TY - IP I - Preformulation studies Ref.pdf
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Feb 19, 2024
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About This Presentation
Preformulation
Slide Content
Pre-formulation Studies
Prof. ShilpaS. Raut
Prof. ShilpaS. Raut
Course
Outcome
After successful completion of course students will be
able to
CO205.1 Know the various pharmaceutical dosage forms and their
manufacturing techniques.
CO205.2 Know various considerations in development of
pharmaceutical dosage forms.
CO205.3 Compare the properties of various excipients and selection of
suitable excipient to develop stable and effective dosage form
CO205.4 Design the dosage form based on Pre-formulation parameters
CO205.5 Formulate solid, liquid and semisolid dosage forms and
evaluate them for their quality
Outcome
After successful completion of course students will be
able to
CO205.1 Know the various pharmaceutical dosage forms and their
manufacturing techniques.
CO205.2 Know various considerations in development of
pharmaceutical dosage forms.
CO205.3 Compare the properties of various excipients and selection of
suitable excipient to develop stable and effective dosage form
CO205.4 Design the dosage form based on Pre-formulation parameters
CO205.5 Formulate solid, liquid and semisolid dosage forms and
evaluate them for their quality
Learning objectives
•To understand the concept and objective of pre-formulation studies
•To explain various physicochemical characteristics of drug substances and their
importance in formulation of dosage form
•To interpret BCS classification of drugs & its significance
•To illustrate application of pre-formulation in the development of solid, liquid
oral and Parenteral dosage forms and its impact on stability of dosage forms
•To understand the concept and objective of pre-formulation studies
•To explain various physicochemical characteristics of drug substances and their
importance in formulation of dosage form
•To interpret BCS classification of drugs & its significance
•To illustrate application of pre-formulation in the development of solid, liquid
oral and Parenteral dosage forms and its impact on stability of dosage forms
Pre-formulation
•Itisdefinedasthephaseofresearchanddevelopmentinwhichpre-
formulationstudiescharacterizephysicalandchemicalpropertiesof
adrugmoleculeinordertodevelopsafe,effectiveandstable
dosageform.
•Inpre-formulationstudies,physicochemicalpropertiesofdrug
moleculesarecharacterizedeitheraloneorincombinationwith
excipients.
•Itisdefinedasthephaseofresearchanddevelopmentinwhichpre-
formulationstudiescharacterizephysicalandchemicalpropertiesof
adrugmoleculeinordertodevelopsafe,effectiveandstable
dosageform.
•Inpre-formulationstudies,physicochemicalpropertiesofdrug
moleculesarecharacterizedeitheraloneorincombinationwith
excipients.
Pre-formulation
•The meaning of pre-formulation refers to the steps to be undertaken before formulation.
•Pre-formulation includes determination of physical chemical properties of drug substance with the goal of
developing a new drug which is safe stable and efficacious.
•Each drug has intrinsic chemical and physical properties that were considered prior to the development of
pharmaceutical formulation the purpose of pre-formulation study is to generate useful information for the
formulator in the development of stable and bioavailable dosage form.
•Inappropriate pre-formulation study results in poor stability of active ingredients increase the overall cost of
development and increased development time.
•After compiling all data it is transferred to the development pharmacist and for the day work on formulation
of dosage form.
•The meaning of pre-formulation refers to the steps to be undertaken before formulation.
•Pre-formulation includes determination of physical chemical properties of drug substance with the goal of
developing a new drug which is safe stable and efficacious.
•Each drug has intrinsic chemical and physical properties that were considered prior to the development of
pharmaceutical formulation the purpose of pre-formulation study is to generate useful information for the
formulator in the development of stable and bioavailable dosage form.
•Inappropriate pre-formulation study results in poor stability of active ingredients increase the overall cost of
development and increased development time.
•After compiling all data it is transferred to the development pharmacist and for the day work on formulation
of dosage form.
OBJECTIVES
•To establish the Physico-chemical parameters of a new drug entity
•To determine its kinetics and stability
•To establish its compatibility with common excipients
•It provides insights into how drug products should be processed and stored to ensure
their quality
•To estimate problem may arise during formulation that is stability problem poor in
Vivo dissolution and poor bioavailability
•To develop optimal drug delivery system.
•To establish the Physico-chemical parameters of a new drug entity
•To determine its kinetics and stability
•To establish its compatibility with common excipients
•It provides insights into how drug products should be processed and stored to ensure
their quality
•To estimate problem may arise during formulation that is stability problem poor in
Vivo dissolution and poor bioavailability
•To develop optimal drug delivery system.
GOALS
•Toestablishphysico-chemicalparameterofcandidatedrugmolecule.
•TodeterminetheKineticrateprofileofdrugsubstance.
•Toestablishthecompatibilityofcandidatedrugmoleculewith
commonexcipients
•Tochoosethecorrectformofdrugsubstance
•Toestablishphysico-chemicalparameterofcandidatedrugmolecule.
•TodeterminetheKineticrateprofileofdrugsubstance.
•Toestablishthecompatibilityofcandidatedrugmoleculewith
commonexcipients
•Tochoosethecorrectformofdrugsubstance
Organoleptic Characters
•Colour, odour, taste of the new drug must be recorded.
Colour Odour Taste
Off-white Pungent Acidic
CreamYellow SulphurousBitter
Tan Fruity Bland
Shiny Aromatic Intense
OdourlessSweet
Tasteless
•Colour, odour, taste of the new drug must be recorded.
Colour Odour Taste
Off-white Pungent Acidic
CreamYellow SulphurousBitter
Tan Fruity Bland
Shiny Aromatic Intense
OdourlessSweet
Tasteless
Physical Properties
1.Physical form (crystal & amorphous)
2.Particle size, shape,
3.Polymorphism
4.Flow properties,
5.Solubility profile (pka, pH, Partition Coefficient),
1.Physical form (crystal & amorphous)
2.Particle size, shape,
3.Polymorphism
4.Flow properties,
5.Solubility profile (pka, pH, Partition Coefficient),
Physical Properties
1.Physical form (crystal & amorphous)
•Solidformarepreferredfortheformulationbecausetheycanbeeasilyconvertedintotabletandcapsule.
•Acompoundcanbecrystallineoramorphousdependuponinternalstructure.
•Thehabitandinternalstructureofthedrugeffectsflowpropertiesaswellaschemicalstability.
•Incrystallinestateatomsormoleculesarearrangedinhighlyorderedformanditsassociatedwiththree
dimensionalarray.
•Whileinamorphousformsareatomsormoleculesarerandomlyplacedasinaliquidtheydonothaveanyfixed
internalstructure.
•Solubility&dissolutionratearegreaterforamorphousformthan crystalline,as amorphousformhas
higherthermodynamic energy.
•Eg. Amorphous form of Novobiocinis well absorbed whereas crystallineformresultsin poorabsorption
1.Physical form (crystal & amorphous)
•Solidformarepreferredfortheformulationbecausetheycanbeeasilyconvertedintotabletandcapsule.
•Acompoundcanbecrystallineoramorphousdependuponinternalstructure.
•Thehabitandinternalstructureofthedrugeffectsflowpropertiesaswellaschemicalstability.
•Incrystallinestateatomsormoleculesarearrangedinhighlyorderedformanditsassociatedwiththree
dimensionalarray.
•Whileinamorphousformsareatomsormoleculesarerandomlyplacedasinaliquidtheydonothaveanyfixed
internalstructure.
•Solubility&dissolutionratearegreaterforamorphousformthan crystalline,as amorphousformhas
higherthermodynamic energy.
•Eg. Amorphous form of Novobiocinis well absorbed whereas crystallineformresultsin poorabsorption
•Crystalhabit&internalstructureofdrugcanaffectbulk&physicochemicalpropertyofmolecule.
•Crystalhabitisdescriptionofouterappearanceofcrystal.
•Internalstructureismoleculararrangementwithinthesolid.
•Changewithinternalstructureusuallyalterscrystalhabit.
•Eg.Conversionofsodiumsalttoitsfreeacidformproducebothchangeininternalstructure&crystalhabit.
•Internal packing of molecules may have no long-range order (amorphous), different repeating packing
arrangements (polymorphic crystals), solvent included (solvates and hydrates).
•These changes in internal packing of a solid will give rise to changes in properties.
•However, it is also possible to change the external shape of a crystal.
Physical Properties
•Crystalhabitisdescriptionofouterappearanceofcrystal.
•Internalstructureismoleculararrangementwithinthesolid.
•Changewithinternalstructureusuallyalterscrystalhabit.
•Eg.Conversionofsodiumsalttoitsfreeacidformproducebothchangeininternalstructure&crystalhabit.
•Internal packing of molecules may have no long-range order (amorphous), different repeating packing
arrangements (polymorphic crystals), solvent included (solvates and hydrates).
•These changes in internal packing of a solid will give rise to changes in properties.
•However, it is also possible to change the external shape of a crystal.
Physical Properties
Crystalline Amorphous
Crystallineformhavefixedinternal
structure.
Amorphousformsdonothaveanyfixed
internalstructure
Crystallineformhaslesserthermodynamic
energyascomparedtoitsamorphousform.
Amorphous form has higher
thermodynamicsenergythanitscrystalline
form
Crystallineformsaremorestablethanits
amorphousforms.
Amorphousformsarelessstablethanits
crystallineforms
Crystallineformshaslessersolubilitythanits
amorphousform
Amorphousformshaveagreatersolubility
thanitscrystallineforms
Crystallineformshaslesstendancyto
changeitsformduringstorage
Amorphoustendstothewordtomore
stableformduringstorage
Meltingpoint: Stable>metastableform>unstableform>amorphousformofthesamedrug
Dissolution rate: Stable<metastableform<unstableform<amorphousformofthesamedrug
Crystallineformhavefixedinternal
structure.
Amorphousformsdonothaveanyfixed
internalstructure
Crystallineformhaslesserthermodynamic
energyascomparedtoitsamorphousform.
Amorphous form has higher
thermodynamicsenergythanitscrystalline
form
Crystallineformsaremorestablethanits
amorphousforms.
Amorphousformsarelessstablethanits
crystallineforms
Crystallineformshaslessersolubilitythanits
amorphousform
Amorphousformshaveagreatersolubility
thanitscrystallineforms
Crystallineformshaslesstendancyto
changeitsformduringstorage
Amorphoustendstothewordtomore
stableformduringstorage
Meltingpoint: Stable>metastableform>unstableform>amorphousformofthesamedrug
Dissolution rate: Stable<metastableform<unstableform<amorphousformofthesamedrug
Differentshapesofcrystals
•Crystalhabit-Theexternalshapeiscalled
thecrystalhabitandthisisaconsequenceof
therateatwhichdifferentfacesgrow.
•Changesininternalpackingusually(butnot
always)giveaneasilydistinguishablechange
inhabit.
•However,forthesamecrystalpackingitis
possibletochangetheexternalappearance
bychangingthecrystallizationconditions.
•Crystalhabit-Theexternalshapeiscalled
thecrystalhabitandthisisaconsequenceof
therateatwhichdifferentfacesgrow.
•Changesininternalpackingusually(butnot
always)giveaneasilydistinguishablechange
inhabit.
•However,forthesamecrystalpackingitis
possibletochangetheexternalappearance
bychangingthecrystallizationconditions.
•The degree of crystallinityof drug substance has marked effect on its hardness, density, transparency and
diffusion.
•This influences both the choices of delivery system and activity as determined by the rate of delivery.
•As crystalline compound contain stoichiometricor non stoichiometric crystallization solvent.
•Non stoichiometric adducts are called inclusion or clathrates.
•While stoichiometric adducts are called solvates.
•The crystalline form of penicillin G as a potassium or sodium salt is considerable more stable and result in
excellent therapeutic response than amorphous forms.
•If the compound contain water as a solvent then it is known as hydrate.
Physical Properties
diffusion.
•This influences both the choices of delivery system and activity as determined by the rate of delivery.
•As crystalline compound contain stoichiometricor non stoichiometric crystallization solvent.
