications:
Improvement of tasteImprovement of taste
Improvement of odorImprovement of odor
Change of physical form for preparation of solidChange of physical form for preparation of solid
dosage formsdosage forms
Reduction of GI irritationReduction of GI irritation
Reduction of pain on injectionReduction of pain on injection
Enhancement of drug solubility and dissolutionEnhancement of drug solubility and dissolution
raterate
Enhancement of chemical stability of drugEnhancement of chemical stability of drug

Applications - ProdrugApplications - Prodrug
Pharmacokinetic ApplicationsPharmacokinetic Applications
Enhancement of bioavailabilityEnhancement of bioavailability
(lipophilicity)(lipophilicity)
Prevention of pre-systemic metabolismPrevention of pre-systemic metabolism
Prolongation of duration of actionProlongation of duration of action
Reduction of toxicityReduction of toxicity
Site specific drug delivery (drug targeting)Site specific drug delivery (drug targeting)

Improvement of tasteImprovement of taste
 Poor patient compliancesPoor patient compliances
Bitterness, acidity etcBitterness, acidity etc
 Two approaches :Overcome tasteTwo approaches :Overcome taste
Reduction of drug solubility in salivaReduction of drug solubility in saliva
To lower the affinity of drug towards tasteTo lower the affinity of drug towards taste
receptorsreceptors
Eg.: Chloramphenicol – Palminate esterEg.: Chloramphenicol – Palminate ester

Improvement of odorImprovement of odor
Depends upon its vapor pressure (BP)Depends upon its vapor pressure (BP)
High v.p has low b.p = Strong odorHigh v.p has low b.p = Strong odor
Eg.: Ethyl mercaptan – foul smell at b.pEg.: Ethyl mercaptan – foul smell at b.p
35°C35°C
Used in treatment of leprosy,is convertedUsed in treatment of leprosy,is converted
to phthalate ester (diethyldithio-to phthalate ester (diethyldithio-
isophthalate) higher b.p and is odorlessisophthalate) higher b.p and is odorless

Change of Physical form of the drugChange of Physical form of the drug
 Liquid form – unsuitable for formulation as tabletLiquid form – unsuitable for formulation as tablet
if dose is highif dose is high
 Conversion of such liquid drug into solid prodrugsConversion of such liquid drug into solid prodrugs
- formation of symmetrical molecules – Higher- formation of symmetrical molecules – Higher
tendency to crystallizetendency to crystallize
 Eg. Trichloroethanol converted toEg. Trichloroethanol converted to
p-acetamidobenzoic acid esterp-acetamidobenzoic acid ester

Reduction of GI irritationReduction of GI irritation
 Irritation and damage to gastric mucosaIrritation and damage to gastric mucosa
Direct contactDirect contact
Increased stimulation of acid secretionIncreased stimulation of acid secretion
Through interference with the protective mucosalThrough interference with the protective mucosal
layerlayer
Eg.: NSAID’s ,especially salicylatesEg.: NSAID’s ,especially salicylates
Lowers the gastric pH and induces or aggravatesLowers the gastric pH and induces or aggravates
ulcerationulceration
Eg: Salicylic acid – AspirinEg: Salicylic acid – Aspirin

Reduction of pain or injectionReduction of pain or injection
IM injection – Painful when drug precipitatesIM injection – Painful when drug precipitates
or penetrates into the surrounding cells oror penetrates into the surrounding cells or
when the solution is strongly acidic , alkalinewhen the solution is strongly acidic , alkaline
or alcoholicor alcoholic
Eg.1:Eg.1: Low aq. solubilityLow aq. solubility of clindamycin HClof clindamycin HCl
Overcome by moreOvercome by more water soluble prodrugwater soluble prodrug
such as 2such as 2``-phosphate ester of clindamycin-phosphate ester of clindamycin

Enhancement of solubility andEnhancement of solubility and
dissolution ratedissolution rate
 Hydrophilicity of drug:Hydrophilicity of drug:
When dissolution is rate limiting step in absorption ofWhen dissolution is rate limiting step in absorption of
poorly aq.soluble agents or when parenteral orpoorly aq.soluble agents or when parenteral or
ophthalmic formulationsophthalmic formulations
Hydrophilic or water soluble drug are desiredHydrophilic or water soluble drug are desired
Eg: Drugs – OH group can be converted into theirEg: Drugs – OH group can be converted into their
hydrophilic forms by use of half esters such ashydrophilic forms by use of half esters such as
hemisuccinates, hemi glutarates etchemisuccinates, hemi glutarates etc
Other half of these acidic carriers can form Na, K orOther half of these acidic carriers can form Na, K or
amine salts – renders the moiety water solubleamine salts – renders the moiety water soluble