•Non stoichiometric adducts are called inclusion or clathrates.
•While stoichiometric adducts are called solvates.
•The crystalline form of penicillin G as a potassium or sodium salt is considerable more stable and result in
excellent therapeutic response than amorphous forms.
•If the compound contain water as a solvent then it is known as hydrate.
Physical Properties
Molecular Adducts
•During the process of crystallization, some compounds have a tendency to trap the solvent molecules.
Non-Stoichiometric inclusion compounds (or adducts)
•In these crystals solvent molecules are entrapped within the crystal lattice and the number of solvent
molecules are not included in stoichiometric number. Depending on the shape they are of three types :-
•Channel When the crystal contains continuous channels in which the solvent molecule can be included.
e.g. Urea forms channel.
•Layers:-Here solvent molecules are entrapped in between layers of crystals.
•Clathrates(Cage):-Solvent molecules are entrapped within the cavity of the crystal from all sides.
•During the process of crystallization, some compounds have a tendency to trap the solvent molecules.
Non-Stoichiometric inclusion compounds (or adducts)
•In these crystals solvent molecules are entrapped within the crystal lattice and the number of solvent
molecules are not included in stoichiometric number. Depending on the shape they are of three types :-
•Channel When the crystal contains continuous channels in which the solvent molecule can be included.
e.g. Urea forms channel.
•Layers:-Here solvent molecules are entrapped in between layers of crystals.
•Clathrates(Cage):-Solvent molecules are entrapped within the cavity of the crystal from all sides.
Molecular Adducts
Stoichiometric inclusion compounds (or stoichiometric adducts)
•Thismolecularcomplexhasincorporatedthecrystallizingsolventmoleculesintospecificsites
withinthecrystallatticeandhasstoichiometricnumberofsolventmoleculescomplexed.
•Whentheincorporatedsolventiswater,thecomplexiscalledhydratesandwhenthesolventis
otherthanwater,thecomplexiscalledsolvates.Dependingontheratioofwatermolecules
withinacomplexthefollowingnomenclatureisfollowed.
•Anhydrous:1molecompound+0molewater
•Hemihydrate:1molecompound+½molewater
•Monohydrate:1molecompound+1molewater
•Dihydrate:1molecompound+2moleswater
•
Stoichiometric inclusion compounds (or stoichiometric adducts)
•Thismolecularcomplexhasincorporatedthecrystallizingsolventmoleculesintospecificsites
withinthecrystallatticeandhasstoichiometricnumberofsolventmoleculescomplexed.
•Whentheincorporatedsolventiswater,thecomplexiscalledhydratesandwhenthesolventis
otherthanwater,thecomplexiscalledsolvates.Dependingontheratioofwatermolecules
withinacomplexthefollowingnomenclatureisfollowed.
•Anhydrous:1molecompound+0molewater
•Hemihydrate:1molecompound+½molewater
•Monohydrate:1molecompound+1molewater
•Dihydrate:1molecompound+2moleswater
•
Physical Properties
•Ifthecompoundhavenowatermoleculewithinitscrystalstructurethenitiscalled
unhydrous.
•Thedissolutionratesofhydratesarelessthancorrespondingunhydrouscrystallineform.
•exampleglutethimidetheophylline,caffeine,succinylsulphathiazol,phenobarbitol.
•Thedissolutionratesoforganicsolvatesarehigherthancorrespondingpurecrystalline
form.
•Example1,4dioxanesolvateofnifedipineshowsbettersolubilitythandihydrateform.
•Ifthecompoundhavenowatermoleculewithinitscrystalstructurethenitiscalled
unhydrous.
•Thedissolutionratesofhydratesarelessthancorrespondingunhydrouscrystallineform.
•exampleglutethimidetheophylline,caffeine,succinylsulphathiazol,phenobarbitol.
•Thedissolutionratesoforganicsolvatesarehigherthancorrespondingpurecrystalline
form.
•Example1,4dioxanesolvateofnifedipineshowsbettersolubilitythandihydrateform.
Properties of solvates / hydrates
•Generally,theanhydrousformofadrughasgreateraqueoussolubilitythanits
hydrates.Thisisbecausethehydratesarealreadyinequilibriumwithwaterand
thereforehavelessdemandforwater.e.g.anhydrousformsoftheophylineand
ampicillinhavehigheraqueoussolubilitythanthehydrates.
•Nonaqueoussolvateshavegreateraqueoussolubilitythanthenon-solvates.
e.g.chloroformsolvatesofgriseofulvinaremorewatersolublethantheir
nonsolvateforms.
•Generally,theanhydrousformofadrughasgreateraqueoussolubilitythanits
hydrates.Thisisbecausethehydratesarealreadyinequilibriumwithwaterand
thereforehavelessdemandforwater.e.g.anhydrousformsoftheophylineand
ampicillinhavehigheraqueoussolubilitythanthehydrates.
•Nonaqueoussolvateshavegreateraqueoussolubilitythanthenon-solvates.
e.g.chloroformsolvatesofgriseofulvinaremorewatersolublethantheir
nonsolvateforms.
2. Particle size
•Particlesizerepresentsthedimensionsofsolidpowders,liquidparticles,andgasesbubbles.
•Particlesizemainlyinfluencedissolutionrate.
•Absorptionrateofpoorlysolubledrugcanbeimprovedbyreducingtheparticlesizeandthus
enhancesthebioavailabilityofdrugs.
•Particlesizeisalsoconsideredduringdevelopmentofnewchemicalentities(NCEs)asitaffect
physicalpropertiesofactivepharmaceuticalingredientsandexcipients.
•Particlesizeandshapesignificantlyaffectvariousmanufacturingstep,suchasmixing,granulation,
drying,milling,blending,coating,encapsulation,andcompression.
•Particlesizerepresentsthedimensionsofsolidpowders,liquidparticles,andgasesbubbles.
•Particlesizemainlyinfluencedissolutionrate.
•Absorptionrateofpoorlysolubledrugcanbeimprovedbyreducingtheparticlesizeandthus
enhancesthebioavailabilityofdrugs.
•Particlesizeisalsoconsideredduringdevelopmentofnewchemicalentities(NCEs)asitaffect
physicalpropertiesofactivepharmaceuticalingredientsandexcipients.
•Particlesizeandshapesignificantlyaffectvariousmanufacturingstep,suchasmixing,granulation,
drying,milling,blending,coating,encapsulation,andcompression.
Particle size
•AsperICHGuidelines,particlesizeiscriticalparameterwhichaffectssafety,efficacy,andstabilityofsolid
dosageformandcertainliquiddosageformslikesuspensionandemulsion.
•Duringmanufacturingofsoliddosageformsliketabletandcapsule,particlesizeinfluencesalarge
numberofparametersinprocessing,includingcapsulefilling,porosity,andflowability.
•Similarlyinsuspension,physicalpropertiesandparticlesizeofdispersedparticles,bothaffectthestability
offormulation.
•AsperICHGuidelines,particlesizeiscriticalparameterwhichaffectssafety,efficacy,andstabilityofsolid
dosageformandcertainliquiddosageformslikesuspensionandemulsion.
•Duringmanufacturingofsoliddosageformsliketabletandcapsule,particlesizeinfluencesalarge
numberofparametersinprocessing,includingcapsulefilling,porosity,andflowability.
•Similarlyinsuspension,physicalpropertiesandparticlesizeofdispersedparticles,bothaffectthestability
offormulation.
Solubility and particle size
The particle size and surface area of drug exposed to a medium can affect
solubility.
log
�
��
=
2????????????
2.303��??????
S –solubility of the small particles
S
0-solubility of the large particles
γ-surface tension
V –molar volume
R-gas constant
T-absolute temperature
r-radius of small particles
The particle size and surface area of drug exposed to a medium can affect
solubility.
log
�
��
=
2????????????
2.303��??????
S –solubility of the small particles
S
0-solubility of the large particles
γ-surface tension
V –molar volume
R-gas constant
T-absolute temperature
r-radius of small particles
Particle size determination (PSD) -
Methods
1. Optical Microscopy (Counting)
2. Sieving Method (Separation)
3. Sedimentation Method
4. Conductivity Method
Methods
1. Optical Microscopy (Counting)
2. Sieving Method (Separation)
3. Sedimentation Method
4. Conductivity Method
Particle Shape
According to their shape particle divided are into two groups.
1) Symmetrical Particle
2) Asymmetrical Particle
According to their shape particle divided are into two groups.
1) Symmetrical Particle
2) Asymmetrical Particle
Symmetrical Particle
•Theparticlehavingspecificcrystalshapeandcanbeexpressedintermoftheirdiameterknownas
symmetricalparticle.
•ForexampleSphericalShape
•Symmetricalparticlearemainlyfoundinsphericalshape.
•Soifweknowthediameterofsphericalparticlewecaneasilydetermineitssurfaceareaand
volume.
Asymmetrical particle
•Theparticlewhichhavenospecificcrystalshapeknownasasymmetricalparticles.
•Astheasymmetryofparticleincreasesthenthesurfaceareaandvolumeoftheparticlealso
becomecomplextobedetermined.
•Inordertodeterminedtheirsurfaceareaandvolumefourdifferenttypesofequivalentdiameter
areusedi.e.Surfacediameter,Volumediameter,Projecteddiameter,Stokesdiameter.
•Theparticlehavingspecificcrystalshapeandcanbeexpressedintermoftheirdiameterknownas
symmetricalparticle.
•ForexampleSphericalShape
•Symmetricalparticlearemainlyfoundinsphericalshape.
•Soifweknowthediameterofsphericalparticlewecaneasilydetermineitssurfaceareaand
volume.
Asymmetrical particle
•Theparticlewhichhavenospecificcrystalshapeknownasasymmetricalparticles.
•Astheasymmetryofparticleincreasesthenthesurfaceareaandvolumeoftheparticlealso
becomecomplextobedetermined.
•Inordertodeterminedtheirsurfaceareaandvolumefourdifferenttypesofequivalentdiameter
areusedi.e.Surfacediameter,Volumediameter,Projecteddiameter,Stokesdiameter.
Particle Shape Determination
Particleshapealsohasinfluenceonsurfacearea,flowproperties,packingand
compactionoftheparticles.
Sphericalparticleshaveminimumsurfaceareaandbetterflowproperties.
Shapecanalsohaveinfluenceonrateofdissolutionofdrugs.
Techniquesofdeterminationare:
Microscopy
Lightscattering
Particleshapealsohasinfluenceonsurfacearea,flowproperties,packingand
compactionoftheparticles.
Sphericalparticleshaveminimumsurfaceareaandbetterflowproperties.
Shapecanalsohaveinfluenceonrateofdissolutionofdrugs.
Techniquesofdeterminationare:
Microscopy
Lightscattering
DifferenttypesofParticleShape
Surface area=α
��
2
�=??????�
�
2
Where α
�is����??????��??????��??????�??????����and �
�is the equivalent surface diameter
Volume= α
v�
3
�=
????????????
??????
2
6
α
v is the volume factor and dv is the equivalent volume diameter.
Surface area and volume
For a sphere α
�= ??????�
�
2
/�
2
�= 3.142 and α
v=
????????????
??????
3
6??????
3
�
= 0.524
The ratio α
�/α
v is used to characterize particle shape
.
If α
�/α
v=6, particle is spherical in shape.
When α
�/α
v >6, particle becomes asymmetric.
��
2
�=??????�
�
2
Where α
�is����??????��??????��??????�??????����and �
�is the equivalent surface diameter
Volume= α
v�
3
�=
????????????
??????
2
6
α
v is the volume factor and dv is the equivalent volume diameter.
Surface area and volume
For a sphere α
�= ??????�
�
2
/�
2
�= 3.142 and α
v=
????????????
??????
3
6??????
3
�
= 0.524
The ratio α
�/α
v is used to characterize particle shape
.
If α
�/α
v=6, particle is spherical in shape.
When α
�/α
v >6, particle becomes asymmetric.
3. Need to study polymorphism????
•Dependingupontheirrelativestability,oneoftheseveralpolymorphicformwillbephysicallymorestablethan
others.