Enhancement of solubility andEnhancement of solubility and
dissolution ratedissolution rate
For alcoholic or phenolic drugs :For alcoholic or phenolic drugs :
Steroidal drugs like cortisol. prednisolone ,Steroidal drugs like cortisol. prednisolone ,
dexamethsone, the sodium succinate salts havedexamethsone, the sodium succinate salts have
poor stability and hence phosphate esters arepoor stability and hence phosphate esters are
preferredpreferred
Eg1: Chloramphenicol – Sodium succinateEg1: Chloramphenicol – Sodium succinate
esterester
Eg2: Tetracycline – TetralysineEg2: Tetracycline – Tetralysine
Eg3: Diazepam – L- lysine esterEg3: Diazepam – L- lysine ester

Enhancement of chemical stabilityEnhancement of chemical stability
 A drug may destabilize - shelf life or GIT OrallyA drug may destabilize - shelf life or GIT Orally
 Shelf life stability- IVShelf life stability- IV
 Conventional approach –Conventional approach – LyophilizeLyophilize suchsuch solutions intosolutions into
powder which is reconstituted before usepowder which is reconstituted before use
 Improves stabilityImproves stability
 Antineoplastic drug: azacytidineAntineoplastic drug: azacytidine
 Aq.solution – hydrolyzed but bisulfite prodrug is stable toAq.solution – hydrolyzed but bisulfite prodrug is stable to
degradation at acidic pH and more water soluble than thedegradation at acidic pH and more water soluble than the
parent drugparent drug
 Conversion at physiologic pH 7.4Conversion at physiologic pH 7.4
 Cefamandole – nafate ester prodrug – improved shelfCefamandole – nafate ester prodrug – improved shelf
life( Reconstitution from dry powder)life( Reconstitution from dry powder)

Prodrug stabilityProdrug stability
 Pencillins – More susceptible to hydrolysis andPencillins – More susceptible to hydrolysis and
destabilization in gastric aciddestabilization in gastric acid
 Carbenicillin – cannot be administered orallyCarbenicillin – cannot be administered orally
Its ester prodrug carindacillin (Its ester prodrug carindacillin (αα indanol ester) andindanol ester) and
carfecillin (carfecillin (αα phenyl ester – more stablephenyl ester – more stable
At pH 7.0 hydrolysis releases the active drug andAt pH 7.0 hydrolysis releases the active drug and
absorbedabsorbed
Erythromycin – stearate( ethyl succinate and estolate )Erythromycin – stearate( ethyl succinate and estolate )

Enhancement of BioavailabilityEnhancement of Bioavailability
 Most drugs – Passive diffusion – lipophilicityMost drugs – Passive diffusion – lipophilicity
 2reasons to enhance oral bioavailability of lipophilic2reasons to enhance oral bioavailability of lipophilic
compoundscompounds
Lipophilic forms – Enhanced membrane/water partitionLipophilic forms – Enhanced membrane/water partition
co-efficient compared with hydrophilic formco-efficient compared with hydrophilic form
Eg.: pivampicillin ,talampicillin prodrugs of ampicillinEg.: pivampicillin ,talampicillin prodrugs of ampicillin
are lipophilic (98%) and rapidly hydrolysed to parentare lipophilic (98%) and rapidly hydrolysed to parent
drug in blooddrug in blood
Esters of erythromycinEsters of erythromycin

 The dipalmitoyl gylcerol ester of NSAID naproxen – lessThe dipalmitoyl gylcerol ester of NSAID naproxen – less
GI and high plasma conc.GI and high plasma conc.
 Intraocular penetration of polar drugs –Intraocular penetration of polar drugs – ββ blockers andblockers and
epinephrine – treatment of glaucoma – use lipophilicepinephrine – treatment of glaucoma – use lipophilic
carriercarrier
 Eg.: diacetate ester of nadolol is 20 times more lipophilicEg.: diacetate ester of nadolol is 20 times more lipophilic
and 10 times more readily absorbed ocularlyand 10 times more readily absorbed ocularly
 The dipivalyl ester of epinephrine – good ocularThe dipivalyl ester of epinephrine – good ocular
penetrability (8-17times) in comparison to the parent drugpenetrability (8-17times) in comparison to the parent drug

 Increased bioavailability through increased lipophilicity – IsIncreased bioavailability through increased lipophilicity – Is
reduction in drug dosagereduction in drug dosage
Eg.: bacampicillin – prodrug for ampicillin (1/3Eg.: bacampicillin – prodrug for ampicillin (1/3rdrd
thethe
dose)dose)
Bioavailability of topically applied drug – depends onBioavailability of topically applied drug – depends on
lipid solubilitylipid solubility
Skin penetrability of polar drugs can be improved bySkin penetrability of polar drugs can be improved by
esterification to form lipid soluble compoundesterification to form lipid soluble compound
Drugs with carboxyl functions is their esterficationDrugs with carboxyl functions is their esterfication
with one of the hydroxyl groups of PG or glycerolwith one of the hydroxyl groups of PG or glycerol
Penetration enhancer – PG or glycerolPenetration enhancer – PG or glycerol
Eg: glyceryl ester of naproxenEg: glyceryl ester of naproxen