•Stablepolymorphrepresentsthelowestenergystate,hashighestmeltingpointandleastaqueous
solubility.
•Metastableformrepresentthehigherenergystate,havelowermeltingpointandhighaqueoussolubility.
•Metastableformconvertedtothestableformduetotheirhigherenergystate.
•Metastableformshowsbetterbioavailabilityandthereforepreferredinformulations.
•Only10%ofthepharmaceuticalsarepresentintheirmetastableform.
•Solubility(particularlyimportantinsuspensionsandbiopharmaceutically),meltingpoint,density,crystalshape,
opticalandelectricalpropertiesandvapourpressureareoftenverydifferentforeachpolymorph.
•Polymorphismisremarkablycommon,particularlywithincertainstructuralgroups:63%ofbarbiturates,67%of
steroidsand40%ofsulphonamidesexhibitpolymorphism.
•Thesteroidprogesteronehasfivepolymorphs,whereasthesulphonamidesulphabenzamidehasfourpolymorphsand
threesolvates.
•Dependingupontheirrelativestability,oneoftheseveralpolymorphicformwillbephysicallymorestablethan
others.
•Stablepolymorphrepresentsthelowestenergystate,hashighestmeltingpointandleastaqueous
solubility.
•Metastableformrepresentthehigherenergystate,havelowermeltingpointandhighaqueoussolubility.
•Metastableformconvertedtothestableformduetotheirhigherenergystate.
•Metastableformshowsbetterbioavailabilityandthereforepreferredinformulations.
•Only10%ofthepharmaceuticalsarepresentintheirmetastableform.
•Solubility(particularlyimportantinsuspensionsandbiopharmaceutically),meltingpoint,density,crystalshape,
opticalandelectricalpropertiesandvapourpressureareoftenverydifferentforeachpolymorph.
•Polymorphismisremarkablycommon,particularlywithincertainstructuralgroups:63%ofbarbiturates,67%of
steroidsand40%ofsulphonamidesexhibitpolymorphism.
•Thesteroidprogesteronehasfivepolymorphs,whereasthesulphonamidesulphabenzamidehasfourpolymorphsand
threesolvates.
Polymorphism
Itistheabilityofthecompoundtocrystallizeasmorethanone distinctcrystallinespecieswith
differentinternallattice.
Differentcrystallineforms arecalledpolymorphsbut their chemical composition remain same.
Polymorphsareof2types
•Enatiotropic
•Monotropic
Thepolymorphwhichcanbechangedfromoneformintoanother byvaryingtemporpressureis
calledasEnantiotropicpolymorph.
•Eg.Sulphur.
Onepolymorphwhichisunstableatalltemp.&pressureiscalledasMonotropic polymorph.
•Eg.Glycerylstearate.
Itistheabilityofthecompoundtocrystallizeasmorethanone distinctcrystallinespecieswith
differentinternallattice.
Differentcrystallineforms arecalledpolymorphsbut their chemical composition remain same.
Polymorphsareof2types
•Enatiotropic
•Monotropic
Thepolymorphwhichcanbechangedfromoneformintoanother byvaryingtemporpressureis
calledasEnantiotropicpolymorph.
•Eg.Sulphur.
Onepolymorphwhichisunstableatalltemp.&pressureiscalledasMonotropic polymorph.
•Eg.Glycerylstearate.
Polymorphs differ from each other with respect to their physicalproperty such as
•Solubility
•Melting point
•Density
•Hardness
•Compression characteristic
Characteristics of polymorphs
Polymorphism
Characteristics Stablepolymorph Metastable
polymorph
Unstablepolymorph
Packingofmoleculesincrystal
lattice
Tightlypacked Lesstightlypacked Looselypacked
Meltingpoint Highest Moderate Lowest
Rateofdissolution Lowest Moderate Highest
•Solubility
•Melting point
•Density
•Hardness
•Compression characteristic
Characteristics of polymorphs
Polymorphism
Characteristics Stablepolymorph Metastable
polymorph
Unstablepolymorph
Packingofmoleculesincrystal
lattice
Tightlypacked Lesstightlypacked Looselypacked
Meltingpoint Highest Moderate Lowest
Rateofdissolution Lowest Moderate Highest
Polymorphism and bioavailability
•Manydrugsarehydrophobicandhaveverylimitedsolubilityinwater.Ifthedrugremainsinseveralpolymorphic
formsthenthestableonewillproducetheslowestrateofdissolutionanditmayshowminimumbioavailability.
•Forhighlywatersolubledrugspolymorphismdoesnotshowanyproblemindissolutionrate
•Example:Chloramphenicolpalmitatehasthreepolymorphsα(stable),β(metastable)andγ(unstable).When
chloramphenicolpalmitatesuspensionispreparedfromαorβpolymorphitisfoundthatbioavailabiltyishigher
withthemetastableform.
•Example:Twopolymorphsofaspirincanbeobtainedbyrecrystallizationofaspirinfrom95%ethanolorn-
hexane.Thepolymorphobtainedfromn-hexaneisfoundtohavegreatersolubilityinwaterthanthepolymorph
obtainedfromethanol.
•Manydrugsarehydrophobicandhaveverylimitedsolubilityinwater.Ifthedrugremainsinseveralpolymorphic
formsthenthestableonewillproducetheslowestrateofdissolutionanditmayshowminimumbioavailability.
•Forhighlywatersolubledrugspolymorphismdoesnotshowanyproblemindissolutionrate
•Example:Chloramphenicolpalmitatehasthreepolymorphsα(stable),β(metastable)andγ(unstable).When
chloramphenicolpalmitatesuspensionispreparedfromαorβpolymorphitisfoundthatbioavailabiltyishigher
withthemetastableform.
•Example:Twopolymorphsofaspirincanbeobtainedbyrecrystallizationofaspirinfrom95%ethanolorn-
hexane.Thepolymorphobtainedfromn-hexaneisfoundtohavegreatersolubilityinwaterthanthepolymorph
obtainedfromethanol.
Polymorphism and melting point of cocoa butter suppositories
•Theobromaoilorcocoabuttersuppositoriesaremeanttobemeltedatbodytemperature37
0
Cbut
shouldremainassolidatroomtemperatureduringstorageperiod.
•Cocoabutterisavailableinthreepolymorphs–α(m.p.20
0
C),β(m.p.36
0
C)andγ(m.p.15
0
C).a-form
isthemetastableform,b-formisthestableformandg-formistheunstableform.Duringmeltingof
cocoabutterbyfusionmethodthefollowingphenomenaarefound:
•Soduringpreparationofcocoabuttersuppositories2/3rdportionofcocoa-butterbaseismeltedand
thenthecontainerisremovedfromtheheatsource.Therestofthebaseismeltedbystirringonly
withoutapplicationofheat.
Procedure Observation Explanation
Thecocoabutteris
meltedapplyinghigh
temperature(60
0
C)
andthenquickly
chilled.
Thesuppositoriesmelts
below30
0
Ci.e.atroom
temperatureitwillmelt.
Soitwillbedifficultto
handle at room
temperature.
Ifmeltedathightemperatureand
cooledveryquicklythenthe
moleculesformthea-crystalsinmore
amountsothesuppositoriesmelt
below30
0
C.Themetastablea-form
willreverttostable
b-form,butitwilltakeseveraldays
forthisprocedure.
Thecocoabutteris
melted at low
temperature(40to
50
0
C)andthencooled
slowly.
Thesuppositoriesdonot
melt at room
temperature. The
meltingpointwillbe
above36
0
C.
Theuseoflowtemperatureandslow
coolingrate
allowsdirectformationofb-crystals
havingameltingpoint of36
0
C.
•Theobromaoilorcocoabuttersuppositoriesaremeanttobemeltedatbodytemperature37
0
Cbut
shouldremainassolidatroomtemperatureduringstorageperiod.
•Cocoabutterisavailableinthreepolymorphs–α(m.p.20
0
C),β(m.p.36
0
C)andγ(m.p.15
0
C).a-form
isthemetastableform,b-formisthestableformandg-formistheunstableform.Duringmeltingof
cocoabutterbyfusionmethodthefollowingphenomenaarefound:
•Soduringpreparationofcocoabuttersuppositories2/3rdportionofcocoa-butterbaseismeltedand
thenthecontainerisremovedfromtheheatsource.Therestofthebaseismeltedbystirringonly
withoutapplicationofheat.
Procedure Observation Explanation
Thecocoabutteris
meltedapplyinghigh
temperature(60
0
C)
andthenquickly
chilled.
Thesuppositoriesmelts
below30
0
Ci.e.atroom
temperatureitwillmelt.
Soitwillbedifficultto
handle at room
temperature.
Ifmeltedathightemperatureand
cooledveryquicklythenthe
moleculesformthea-crystalsinmore
amountsothesuppositoriesmelt
below30
0
C.Themetastablea-form
willreverttostable
b-form,butitwilltakeseveraldays
forthisprocedure.
Thecocoabutteris
melted at low
temperature(40to
50
0
C)andthencooled
slowly.
Thesuppositoriesdonot
melt at room
temperature. The
meltingpointwillbe
above36
0
C.
Theuseoflowtemperatureandslow
coolingrate
allowsdirectformationofb-crystals
havingameltingpoint of36
0
C.
Polymorphism and caking of suspension
Incaseofasuspensiontheparticleswillsedimentbelowandtheparticleswill
comeclosertoeachother.
Duringalongstoragelifethesuspensionmayexperienceseveralcyclesof
temperaturechange.
Duringthehotperiodthemetastableformwillgetdissolvedinthestagnant
layerandduringthecoolperiodtheparticleswillgrowandcrystalbridgesmay
formwiththestablecrystals.
Thesecrystal-bridgeswillgiverisetoirreversiblecakingofsuspension.
Incaseofasuspensiontheparticleswillsedimentbelowandtheparticleswill
comeclosertoeachother.
Duringalongstoragelifethesuspensionmayexperienceseveralcyclesof
temperaturechange.
Duringthehotperiodthemetastableformwillgetdissolvedinthestagnant
layerandduringthecoolperiodtheparticleswillgrowandcrystalbridgesmay
formwiththestablecrystals.
Thesecrystal-bridgeswillgiverisetoirreversiblecakingofsuspension.
Methods of characterization of polymorphs
1. Hot stage microscopy,
2. Differential Thermal Analysis,
3. Differential Scanning Calorimetry
4. ThermogravimetricAnalysis (TGA)
5. X-ray powder diffraction
6. IR-Spectroscopy
1. Hot stage microscopy,
2. Differential Thermal Analysis,
3. Differential Scanning Calorimetry
4. ThermogravimetricAnalysis (TGA)
5. X-ray powder diffraction
6. IR-Spectroscopy
4. Flow Properties of Powders
•Powdersmaybefree-flowingorcohesive(Sticky).
•Manycommonmanufacturingproblemsareattributestopowderflowwhenpowdertransfer
throughlargeequipmentsuchashopper.
•Unevenpowderflow-excessentrappedairwithinpowderscappingorlamination.
•Unevenpowderflowincreaseparticle’sfrictionwithdiewallcausinglubricationproblemsand
increasedustcontaminationrisksduringpowdertransfer.
•Powderstorage,whichforexampleresultincakingtendencieswithinavialorbagafter
shippingorstoragetime.
•Separationofsmallquantityofthepowderfromthebulk-specificallyjustbeforethecreationof
individualdosessuchasduringtableting,encapsulationandvialfillingwhichaffecttheweight
uniformityofthedose(underoroverdosage).
•Powdersmaybefree-flowingorcohesive(Sticky).
•Manycommonmanufacturingproblemsareattributestopowderflowwhenpowdertransfer
throughlargeequipmentsuchashopper.
•Unevenpowderflow-excessentrappedairwithinpowderscappingorlamination.
•Unevenpowderflowincreaseparticle’sfrictionwithdiewallcausinglubricationproblemsand
increasedustcontaminationrisksduringpowdertransfer.
•Powderstorage,whichforexampleresultincakingtendencieswithinavialorbagafter
shippingorstoragetime.