First Pass MetabolismFirst Pass Metabolism
 Corticosteroids – extensive FPMCorticosteroids – extensive FPM
Use their ester or ether prodrugsUse their ester or ether prodrugs
Eg.: triamcinolone acetonideEg.: triamcinolone acetonide
 Propanolol – its hemisuccinate prodrug resistant toPropanolol – its hemisuccinate prodrug resistant to
esterases of liveresterases of liver

Duration Of ActionDuration Of Action
 Prolonged DOA:Prolonged DOA:
 Shorter half life: Frequent dosing requiredShorter half life: Frequent dosing required
 Overcome by use of both controlled release and prodrugOvercome by use of both controlled release and prodrug
approchesapproches
 Rate of release of prodrug – Controlled releaseRate of release of prodrug – Controlled release
 Conversion of prodrug to drug- Controlled releaseConversion of prodrug to drug- Controlled release
 Eg: IM depot inj. Of lipophilic ester prodrugs of steroidsEg: IM depot inj. Of lipophilic ester prodrugs of steroids
(testosterone cypionate and propionate,estradiol propionate)(testosterone cypionate and propionate,estradiol propionate)
 Antipsychotics (fluphenazine enanthate and decanoate)Antipsychotics (fluphenazine enanthate and decanoate)
 Pilocarpine – glaucoma( diesters of the drug)Pilocarpine – glaucoma( diesters of the drug)

Reduction of toxicityReduction of toxicity
 Objective of drug design : high activity with low toxicityObjective of drug design : high activity with low toxicity
 Eg.: timolol and epinephrineEg.: timolol and epinephrine
High dose – Poor penetration , CV side effectsHigh dose – Poor penetration , CV side effects
Lipophilic esters – Better intraocular penetration andLipophilic esters – Better intraocular penetration and
reduces the instilled doses – reduces adverse effectsreduces the instilled doses – reduces adverse effects
Eg.: TI of alkyl ester prodrug of timolol – improvedEg.: TI of alkyl ester prodrug of timolol – improved
16times while that of dipivalyl epinephrine or dipivefrin16times while that of dipivalyl epinephrine or dipivefrin
(a diester of epinephrine with pivalic acid) increased(a diester of epinephrine with pivalic acid) increased
10times10times
Improved biochemical(decreased metabolic rate inImproved biochemical(decreased metabolic rate in
ocular tissues) and chemical stability (resistance toocular tissues) and chemical stability (resistance to
oxidation)oxidation)

Site Specific Drug DeliverySite Specific Drug Delivery
 Selective Uptake systemsSelective Uptake systems
 Redox system for drug delivery to brainRedox system for drug delivery to brain
 Site specific drug delivery in cancerSite specific drug delivery in cancer
 Limitations of prodrug design :Limitations of prodrug design :
 Toxicity – may be due toToxicity – may be due to
 Formation of an unexpected metabolite from total prodrug thatFormation of an unexpected metabolite from total prodrug that
may be toxicmay be toxic
 Inert carrier generated following cleavage of prodrug may alsoInert carrier generated following cleavage of prodrug may also
transform into a toxic metabolitetransform into a toxic metabolite
 During activation, consumption of vital cell constitutent such asDuring activation, consumption of vital cell constitutent such as
glutathione leading to its depletionglutathione leading to its depletion
 Eg.: Prodrug Phenacetin – paracetamol – de-ethylation. OtherEg.: Prodrug Phenacetin – paracetamol – de-ethylation. Other
intermediates like p-phenetidine and n hydroxy phenacetin is alsointermediates like p-phenetidine and n hydroxy phenacetin is also
formedformed
 p-phenetidine – further metabolizes to pptp-phenetidine – further metabolizes to ppt
methemoglobinemia,hemolysis and renal toxicitymethemoglobinemia,hemolysis and renal toxicity

REFERENCESREFERENCES
 The Theory and Practice of Industrial PharmacyThe Theory and Practice of Industrial Pharmacy
By Leon Lachman, H.A Lieberman, Joseph Kanig, 3By Leon Lachman, H.A Lieberman, Joseph Kanig, 3rdrd
edition ,page: 184-195edition ,page: 184-195

REFERENCESREFERENCES
 The Theory and Practice of IndustrialThe Theory and Practice of Industrial
PharmacyPharmacy
By Leon Lachman, H.A Lieberman, JosephBy Leon Lachman, H.A Lieberman, Joseph
Kanig, 3Kanig, 3rdrd
edition ,page: 171-176edition ,page: 171-176
 www.pharmacy.utah.edu/pharmaceutics/pwww.pharmacy.utah.edu/pharmaceutics/p
df/df/PreformulationPreformulation.pdf.pdf

ReferencesReferences
 Biopharmaceutics and PharmacokineticsBiopharmaceutics and Pharmacokinetics
A treatise – By D.M Brahmankar and SunilA treatise – By D.M Brahmankar and Sunil
B.Jaiswal,Page :159-177B.Jaiswal,Page :159-177

ReferencesReferences
 Lachman , Page: 772-786Lachman , Page: 772-786

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