•Separationofsmallquantityofthepowderfromthebulk-specificallyjustbeforethecreationof
individualdosessuchasduringtableting,encapsulationandvialfillingwhichaffecttheweight
uniformityofthedose(underoroverdosage).
Parameters to evaluate the flowabilityof a powder.
•Carr’s compressibility index.
•Hausnerratio.
•The angle of repose(Ɵ).
•Carr’s compressibility index.
•Hausnerratio.
•The angle of repose(Ɵ).
•Avolumeofpowderisfilledintoagraduatedglasscylinderandrepeatedlytappedforaknown
duration.Thevolumeofpowderaftertappingismeasure.
•Carr’sindex(%)=���(
????????????????????????����??????�??????�??????−??????�����??????�??????�??????
????????????????????????����??????�??????�??????
)
•Bulkdensity=
Weight
Bulkvolume
•Tappeddensity=
Weight
Tappedvolume
Carr’s compressibilityindex
duration.Thevolumeofpowderaftertappingismeasure.
•Carr’sindex(%)=���(
????????????????????????����??????�??????�??????−??????�����??????�??????�??????
????????????????????????����??????�??????�??????
)
•Bulkdensity=
Weight
Bulkvolume
•Tappeddensity=
Weight
Tappedvolume
Carr’s compressibilityindex
Flowdescription% Compressibility
Examples
Excellent flow 5 –15 Free flowing granules
Good 12–16 Free flowing powdered
granules
Fairto Passable 18–21 Powdered granules
Poor 23–35 Very fluid powders
Very Poor 33-38 Fluid cohesive powders
Extremely poor >40 Fluid cohesive powders
Relationship between powder flowability and %compressibility
Carr’s compressibility index
Examples
Excellent flow 5 –15 Free flowing granules
Good 12–16 Free flowing powdered
granules
Fairto Passable 18–21 Powdered granules
Poor 23–35 Very fluid powders
Very Poor 33-38 Fluid cohesive powders
Extremely poor >40 Fluid cohesive powders
Relationship between powder flowability and %compressibility
Carr’s compressibility index
Hausnerratio=
Tappeddensity
Pouredorbulkdensity
Hausner ratio was related to inter-particlefriction:
•Value less than 1.25 indicates good flow (=20%Carr).
•Thepowderwithlowinter-particlefriction,suchascoarsespheres.
•V a l u egreater than1.5 indicates poor flow (= 33% Carr’s or CompressibilityIndex)).
•Morecohesive,lessfree-flowingpowderssuchasflakes.
•Between1.25and1.5(addedglidantnormallyimprovesflow).
•>1.5(addedglidantdoesn’timproveflow).
Hausner Ratio
Tappeddensity
Pouredorbulkdensity
Hausner ratio was related to inter-particlefriction:
•Value less than 1.25 indicates good flow (=20%Carr).
•Thepowderwithlowinter-particlefriction,suchascoarsespheres.
•V a l u egreater than1.5 indicates poor flow (= 33% Carr’s or CompressibilityIndex)).
•Morecohesive,lessfree-flowingpowderssuchasflakes.
•Between1.25and1.5(addedglidantnormallyimprovesflow).
•>1.5(addedglidantdoesn’timproveflow).
Hausner Ratio
•Significance: It is related to interparticlefriction. So it can be used to predict powder
flow properties. For coarse, free flowing powders the Hausnerratio is approximately
1.2.
•For more cohesive, less ree-flowing powder (e.g. flakes) will have a Hausnerration
greater than 1.5.
•Interpretation: Greater the Hausnerratio more cohesive will be the powder and
flowability will be reduced.
flow properties. For coarse, free flowing powders the Hausnerratio is approximately
1.2.
•For more cohesive, less ree-flowing powder (e.g. flakes) will have a Hausnerration
greater than 1.5.
•Interpretation: Greater the Hausnerratio more cohesive will be the powder and
flowability will be reduced.
Angle of repose
•Angleofreposeofapowdersampleisaparameterthatshowsinterparticle
cohesion.
•Ifcohesionbetweenpowderparticlesislessthenpowderflow-propertyisbetter.
Duetocohesion,powderexperiencesadragforceagainstflow.
•Interparticlecohesiveforcesareduetonon-specificvanderWaalsforces.
•Itincreasesasparticlesizedecreasesandmoisturecontentincreases.
•Surfacetensionforcesbetweenadsorbedliquidlayersattheparticlesurfaceand
Electrostaticforcesarisingfromcontactorfrictionwiththewalloftheequipment.
•Angleofreposeofapowdersampleisaparameterthatshowsinterparticle
cohesion.
•Ifcohesionbetweenpowderparticlesislessthenpowderflow-propertyisbetter.
Duetocohesion,powderexperiencesadragforceagainstflow.
•Interparticlecohesiveforcesareduetonon-specificvanderWaalsforces.
•Itincreasesasparticlesizedecreasesandmoisturecontentincreases.
•Surfacetensionforcesbetweenadsorbedliquidlayersattheparticlesurfaceand
Electrostaticforcesarisingfromcontactorfrictionwiththewalloftheequipment.
•Thesampleispouredontothehorizontalsurfaceandtheangleofthe
resultingpyramidismeasured.
•Theusernormallyselectsthefunnelorificethroughwhichthepowderflows
slowlyandreasonablyconstantly.
Angle of repose=Tan ø=h/r
Ø=tan
-1
(h/r)
Angle of Repose
resultingpyramidismeasured.
•Theusernormallyselectsthefunnelorificethroughwhichthepowderflows
slowlyandreasonablyconstantly.
Angle of repose=Tan ø=h/r
Ø=tan
-1
(h/r)
Angle of Repose
Therougherandmoreirregularthesurfaceoftheparticles,thehigherwillbetheangleofrepose.
Angle of Repose
Angle of Repose
Factors affecting the flow properties of powder
1.Particle’s size & Distribution
2.Particle shape & texture
3.Surface Forces
How flow properties can be improved
1.Alteration of Particle’s size & Distribution
2.Alteration of Particle shape & texture
3.Alteration of Surface Forces
4.Formulation additives (Flow activators)
1.Particle’s size & Distribution
2.Particle shape & texture
3.Surface Forces
How flow properties can be improved
1.Alteration of Particle’s size & Distribution
2.Alteration of Particle shape & texture
3.Alteration of Surface Forces
4.Formulation additives (Flow activators)
Alteration of Particle’s size &Distribution
•Thereiscertainparticlesizeatwhichpowder’sflowabilityisoptimum.
•Coarseparticlesaremorepreferredthanfineonesastheyarelesscohesive.
•Thesizedistributioncanalsobealteredtoimproveflowabilitybyremovingaproportionofthe
fineparticlefractionorbyincreasingtheproportionofcoarserparticle’ssuchasoccursin
granulation.
•Thereiscertainparticlesizeatwhichpowder’sflowabilityisoptimum.
•Coarseparticlesaremorepreferredthanfineonesastheyarelesscohesive.
•Thesizedistributioncanalsobealteredtoimproveflowabilitybyremovingaproportionofthe
fineparticlefractionorbyincreasingtheproportionofcoarserparticle’ssuchasoccursin
granulation.
Alteration of Particle shape &texture
•Generally,moresphericalparticleshavebetterflow properties than more irregular
particles.
•Sphericalparticlesareobtainedbyspraydrying,orby temperature cycling
crystallization.
Alteration of Particle shape & texture
•Particles with very rough surfaces will be more cohesive and have a greater tendency to
interlock than smooth surfaced particles.
•Generally,moresphericalparticleshavebetterflow properties than more irregular
particles.
•Sphericalparticlesareobtainedbyspraydrying,orby temperature cycling
crystallization.
Alteration of Particle shape & texture
•Particles with very rough surfaces will be more cohesive and have a greater tendency to
interlock than smooth surfaced particles.
Alteration of SurfaceForces
•Reductionofelectrostaticchargescanimprovepowderflowability.
•Electrostaticchargescanbereducedbyalteringprocessconditionstoreduce
frictionalcontacts.
•Moisturecontentofparticlegreatlyaffectspowder’sflowability.
•Adsorbedsurfacemoisturefilmstendtoincreasebulkdensityandreduceporosity.
•Dryingtheparticleswillreducethecohesivenessandimprovetheflow.
•Hygroscopicpowder’sstoredandprocessedunderlowhumidityconditions.
•Reductionofelectrostaticchargescanimprovepowderflowability.
•Electrostaticchargescanbereducedbyalteringprocessconditionstoreduce
frictionalcontacts.
•Moisturecontentofparticlegreatlyaffectspowder’sflowability.
•Adsorbedsurfacemoisturefilmstendtoincreasebulkdensityandreduceporosity.
•Dryingtheparticleswillreducethecohesivenessandimprovetheflow.
•Hygroscopicpowder’sstoredandprocessedunderlowhumidityconditions.
Addition of Formulation additives (Flow activators)
•Flowactivatorsarecommonlyreferredasa glidants.
•Flowactivatorsimprovetheflowabilityof powders by reducing adhesion and
cohesion.
e. g. Talc, maize starch and magnesiumstearate.
•Flowactivatorsarecommonlyreferredasa glidants.
•Flowactivatorsimprovetheflowabilityof powders by reducing adhesion and
cohesion.
e. g. Talc, maize starch and magnesiumstearate.
Application of free flowing powders in pharmacy
•Powdersarerequiredtoproducetabletsorcapsules.Freeflowingpowdersflowuniformlyintothe
diecavityoftabletpunchingmachineandinsidetheemptygelatinshells.Afreeflowingpowder
producesuniformcontentofdruginthetabletsandcapsules.
•Freeflowingpowdersshowreproduciblefillingoftabletdiesandcapsulesdosators,whichimprove
weightuniformityandphysicomechanicalproperties(e.g.hardness).
•Poorpowderflowcanresultinexcessentrappedairwithinpowderswhichinsomehigh-speed
tablettingconditionsmaypromotecappingorlaminations.
•Powdersarerequiredtoproducetabletsorcapsules.Freeflowingpowdersflowuniformlyintothe
diecavityoftabletpunchingmachineandinsidetheemptygelatinshells.Afreeflowingpowder
producesuniformcontentofdruginthetabletsandcapsules.
•Freeflowingpowdersshowreproduciblefillingoftabletdiesandcapsulesdosators,whichimprove
weightuniformityandphysicomechanicalproperties(e.g.hardness).
•Poorpowderflowcanresultinexcessentrappedairwithinpowderswhichinsomehigh-speed
tablettingconditionsmaypromotecappingorlaminations.
Application of free flowing powders in pharmacy
•Poorpowderflowcanresultfromexcessfineparticlesinapowder,whichincreasefrictionin
betweenparticleanddiewall.Itmaycauselubricationproblem.
•Inindustrypowdersarerequiredtoflowfromonelocationtoanotherandthisisachievedby
differentmethods,suchasgravityfeeding,fluidizationingasesandliquidsandhydraulictransefer.
Ineachoftheseexamplespowdersarerequiredtoflow.
•Incapsulefillingmachine,especiallyLilytypecapsulefillingmachinethepowdermustbefree
flowingtouniformlyfillthebaseofthecapsuleshells.IncaseofZanasi-typefillingmachinecohesive
powdersarerequired.
•Poorpowderflowcanresultfromexcessfineparticlesinapowder,whichincreasefrictionin
betweenparticleanddiewall.Itmaycauselubricationproblem.
•Inindustrypowdersarerequiredtoflowfromonelocationtoanotherandthisisachievedby
differentmethods,suchasgravityfeeding,fluidizationingasesandliquidsandhydraulictransefer.
Ineachoftheseexamplespowdersarerequiredtoflow.
•Incapsulefillingmachine,especiallyLilytypecapsulefillingmachinethepowdermustbefree
flowingtouniformlyfillthebaseofthecapsuleshells.IncaseofZanasi-typefillingmachinecohesive
powdersarerequired.
5. solubility profile
Solubility and pH
•Anothertechnique,ifthedrugistobeformulatedintoaliquidproduct,is
adjustmentofthepHofthesolventtoenhancesolubility.
•However,formanydrugsubstancespHadjustmentisnotaneffective
meansofimprovingsolubility.Weakacidicorbasicdrugsmayrequire
extremesinpHthatareoutsideacceptedphysiologiclimitsorthatmay
causestabilityproblemswithformulationingredients.
•AdjustmentofpHusuallyhaslittleeffectonthesolubilityofsubstances
otherthanelectrolytes.
•Inmanycases,itisdesirabletouseco-solventsorothertechniquessuchas
complexation,micronization,orsoliddispersiontoimprovesolubility.
Solubility and pH
•Anothertechnique,ifthedrugistobeformulatedintoaliquidproduct,is
adjustmentofthepHofthesolventtoenhancesolubility.
•However,formanydrugsubstancespHadjustmentisnotaneffective
meansofimprovingsolubility.Weakacidicorbasicdrugsmayrequire
extremesinpHthatareoutsideacceptedphysiologiclimitsorthatmay
causestabilityproblemswithformulationingredients.
•AdjustmentofpHusuallyhaslittleeffectonthesolubilityofsubstances
otherthanelectrolytes.
•Inmanycases,itisdesirabletouseco-solventsorothertechniquessuchas
complexation,micronization,orsoliddispersiontoimprovesolubility.
Ionization constant
•Ionization constant: theequilibrium constantfor the ionization of aweak acidorbase. Strong
acids, e.g., HCl, are ionized at all pH values, whereas the ionization of weak acids is dependent
on pH.
•Weak acid: anacidthat gives a 10% or lessyieldofhydronium ionswhen dissolved in water.
•Weak base: abasethat gives a 10% or lessyieldof hydroxide ions when dissolved in water.
•A constant that depends upon the equilibrium between the ions and the molecules that are not
ionized in a solution or liquid—symbol K; also called dissociation constant
•It is necessary to know the extent to which the molecule is ionized at a certain pH, since
properties such as solubility, stability, drug absorption and activity are affected by this
parameter.
•The degree of a drug’s ionization depends both on the pH of the solution in which it is presented
to the biologic membrane and on the pKa, or dissociation constant, of the drug (whether an
acid or base). The concept of pKais derived from the Henderson–Hasselbalchequation.
•Ionization constant: theequilibrium constantfor the ionization of aweak acidorbase. Strong
acids, e.g., HCl, are ionized at all pH values, whereas the ionization of weak acids is dependent
on pH.
•Weak acid: anacidthat gives a 10% or lessyieldofhydronium ionswhen dissolved in water.
•Weak base: abasethat gives a 10% or lessyieldof hydroxide ions when dissolved in water.
•A constant that depends upon the equilibrium between the ions and the molecules that are not
ionized in a solution or liquid—symbol K; also called dissociation constant
•It is necessary to know the extent to which the molecule is ionized at a certain pH, since
properties such as solubility, stability, drug absorption and activity are affected by this
parameter.
•The degree of a drug’s ionization depends both on the pH of the solution in which it is presented
to the biologic membrane and on the pKa, or dissociation constant, of the drug (whether an
acid or base). The concept of pKais derived from the Henderson–Hasselbalchequation.
Ionization constant:
•Acid dissociation constants are sometimes expressed by
pKa=-log
10 Ka
•The Henderson–Hassel Balch equation provides an estimate of the ionized and
unionized drug concentration at a particular pH.
H??????=H
+
+??????
−
•For acidic compounds
pH=pKa+??????��
(ionizeddrug)
(unionizeddrug)
=pKa+??????��
(A
−
)
(????????????)
•For basic compounds
pH=pKa+??????��
(unionizeddrug)
(ionizeddrug)
=pKa+??????��
(HA)
(A
−
)
•Acid dissociation constants are sometimes expressed by
pKa=-log
10 Ka
•The Henderson–Hassel Balch equation provides an estimate of the ionized and
unionized drug concentration at a particular pH.
H??????=H
+
+??????
−
•For acidic compounds
pH=pKa+??????��
(ionizeddrug)
(unionizeddrug)
=pKa+??????��
(A
−
)
(????????????)
•For basic compounds
pH=pKa+??????��
(unionizeddrug)
(ionizeddrug)
=pKa+??????��
(HA)
(A
−
)
Determination of pKa
•pKaof a drug molecule can be determined by various methods:
•Potentiometric (pH) method
•Spectrophotometric method
•Partition-coefficient method
•Conductometricmethod
•Solubility method
•Among all the methods potentiometric and spectrophotometric
methods are most popular and accurate methods by which the pKa
are determined
•pKaof a drug molecule can be determined by various methods:
•Potentiometric (pH) method
•Spectrophotometric method
•Partition-coefficient method
•Conductometricmethod
•Solubility method
•Among all the methods potentiometric and spectrophotometric
methods are most popular and accurate methods by which the pKa
are determined
Significance of pKa
•FromthepKaofaweakacidorweakbasetheunionizedfractionofadrugcanbe
determinedatacertainpH.
•Theunionizedfractionhasgreaterabsorptionratethroughanybiologicalmembrane.
Sowhiledesigningadosageformhowaweakacidorweakbasewillbehaveinany
biologicalfluidanditsrateofabsorptionandthesiteofabsorptioncanbeguessed
fromthepKa.
•Ibuprofen,aweakacidisabsorbedmaximumfromstomachandNitrazepam,aweak
basewillbeabsorbedpreferrentiallyfromduodenum.
•Thesolubilityofaweaklyacidicandweaklybasicdrugcanbeincreasedifthedrug
remainsinionizedstate.Sothesolubilityvs.pHisplottedtogetpH-solubilityprofileof
adrug.Whiledesigningadosageform(oral,ophthalmicorparenteral)thepHthe
solutionisbufferedtothatpHwherethesolubilityismaximumandthedrugis
reasonablystable.
•FromthepKaofaweakacidorweakbasetheunionizedfractionofadrugcanbe
determinedatacertainpH.
•Theunionizedfractionhasgreaterabsorptionratethroughanybiologicalmembrane.
Sowhiledesigningadosageformhowaweakacidorweakbasewillbehaveinany
biologicalfluidanditsrateofabsorptionandthesiteofabsorptioncanbeguessed
fromthepKa.
•Ibuprofen,aweakacidisabsorbedmaximumfromstomachandNitrazepam,aweak
basewillbeabsorbedpreferrentiallyfromduodenum.
•Thesolubilityofaweaklyacidicandweaklybasicdrugcanbeincreasedifthedrug
remainsinionizedstate.Sothesolubilityvs.pHisplottedtogetpH-solubilityprofileof
adrug.Whiledesigningadosageform(oral,ophthalmicorparenteral)thepHthe
solutionisbufferedtothatpHwherethesolubilityismaximumandthedrugis
reasonablystable.
SOLUBILITY
•Definition
•The maximum amount of solute that is soluble in one part of solution to make a saturated
solution at a certain temperature is called the solubility of the drug.
•
•Significance of solubility
•Increasedbioavailability:
•In dealing with a new drug substance, it is extremely important to know something about its solubility
characteristics, especially in aqueous solution, in order to elicit a therapeutic response. Any drug having
solubility less than 10mg/mL in physiologic pH range (pH 1 to 7) will produce bioabsorptionproblem. A
solubility less than 1mg/mL require salt formation of the drug for better bioavailability.
•When the solubility of a drug cannot be increased by salt formation (e.g. in neutral molecules, glycosides,
alcohols, steroids or where the pKaof a basic drug is less than 3 and the pKaof an acidic drug is more
than10) then the drug is dissolved with a cosolventand filled in a soft gelatin capsule.
•Griseofulvin, an antifungal drug, when given orally the absorption is very less. So it is given with fat meal.
The rate of dissolution rate of griseofulvinis increased by micronization(in a fluid energy mill) or by solid
dispersion technique to increase its oral bioavailability.
•Definition
•The maximum amount of solute that is soluble in one part of solution to make a saturated
solution at a certain temperature is called the solubility of the drug.
•
•Significance of solubility
•Increasedbioavailability:
•In dealing with a new drug substance, it is extremely important to know something about its solubility
characteristics, especially in aqueous solution, in order to elicit a therapeutic response. Any drug having
solubility less than 10mg/mL in physiologic pH range (pH 1 to 7) will produce bioabsorptionproblem. A
solubility less than 1mg/mL require salt formation of the drug for better bioavailability.
•When the solubility of a drug cannot be increased by salt formation (e.g. in neutral molecules, glycosides,
alcohols, steroids or where the pKaof a basic drug is less than 3 and the pKaof an acidic drug is more
than10) then the drug is dissolved with a cosolventand filled in a soft gelatin capsule.
•Griseofulvin, an antifungal drug, when given orally the absorption is very less. So it is given with fat meal.
The rate of dissolution rate of griseofulvinis increased by micronization(in a fluid energy mill) or by solid
dispersion technique to increase its oral bioavailability.
SOLUBILITY
•Tastemasking:Chloramphenicolisverybitterintastesoitisverydifficulttomakea
paediatricliquiddosageformwithchloramphenicolbase.Chloramphenicolpalmitate
istaken,thesolubilityofwhichisverylowcomparedtochloramphenicolbase.Whena
suspensionispreparedduetoitslowsolubilityitdoesnotproduceanybittertaste.
•ReducingdegradationintheGIT:Drugslikeerythromycinwilldegradewhilepassing
throughtheacidenvironmentofstomach,soerythromycinisdeliveredaserythromycin
proprionateorestolatewhilepreparingpaediatricsuspension.Thissolubilityofthese
estersareverylessinacidicpH.ThustheyaresavedfromgastricpH.
•
•Tastemasking:Chloramphenicolisverybitterintastesoitisverydifficulttomakea
paediatricliquiddosageformwithchloramphenicolbase.Chloramphenicolpalmitate
istaken,thesolubilityofwhichisverylowcomparedtochloramphenicolbase.Whena
suspensionispreparedduetoitslowsolubilityitdoesnotproduceanybittertaste.
•ReducingdegradationintheGIT:Drugslikeerythromycinwilldegradewhilepassing
throughtheacidenvironmentofstomach,soerythromycinisdeliveredaserythromycin
proprionateorestolatewhilepreparingpaediatricsuspension.Thissolubilityofthese
estersareverylessinacidicpH.ThustheyaresavedfromgastricpH.
•
Determination of solubility of the drug
Step-1:
•MethodA:Someexcessamountofdrugisdissolvedin10mlofsolvent.The
suspensionisshakenovernight(24hrs)inafixedtemperaturewaterbath.
•MethodB:Someexcessamountofdrugisdissolvedin10mlofsolventby
heating,thenthesuspensionisputinafixedtemperaturewaterbath.
Step-2:Thesolidsareseparatedfromsaturatedsolutioneitherbyfiltration
throughmembraneorbycentrifugation.
Step-3:Thefiltrate(orsupernatantliquidaftercentrifugation)isassayedto
determinethesolubilityofthedrug.Theassaymethodmaybegravimetric,
UV-spectrophotometric,HPLCetc.
Step-1:
•MethodA:Someexcessamountofdrugisdissolvedin10mlofsolvent.The
suspensionisshakenovernight(24hrs)inafixedtemperaturewaterbath.
•MethodB:Someexcessamountofdrugisdissolvedin10mlofsolventby
heating,thenthesuspensionisputinafixedtemperaturewaterbath.
Step-2:Thesolidsareseparatedfromsaturatedsolutioneitherbyfiltration
throughmembraneorbycentrifugation.
Step-3:Thefiltrate(orsupernatantliquidaftercentrifugation)isassayedto
determinethesolubilityofthedrug.Theassaymethodmaybegravimetric,
UV-spectrophotometric,HPLCetc.
Intrinsic solubility of a drug (S
0)
•This is the fundamental solubility of a drug when it is completely unionized.
•For a weak acid the intrinsic solubility is the solubility of the drug determined in a strongly
acidic solution.
•For a weak base the intrinsic solubility is the solubility of the drug determined in a strongly
alkaline solution.
•For a non-ionic molecule there will be no measurable change in the solubility in either acidic
or alkaline solution.
•
•In case of weak acid and weak base the solubility can be manipulated by
changing the pH of the solution.
•In case of non-ionizablemolecules the solubility can be manipulated either by
changing the solvent, or by addition of cosolventor by complexation.
•
0)
•This is the fundamental solubility of a drug when it is completely unionized.
•For a weak acid the intrinsic solubility is the solubility of the drug determined in a strongly
acidic solution.
•For a weak base the intrinsic solubility is the solubility of the drug determined in a strongly
alkaline solution.
•For a non-ionic molecule there will be no measurable change in the solubility in either acidic
or alkaline solution.
•
•In case of weak acid and weak base the solubility can be manipulated by
changing the pH of the solution.
•In case of non-ionizablemolecules the solubility can be manipulated either by
changing the solvent, or by addition of cosolventor by complexation.
•
Approaches of increasing the solubility of drugs
1. By changing the pH of the solution
•For a weak acid the relationship between the pH of the solution and the solubility of the drug is:
•
pH = pKa+log S -S0
S 0
where S = overall solubility of the drug = Concentration of ionized fraction + Concentration of
unionized fraction (S
u) For a weak base (BH
+
) the relationship between the pH of the solution and
the solubility of the drug is:
pH = pKa+log S0
S -S 0
•
So in case of a weakly acidic drug the solubility can be increased by increasing the pH and for a
weakly basic drug the solubility can be increased by decreasing the pH.
1. By changing the pH of the solution
•For a weak acid the relationship between the pH of the solution and the solubility of the drug is:
•
pH = pKa+log S -S0
S 0
where S = overall solubility of the drug = Concentration of ionized fraction + Concentration of
unionized fraction (S
u) For a weak base (BH
+
) the relationship between the pH of the solution and
the solubility of the drug is:
pH = pKa+log S0
S -S 0
•
So in case of a weakly acidic drug the solubility can be increased by increasing the pH and for a
weakly basic drug the solubility can be increased by decreasing the pH.
2. By changing the solvent
•Thefirstpreferenceofsolventiswater.Ifthesolubilityisverylessin
waterthenwatermaybereplaced,eitherpartiallyorcompletely,
withoneormorewater-solublesolventslikeethanol,glycerol,
sorbitol,propyleneglycoletc.
•Thesolventsarecalledcosolvents,andthephenomenonas
cosolvency.Thesetypesofnon-toxiccosolventsareusedindesigning
oralliquiddosageforms
•Thefirstpreferenceofsolventiswater.Ifthesolubilityisverylessin
waterthenwatermaybereplaced,eitherpartiallyorcompletely,
withoneormorewater-solublesolventslikeethanol,glycerol,
sorbitol,propyleneglycoletc.
•Thesolventsarecalledcosolvents,andthephenomenonas
cosolvency.Thesetypesofnon-toxiccosolventsareusedindesigning
oralliquiddosageforms
3.By changing the polymorphs
•Whenever a drug is crystallized from some solvent, depending on the
conditions of crystallization, the polymorphic shape is changed.
•For example, if cooled very quickly then metastable polymorphs will be
formed and if cooled very slowly then stable crystallswill form. The
metastable form has higher solubility that the stable polymorph.
•While crystallization solvent molecules may be entrapped within the crystal
lattice in stochiometricratio –these types of crystals are called solvates. If the
solvent molecule entrapped are water (H
2O) molecules then the crystals will
be called hydrates.
•The solubility of these pseudopolymorphsmay be arranged in ascending
order:
Hydrates < Anhydrous < Solvates
•Whenever a drug is crystallized from some solvent, depending on the
conditions of crystallization, the polymorphic shape is changed.
•For example, if cooled very quickly then metastable polymorphs will be
formed and if cooled very slowly then stable crystallswill form. The
metastable form has higher solubility that the stable polymorph.
•While crystallization solvent molecules may be entrapped within the crystal
lattice in stochiometricratio –these types of crystals are called solvates. If the
solvent molecule entrapped are water (H
2O) molecules then the crystals will
be called hydrates.
•The solubility of these pseudopolymorphsmay be arranged in ascending
order:
Hydrates < Anhydrous < Solvates
4.By adding a suitable surfactant
•A sufractantwhen dissolved in water in a concentration over the critical micelle
concentration (CMC) will produce micelles. The drug, both ionized and
unionized forms, will partition between water and micelle. If the concentration
of surfactant is increased over CMC the partition of the drug into the micelle will
increase which will show an apparent increase of solubility of the drug.
•Sodium lauryl sulfate, a surfactant, increases the solubility of benzoic acid.
•In case of oral liquid dosage forms generally non-ionized surfactants are used
(e.gpolysorbate80 i.e. Tween80) to increase the solubility of a drug.
5.By complexation
•Caffeine increase the solubility of benzoic acid by forming a water-soluble
complex. Solubility of para aminobenzoicacid (PABA) can be increased by
complexingwith caffeine.
•A sufractantwhen dissolved in water in a concentration over the critical micelle
concentration (CMC) will produce micelles. The drug, both ionized and
unionized forms, will partition between water and micelle. If the concentration
of surfactant is increased over CMC the partition of the drug into the micelle will
increase which will show an apparent increase of solubility of the drug.
•Sodium lauryl sulfate, a surfactant, increases the solubility of benzoic acid.
•In case of oral liquid dosage forms generally non-ionized surfactants are used
(e.gpolysorbate80 i.e. Tween80) to increase the solubility of a drug.
5.By complexation
•Caffeine increase the solubility of benzoic acid by forming a water-soluble
complex. Solubility of para aminobenzoicacid (PABA) can be increased by
complexingwith caffeine.
Approaches of decreasing the solubility of drugs
Byesterification:
•Thesoubilityofchlopramphenicolcanbedecreasebyformingitsesterwithpalmiticacid.
Bycoatingwithpolymers
•Drugparticlesmaybecoatedwithethylcellulosetoretarditswatersolubility.Celluloseacetate
phthalate(CAP),hydroxypropylmethylcellulosephthalate(HPMCP)etc.polymersreducethe
solubilityofdrugparticlesintheacidmediumofstomach.
Bychangingthepolymorph
•Stablepolymorphshaveloweraqueoussolubilitythanthemetastableforms.Sobychangingthe
conditionofcrystallizationstablepolymorphsmaybeproduced.
Byselectingthehydratedforms
•Anhydrousampicillinhasgreaterwatersolubilitythanampicillin-trihydrate.Inanhydrousforms
thedrugpowderhasaninherentdemandforwater,henceitssolubilityishigherthanthe
hydrateswherethedemandforwaterissatisfied.
Byesterification:
•Thesoubilityofchlopramphenicolcanbedecreasebyformingitsesterwithpalmiticacid.
Bycoatingwithpolymers
•Drugparticlesmaybecoatedwithethylcellulosetoretarditswatersolubility.Celluloseacetate
phthalate(CAP),hydroxypropylmethylcellulosephthalate(HPMCP)etc.polymersreducethe
solubilityofdrugparticlesintheacidmediumofstomach.
Bychangingthepolymorph
•Stablepolymorphshaveloweraqueoussolubilitythanthemetastableforms.Sobychangingthe
conditionofcrystallizationstablepolymorphsmaybeproduced.
Byselectingthehydratedforms
•Anhydrousampicillinhasgreaterwatersolubilitythanampicillin-trihydrate.Inanhydrousforms
thedrugpowderhasaninherentdemandforwater,henceitssolubilityishigherthanthe
hydrateswherethedemandforwaterissatisfied.
Partition coefficient
Thelipophilicityofanorganiccompoundisusuallydescribedintermsofa
partitioncoefficient,logP,whichcanbedefinedastheratioofthe
concentrationoftheunionizedcompound,atequilibrium,betweenorganic
andaqueousphases:
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Thelipophilicityofanorganiccompoundisusuallydescribedintermsofa
partitioncoefficient,logP,whichcanbedefinedastheratioofthe
concentrationoftheunionizedcompound,atequilibrium,betweenorganic
andaqueousphases:
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•Theoctanol–waterpartitioncoefficientiscommonlyusedinformulation
development.
•Pdependsonthedrugconcentrationonlyifthedrugmoleculeshaveatendencyto
associateinsolution.Foranionizabledrug,thefollowingequationisapplicable:
where αequals the degree of ionization.
Partition coefficient
development.
•Pdependsonthedrugconcentrationonlyifthedrugmoleculeshaveatendencyto
associateinsolution.Foranionizabledrug,thefollowingequationisapplicable:
where αequals the degree of ionization.
Partition coefficient
•Themostcommonmethodfordeterminingpartitionanddistribution
coefficientsistheshakeflaskmethod.
•Inthistechnique,thecandidatedrugisshakenbetweenoctanol(previously
shakentogethertopresaturateeachphasewiththeother)andwaterlayers,
fromwhichanaliquotistakenandanalyzedusingUVabsorption,HPLCor
titration.
•Intermsofexperimentalconditions,thevalueofthepartitioncoefficient
obtainedfromthistypeofexperimentisaffectedbysuchfactorsas
temperature,insufficientmutualphasesaturation,pHandbufferionsandtheir
concentration,aswellasthenatureofthesolventsusedandsoluteexamine.
Partition coefficient
coefficientsistheshakeflaskmethod.
•Inthistechnique,thecandidatedrugisshakenbetweenoctanol(previously
shakentogethertopresaturateeachphasewiththeother)andwaterlayers,
fromwhichanaliquotistakenandanalyzedusingUVabsorption,HPLCor
titration.
•Intermsofexperimentalconditions,thevalueofthepartitioncoefficient
obtainedfromthistypeofexperimentisaffectedbysuchfactorsas
temperature,insufficientmutualphasesaturation,pHandbufferionsandtheir
concentration,aswellasthenatureofthesolventsusedandsoluteexamine.
Partition coefficient
•CompoundswithlogPvaluesbetween1and3showgoodabsorption,
•logPgreaterthan6orlessthan3oftenhavepoortransportcharacteristics.
•Highlynon-polarmoleculeshaveapreferencetoresideinthelipophilicregions
ofmembranes,andverypolarcompoundsshowpoorbioavailabilitybecauseof
theirinabilitytopenetratemembranebarriers.
•Thus,thereisaparabolicrelationshipbetweenlogPandtransport,i.e.,
candidatedrugsthatexhibitabalancebetweenthesetwopropertieswill
probablyshowthebestoralbioavailability.
Partition coefficient
•logPgreaterthan6orlessthan3oftenhavepoortransportcharacteristics.
•Highlynon-polarmoleculeshaveapreferencetoresideinthelipophilicregions
ofmembranes,andverypolarcompoundsshowpoorbioavailabilitybecauseof
theirinabilitytopenetratemembranebarriers.
•Thus,thereisaparabolicrelationshipbetweenlogPandtransport,i.e.,
candidatedrugsthatexhibitabalancebetweenthesetwopropertieswill
probablyshowthebestoralbioavailability.
Partition coefficient
Methods to determineP
Shake flaskmethod
Chromatographic method (TLC,HPTLC)
Counter current and filter probemethod
Applications ofP:-
1. Extraction of crude drugs
2. Recovery of antibiotics from fermentation broth
3. Recovery of biotechnology-derived drugs from bacterial cultures
4. Extraction of drugs from biologic fluids for therapeutic drug monitoring
5. Absorption of drugs from dosage forms (ointments, suppositories, transdermal patches)
6. Study of the distribution of flavouring oil between oil and water phases of emulsions
Shake flaskmethod
Chromatographic method (TLC,HPTLC)
Counter current and filter probemethod
Applications ofP:-
1. Extraction of crude drugs
2. Recovery of antibiotics from fermentation broth
3. Recovery of biotechnology-derived drugs from bacterial cultures
4. Extraction of drugs from biologic fluids for therapeutic drug monitoring
5. Absorption of drugs from dosage forms (ointments, suppositories, transdermal patches)
6. Study of the distribution of flavouring oil between oil and water phases of emulsions
Chemical Properties of Drug Substances
a)Oxidation & Reduction
b)Hydrolysis
c)Photolysis
d)Racemisation
e)Polymerization
f)Isomerisation
a)Oxidation & Reduction
b)Hydrolysis
c)Photolysis
d)Racemisation
e)Polymerization
f)Isomerisation
Oxidation:
It is very common pathway for drug degradation in both
liquid and solidformulation.
Oxidation is the gain of oxygen, loss of hydrogen and/or
loss of electrons.
When iron reacts with oxygen it forms a chemical called
rust. The iron is oxidized and the oxygen is reduced.
Oxidation occurs in two ways
Auto oxidation
Free radical oxidation
It is very common pathway for drug degradation in both
liquid and solidformulation.
Oxidation is the gain of oxygen, loss of hydrogen and/or
loss of electrons.
When iron reacts with oxygen it forms a chemical called
rust. The iron is oxidized and the oxygen is reduced.
Oxidation occurs in two ways
Auto oxidation
Free radical oxidation
Functional group having high susceptibility towards
oxidation:-
•Substituted aromatic group (Toluene, Phenols, Anisole).
•Alkenes
•Ethers
•Thioethers
•Amines
oxidation:-
•Substituted aromatic group (Toluene, Phenols, Anisole).
•Alkenes
•Ethers
•Thioethers
•Amines
Factors affecting oxidation process
1)Oxygenconcentration
2)Light
3)Heavy metals particularly those having two or more
valencestate
4)Hydrogen & HydroxylIon
5)Temperature
1)Oxygenconcentration
2)Light
3)Heavy metals particularly those having two or more
valencestate
4)Hydrogen & HydroxylIon
5)Temperature
How to prevent oxidation?
1.Reducing oxygen content
2.Storage in a dark and coolcondition
3.Addition of chelating agent (Eg. EDTA, Citric acid, Tartaricacid)
4.Adjustment ofpH
5.Changing solvent (Eg. Aldehydes, ethers, Ketones, may influence
free radicalreaction)
6.Addition of an antioxidant or reducing agent (e.g. H2, CO, Znetc)
1.Reducing oxygen content
2.Storage in a dark and coolcondition
3.Addition of chelating agent (Eg. EDTA, Citric acid, Tartaricacid)
4.Adjustment ofpH
5.Changing solvent (Eg. Aldehydes, ethers, Ketones, may influence
free radicalreaction)
6.Addition of an antioxidant or reducing agent (e.g. H2, CO, Znetc)
Hydrolysis
oIt is the cleavage of chemical bonds by the addition ofwater.
oThereactionofwaterwithanotherchemicalcompoundtoformtwoormore
products,involvingionizationofthewatermoleculeusuallysplittingtheother
compound.
•Examplesinclude:
othe catalytic conversion of starch toglucose,
osaponification,and
othe formation of acids or bases from dissolvedions.
•When this attack is by a solvent other than water then it is known assolvolysis.
oIt is the cleavage of chemical bonds by the addition ofwater.
oThereactionofwaterwithanotherchemicalcompoundtoformtwoormore
products,involvingionizationofthewatermoleculeusuallysplittingtheother
compound.
•Examplesinclude:
othe catalytic conversion of starch toglucose,
osaponification,and
othe formation of acids or bases from dissolvedions.
•When this attack is by a solvent other than water then it is known assolvolysis.
Conditions that catalysis the breakdown are:
1.Presence of hydroxylion
2.Presence of hydride ion
3.Presence of divalention
4.Heat
5.Light
6.Ionichydrolysis
7.Solution polarity and ionicstrength
8.High drugconcentration
1.Presence of hydroxylion
2.Presence of hydride ion
3.Presence of divalention
4.Heat
5.Light
6.Ionichydrolysis
7.Solution polarity and ionicstrength
8.High drugconcentration
Prevention of hydrolysis:
pHAdjustment
oFormulate the drug solution close to its pH of optimum stability.
oAddition of water miscible solvent informulation.
oOptimum bufferconcentration.
Addition of surfactant
oNonionic, cationic, and anionic surfactant stabilizes the drug against base catalysis.
Salts and Esters Eg. Phosphate esters of clindamycine
oThe solubility of pharmaceuticals undergoing ester hydrolysis can be reduced by
forming less soluble salts.
oBy use of complexingagent.
pHAdjustment
oFormulate the drug solution close to its pH of optimum stability.
oAddition of water miscible solvent informulation.
oOptimum bufferconcentration.
Addition of surfactant
oNonionic, cationic, and anionic surfactant stabilizes the drug against base catalysis.
Salts and Esters Eg. Phosphate esters of clindamycine
oThe solubility of pharmaceuticals undergoing ester hydrolysis can be reduced by
forming less soluble salts.
oBy use of complexingagent.
Photolysis:
Photodissociation,photolysis,orphotodecompositionisa
chemicalreactioninwhichachemicalcompoundisbrokendown
byphotons.
Sinceaphoton'senergyisinverselyproportionaltoitswavelength,
electromagneticwaveswiththeenergyofvisiblelightorhigher,
suchasultraviolet,X-raysandgammaraysareusuallyinvolvedin
suchreactions.
Photodissociation,photolysis,orphotodecompositionisa
chemicalreactioninwhichachemicalcompoundisbrokendown
byphotons.
Sinceaphoton'senergyisinverselyproportionaltoitswavelength,
electromagneticwaveswiththeenergyofvisiblelightorhigher,
suchasultraviolet,X-raysandgammaraysareusuallyinvolvedin
suchreactions.
Photodecomposition pathway
•N-Dealkylation
Di-phenylhydramine, Chloroquine,Methotrexate
•Dehalogination
Chlorpropamide, Furosemide
•Dehydrogenation of Ca++channel blocker
Solution of Nifedipine
•Oxidation
Chlorpromazine & other Phenothiazinesgive N-& S-
oxides in the presence of sunlight
•N-Dealkylation
Di-phenylhydramine, Chloroquine,Methotrexate
•Dehalogination
Chlorpropamide, Furosemide
•Dehydrogenation of Ca++channel blocker
Solution of Nifedipine
•Oxidation
Chlorpromazine & other Phenothiazinesgive N-& S-
oxides in the presence of sunlight
Prevention of photodecomposition
oSuitablepacking.
Yellow-green glass gives the best protection in U.V. region while Amber gives
considerable protection against U.V. radiation but little fromI.R.
oProtection of drug from light
Nifedipineis manufactured under Nalight.
oAvoiding sunbath
oSuitablepacking.
Yellow-green glass gives the best protection in U.V. region while Amber gives
considerable protection against U.V. radiation but little fromI.R.
oProtection of drug from light
Nifedipineis manufactured under Nalight.
oAvoiding sunbath
Racemization
•Itistheprocessinwhichoneenantiomerof
acompound,suchasanL-aminoacid,
convertstotheotherenantiomer.
•Thecompoundthenalternatesbetweeneach
formwhiletheratiobetweenthe(+)and(–)
groupsapproaches1:1,atwhichpointit
becomesopticallyinactive.
•Iftheracemizationresultsinamixturewhere
theenantiomersarepresentinequal
quantities,theresultingsampleisdescribedas
racemericoraracemate.
•Itistheprocessinwhichoneenantiomerof
acompound,suchasanL-aminoacid,
convertstotheotherenantiomer.
•Thecompoundthenalternatesbetweeneach
formwhiletheratiobetweenthe(+)and(–)
groupsapproaches1:1,atwhichpointit
becomesopticallyinactive.
•Iftheracemizationresultsinamixturewhere
theenantiomersarepresentinequal
quantities,theresultingsampleisdescribedas
racemericoraracemate.
Theinter-conversionfromoneisomertoanothercanleadtodifferentpharmacokinetic
properties(ADME)aswellasdifferentpharmacological&toxicologicaleffect.
Example: L-epinephrine is 15 to 20 times more active than D-form, while activity of
racemic mixture is just one half of the L-form.
It depends on
•Temperature,
•Solvent,
•Catalyst &
•Presence or absence of light
properties(ADME)aswellasdifferentpharmacological&toxicologicaleffect.
Example: L-epinephrine is 15 to 20 times more active than D-form, while activity of
racemic mixture is just one half of the L-form.
It depends on
•Temperature,
•Solvent,
•Catalyst &
•Presence or absence of light
•Biologicalsignificance:
•Manypsychotropicdrugsshowdifferingactivityorefficacybetweenisomers,e.g.
Amphetamineisoftendispensedasracemicsaltswhilethemoreactivedextro-
amphetamineisreservedforsevereindications;
•AnotherexampleisMethadone,ofwhichoneisomerhasactivityasanopioidagonistand
theotherasanNMDAantagonist.
•Manypsychotropicdrugsshowdifferingactivityorefficacybetweenisomers,e.g.
Amphetamineisoftendispensedasracemicsaltswhilethemoreactivedextro-
amphetamineisreservedforsevereindications;
•AnotherexampleisMethadone,ofwhichoneisomerhasactivityasanopioidagonistand
theotherasanNMDAantagonist.
Polymerization
•Polymerizationisaprocessofreactingmonomermoleculestogetherinachemicalreactiontoformpolymer
chainsorthree-dimensionalnetworks.
•Itisacontinuousreactionbetweenmolecules.
•Morethanonemonomerreactstoformapolymer.
•Darkeningofglucosesolutionisduetopolymerizationofbreakdownproduct[5-(hydroxylmethyl)
furfural.(acolorlessliquidusedinsyntheticresinmanufacture).
•Eg.Shellaconagingundergoespolymerization&henceprolongsdisintegrationtime&dissolutiontime.
•Polymerizationisaprocessofreactingmonomermoleculestogetherinachemicalreactiontoformpolymer
chainsorthree-dimensionalnetworks.
•Itisacontinuousreactionbetweenmolecules.
•Morethanonemonomerreactstoformapolymer.
•Darkeningofglucosesolutionisduetopolymerizationofbreakdownproduct[5-(hydroxylmethyl)
furfural.(acolorlessliquidusedinsyntheticresinmanufacture).
•Eg.Shellaconagingundergoespolymerization&henceprolongsdisintegrationtime&dissolutiontime.
Isomerizaton
Istheprocessbywhichonemoleculeistransformedintoanothermoleculewhichhas
exactlythesameatoms,buttheatomshaveadifferentarrangement.
e.g.A-B-C→B-A-C(theserelatedmoleculesareknownasisomers).
Examples:-
oTetracycline&itsderivativescanundergoreversibleIsomerizationatpHrange2-6.
oTrans-cisIsomerizationofAmphotericinB.
Istheprocessbywhichonemoleculeistransformedintoanothermoleculewhichhas
exactlythesameatoms,buttheatomshaveadifferentarrangement.
e.g.A-B-C→B-A-C(theserelatedmoleculesareknownasisomers).
Examples:-
oTetracycline&itsderivativescanundergoreversibleIsomerizationatpHrange2-6.
oTrans-cisIsomerizationofAmphotericinB.
Significance:
Isomerismfindsitsimportanceinthefieldofclinicalpharmacologyandpharmacotherapeutics,asisomers
differintheirpharmacokineticandpharmacodyanmicproperties.
•Cetrizinetolevocetrizineisoneofsuchexamples,whereeffectiveandsaferdrughasbeenmadeavailable.
•Levocetrizinehassmallervolumeofdistributionthanitsdextroisomer.
•Esomeprazoleismorebioavailablethanracemicomeprazole;
Isomerismfindsitsimportanceinthefieldofclinicalpharmacologyandpharmacotherapeutics,asisomers
differintheirpharmacokineticandpharmacodyanmicproperties.
•Cetrizinetolevocetrizineisoneofsuchexamples,whereeffectiveandsaferdrughasbeenmadeavailable.
•Levocetrizinehassmallervolumeofdistributionthanitsdextroisomer.
•Esomeprazoleismorebioavailablethanracemicomeprazole;
Biopharmaceutical Classification System
A scientific framework for classifying drug substances based on
their aqueous solubility and intestinal permeability
Established by Gordon Amidonet al.
BCS has gained importance worldwide as a drug
product regulation tool for scale-up and post-
approval changes
The aim of the BCS is to provide a regulatory tool for the
replacement of certain BE studies by conducting accurate in
vitro dissolution tests.
A scientific framework for classifying drug substances based on
their aqueous solubility and intestinal permeability
Established by Gordon Amidonet al.
BCS has gained importance worldwide as a drug
product regulation tool for scale-up and post-
approval changes
The aim of the BCS is to provide a regulatory tool for the
replacement of certain BE studies by conducting accurate in
vitro dissolution tests.
Biopharmaceutical Classification System (BCS)
of drug substances
•Example:metoprolol,paracetamol
•Thosecompoundsarewellabsorbedand
theirabsorptionrateisusuallyhigherthan
excretion.
Class I
HighPermeability
HighSolubility
•Example:glibenclamide,bicalutamide,
•ezetimibe,aceclofenac
•Thebioavailabilityofthoseproductsis
limitedbytheirsolvationrate.Acorrelation
betweentheinvivobioavailabilityand
theinvitrosolvationcanbefound.
Class II
High permeability
Low solubility
•Example:cimetidine
•Theabsorptionislimitedbythepermeation
ratebutthedrugissolvatedveryfast.Ifthe
formulationdoesnotchangethe
permeabilityorgastro-intestinalduration
time,thenclassIcriteriacanbeapplied.
Class III
Low permeability
High solubility
•Example:Bifonazole
•Thosecompoundshaveapoor
bioavailability.Usuallytheyarenotwell
absorbedovertheintestinalmucosaanda
highvariabilityisexpected.
Class IV
Low permeability,
Low solubility
of drug substances
•Example:metoprolol,paracetamol
•Thosecompoundsarewellabsorbedand
theirabsorptionrateisusuallyhigherthan
excretion.
Class I
HighPermeability
HighSolubility
•Example:glibenclamide,bicalutamide,
•ezetimibe,aceclofenac
•Thebioavailabilityofthoseproductsis
limitedbytheirsolvationrate.Acorrelation
betweentheinvivobioavailabilityand
theinvitrosolvationcanbefound.
Class II
High permeability
Low solubility
•Example:cimetidine
•Theabsorptionislimitedbythepermeation
ratebutthedrugissolvatedveryfast.Ifthe
formulationdoesnotchangethe
permeabilityorgastro-intestinalduration
time,thenclassIcriteriacanbeapplied.
Class III
Low permeability
High solubility
•Example:Bifonazole
•Thosecompoundshaveapoor
bioavailability.Usuallytheyarenotwell
absorbedovertheintestinalmucosaanda
highvariabilityisexpected.
Class IV
Low permeability,
Low solubility
Biopharmaceutical Classification System (BCS)
(as defined by the FDA after Amidonet al.)
(as defined by the FDA after Amidonet al.)
High Solubility LowSolubility
H
igh
Permeability
Class1
Abacavir
Acetaminophen
Acyclovir
b
Amiloride
S , I
S,I
Amitryptyline
Antipyrine
Atropine
Buspirone
c
Caffeine
Captopril
Chloroquine
S,I
Chlorpheniramine
Cyclophosphamide
Desipramine
Diazepam
Diltiazem
S,I
Diphenhydramine
Disopyramide
Doxepin
Doxycycline
Enalapril
Ephedrine
Ergonovine
Ethambutol
EthinylEstradiol
Fluoxetine
I
Glucose
Imipramine
I
Ketorolac
Ketoprofen
Labetolol
S
S
Levodopa
Levofloxacin
Lidocaine
I
Lomefloxacin
Meperidine
Metoprolol
Metronidazole
Midazolam
S,I
Minocycline
Misoprostol
Nifedipine
S
Phenobarbital
Phenylalanine
Prednisolone
S
Primaquine
Promazine
Propranolol
I
Quinidine
S,I
Rosiglitazone
Salicylicacid
Theophylline
Valproicacid
Verapamil
I
Zidovudine
Class2
Amiodarone
I
Atorvastatin
S , I
Azithromycin
S ,I
Carbamazepine
S,I
Carvedilol
Chlorpromazine
I
Cisapride
S
Ciprofloxacin
S
Cyclosporine
S, I
Danazol
Dapsone
Diclofenac
Diflunisal
Digoxin
S
Erythromycin
S, I
Flurbiprofen
Glipizide
Glyburide
S , I
Griseofulvin
Ibuprofen
Indinavir
S
Indomethacin
Itraconazole
S, I
Ketoconazole
I
Lansoprazole
I
Lovastatin
S,I
Mebendazole
Naproxen
Nelfinavir
S, I
Ofloxacin
Oxaprozin
Phenazopyridine
Phenytoin
S
Piroxicam
Raloxifene
S
Ritonavir
S,I
Saquinavir
S, I
Sirolimus
S
Spironolactone
I
Tacrolimus
S, I
Talinolol
S
Tamoxifen
I
I
Terfenadine
Warfarin
H
igh
Permeability
Class1
Abacavir
Acetaminophen
Acyclovir
b
Amiloride
S , I
S,I
Amitryptyline
Antipyrine
Atropine
Buspirone
c
Caffeine
Captopril
Chloroquine
S,I
Chlorpheniramine
Cyclophosphamide
Desipramine
Diazepam
Diltiazem
S,I
Diphenhydramine
Disopyramide
Doxepin
Doxycycline
Enalapril
Ephedrine
Ergonovine
Ethambutol
EthinylEstradiol
Fluoxetine
I
Glucose
Imipramine
I
Ketorolac
Ketoprofen
Labetolol
S
S
Levodopa
Levofloxacin
Lidocaine
I
Lomefloxacin
Meperidine
Metoprolol
Metronidazole
Midazolam
S,I
Minocycline
Misoprostol
Nifedipine
S
Phenobarbital
Phenylalanine
Prednisolone
S
Primaquine
Promazine
Propranolol
I
Quinidine
S,I
Rosiglitazone
Salicylicacid
Theophylline
Valproicacid
Verapamil
I
Zidovudine
Class2
Amiodarone
I
Atorvastatin
S , I
Azithromycin
S ,I
Carbamazepine
S,I
Carvedilol
Chlorpromazine
I
Cisapride
S
Ciprofloxacin
S
Cyclosporine
S, I
Danazol
Dapsone
Diclofenac
Diflunisal
Digoxin
S
Erythromycin
S, I
Flurbiprofen
Glipizide
Glyburide
S , I
Griseofulvin
Ibuprofen
Indinavir
S
Indomethacin
Itraconazole
S, I
Ketoconazole
I
Lansoprazole
I
Lovastatin
S,I
Mebendazole
Naproxen
Nelfinavir
S, I
Ofloxacin
Oxaprozin
Phenazopyridine
Phenytoin
S
Piroxicam
Raloxifene
S
Ritonavir
S,I
Saquinavir
S, I
Sirolimus
S
Spironolactone
I
Tacrolimus
S, I
Talinolol
S
Tamoxifen
I
I
Terfenadine
Warfarin
HighSolubility Low Solubility
Low
Permeability
Class 3
Acyclovir
Amiloride
Amoxicillin
Atenolol
Atropine
Bisphosphonates
Bidisomide
Captopril
Cefazolin
Cetirizine
Cimetidine
Ciprofloxacin
Cloxacillin
Dicloxacillin
Erythromycin
Famotidine
Fexofenadine
Folinic acid
Furosemide
Ganciclovir
Hydrochlorothiazide
Lisinopril
Metformin
Methotrexate
Nadolol
PravastatinS
Penicillins
Ranitidine
Tetracycline
Trimethoprim
Valsartan
Zalcitabine
Class 4
AmphotericinB
Chlorthalidone
Chlorothiazide
Colistin
Ciprofloxacin
Furosemide
Hydrochlorothiazi
deMebendazole
Methotrexate
Neomycin
Low
Permeability
Class 3
Acyclovir
Amiloride
Amoxicillin
Atenolol
Atropine
Bisphosphonates
Bidisomide
Captopril
Cefazolin
Cetirizine
Cimetidine
Ciprofloxacin
Cloxacillin
Dicloxacillin
Erythromycin
Famotidine
Fexofenadine
Folinic acid
Furosemide
Ganciclovir
Hydrochlorothiazide
Lisinopril
Metformin
Methotrexate
Nadolol
PravastatinS
Penicillins
Ranitidine
Tetracycline
Trimethoprim
Valsartan
Zalcitabine
Class 4
AmphotericinB
Chlorthalidone
Chlorothiazide
Colistin
Ciprofloxacin
Furosemide
Hydrochlorothiazi
deMebendazole
Methotrexate
Neomycin
•Drugs dissolvedrapidly
•Drugs absorbedrapidly
•Rapid therapeuticaction
•Excellentproperty
•Ideal for oralroute
•e.g. Metoprolol, Diltiazem, Verapamil,
Propranolol,
Class–IHighSolubility High Permeability
•Drugs absorbedrapidly
•Rapid therapeuticaction
•Excellentproperty
•Ideal for oralroute
•e.g. Metoprolol, Diltiazem, Verapamil,
Propranolol,
Class–IHighSolubility High Permeability
•Drugs dissolveslowly
•Drugs absorbedrapidly
•Controlled releaseddrugs
•Oral / IV route foradministration
•E.g. Glibenclamide, Ezetimibe, Phenytoin,Nifedipine
Class –II LowSolubility High Permeability
•Drugs absorbedrapidly
•Controlled releaseddrugs
•Oral / IV route foradministration
•E.g. Glibenclamide, Ezetimibe, Phenytoin,Nifedipine
Class –II LowSolubility High Permeability
•Dissolvedrapidly
•Absorbance islimited
•Incompletebioavailability
•Oral / IV route foradministration
•Ex. Cimetidine, Acyclovir,Captopril
Class–IIIHighSolubility Low Permeability
•Absorbance islimited
•Incompletebioavailability
•Oral / IV route foradministration
•Ex. Cimetidine, Acyclovir,Captopril
Class–IIIHighSolubility Low Permeability
Class –IV-LowSolubility Low Permeability
•Low dissolutionrate
•Low permeabilityproperty
•Slow or low therapeuticaction
•IV or other routes arerequired
•Ex.Hydrochlorothiazide
•Low dissolutionrate
•Low permeabilityproperty
•Slow or low therapeuticaction
•IV or other routes arerequired
•Ex.Hydrochlorothiazide
BCS can be used as a key component to guide drug
delivery system design for any route ofadministration
delivery system design for any route ofadministration
Significance ofBCS
•RegulatorytoolforreplacementofcertainBEstudies.
•Itcansavebothtimeandmoney—iftheimmediate-release,orallyadministereddrugmeets
specificcriteria,theFDAwillgrantawaiverforexpensiveandtime-consumingbio-
equivalencestudies.
•Valuabletoolforformulationscientistforselectionofdesignofformulateddrugsubstance.
•Whenintegratedwithotherinformationprovideatremendoustoolforefficientdrug
development.
•ReducescostandtimeofapprovingScale-upandpostapprovalchallenges.
•Applicableinbothpre-clinicalandclinicaldrugdevelopmentprocess.
•Worksasaguidingtoolindevelopmentofvariousoraldrugdeliverysystems.
•RegulatorytoolforreplacementofcertainBEstudies.
•Itcansavebothtimeandmoney—iftheimmediate-release,orallyadministereddrugmeets
specificcriteria,theFDAwillgrantawaiverforexpensiveandtime-consumingbio-
equivalencestudies.
•Valuabletoolforformulationscientistforselectionofdesignofformulateddrugsubstance.
•Whenintegratedwithotherinformationprovideatremendoustoolforefficientdrug
development.
•ReducescostandtimeofapprovingScale-upandpostapprovalchallenges.
•Applicableinbothpre-clinicalandclinicaldrugdevelopmentprocess.
•Worksasaguidingtoolindevelopmentofvariousoraldrugdeliverysystems.
Thank You
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