Polymorphism in Pharmaceuticals

Polymorphism is very important in those areas of chemical research where full
characterization of a material has a pivotal role in determining its ultimate use, e.g., in
pharmaceutical, pigment, agrochemical, explosive, and fine chemical industries.
Polymorphism has been recognized as an important element of drug development
 Polymorphic forms of a drug substance can have different chemical and physical
properties, including melting point, chemical reactivity, apparent solubility, apparent
solubility, dissolution rate, optical, electrical, and mechanical properties, vapor pressure,
stability, and density.
 These properties can have a direct effect on the ability to process and/or manufacture the
drug substance and the drug product, as well as on drug product stability, dissolution, and
bioavailability.
 Polymorphism is very common among pharmaceutical substances and thermodynamic
stability of a polymorph can impact pharmaceutical properties such as bioavailability,
processability and manufacturability.
 Polymorphic forms possess higher potential energy with respect to the
thermodynamically stable or lowest entry forms.
 Different polymorphic phase’s exhibit unique physicochemical properties include
solubility, dissolution rates which can influence bioavailability.
 The ability to isolate, differentiate, and characterize individual polymorphs is a major
challenge to the pharmaceutical industry.
PHARMACEUTICAL APPLICATIONS OF POLYMORPHISM
- Improved physical stability
- Ease of handling
- Improved bioavailability
- Better chemical stability
- Sustained release

1. Department of
Pharmaceutics
Presented by :
Manu Singhai
(M.Pharm-1
st
semester)
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2. POLYMORPHISM
AND ITS
APPLICATIONS
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3. Path for Presentation
➢Introduction
➢Need to studypolymorphism(rational for selectingpolymorph)
➢Structural aspects ofpolymorphs
➢Properties ofpolymorphs
➢Types ofpolymorphism
➢Methods of preparation ofpolymorph
➢Characterization ofpolymorphism
➢Pharmaceutical applicationsofpolymorphism
➢Regulatoryconsiderations
➢Polymorphism of severaldrugs
➢Conclusion
➢References
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4. Introduction
•When a substance exists in more than one crystalline form, the different form
are designated as polymorphs and the phenomenon aspolymorphism.
e.g.:-
•Carbon: diamond in a cubic ( tetrahedral lattice arrangement)
•Graphite in sheet of a hexagonallattice.
•Differencesintheinternalstructuresofpolymorphsresultintheirdistinct
physicalandchemicalproperties.
•Morethan50%ofAPIsareestimatedtohavemorethanonepolymorphicform.
•Thebestknownpolymorphsshowingasignificantlydifferentbioavailabilityare
ChloramphenicolpalmitateandMefenamicacid.
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Need to study polymorphism
•Dependingupontheirrelativestability,oneoftheseveralpolymorphicformwill
bephysicallymorestablethanothers.
•Stablepolymorphrepresentsthelowestenergystate,hashighestmelting
pointandleastaqueoussolubility.
•Metastableformrepresentthehigherenergystate,havelowermeltingpoint
andhighaqueoussolubility.
•Metastableformconvertedtothestableformduetotheirhigherenergystate.
•Metastableformshowsbetterbioavailabilityandthereforepreferredin
formulations.
•Only10%ofthepharmaceuticalsarepresentintheirmetastableform.
•Theexampleischloramphenicolpalmitate.
Otherlikenovobiocin,griseofulvine,Carbamazepine,aspirinandampicilline.

7. Structural aspects ofpolymorph
•Configurationalpolymorph
occurswithmoleculesthathave
arelativelyrigidconformation.
Suchpolymorphshavedifferent
3Dstructures.
•e.g.:-Carbamazepine
Configurational
polymorph
•Conformationalpolymorph
occurswithdrugmoleculesthat
haveflexiblestructuresandthe
moleculecantakevarious
conformations.
•e.g.:-Ritonavir
Conformational
polymorph
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8. Properties ofpolymorphs
Packingproperties
Thermodynamic
properties
Spectroscopic
properties
Kinetic
properties
Surface
properties
Mechanical
properties
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9. Types ofpolymorphism
•Whenthechangeofone
polymorphicformtootheratthe
transitiontemperatureisreversible,
the phenomenon called
Enantiotropyandthepolymorphic
formsarecalledenantiotropes.
•e.g.:-Sulphur,Carbamazepine
Enantiotropy
•Monotropyoccurswhenoneform
isstableandtheothermetastable.
Themetastablechangestothe
stableformatalltemperatureand
thechangeisnotreversible.
•e.g.:-Chloramphenicolpalmitate,
Metolazone
Monotropy
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10. Methods ofpreparation
Solventevaporation
method
Slowcooling
approach
Solventdiffusion
technique
Vapourdiffusion
method
Vacuumsublimation
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11. Characterization ofpolymorphism
Optical
crystallography
Scanning
electron
microscopy
Hotstage
microscopy
Singlecrystal
X-ray
Diffraction
PowderX-ray
Diffraction
Differential
thermalanalysis
(DTA)
Differential
Scanning
Calorimetry
(DSC)
Solidstate
NMR
spectroscopy
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12. Pharmaceuticalapplications
Preparation ofphysically
stable dosageform
Influence onsolubility,
dissolution and
bioavailability
Influenceondrug
product
manufacturability
Influenceon
stability
Effect ontableting
Miscellaneous
application
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13. Regulatoryconsiderations
•Duetodifferenceinthephysicochemicalpropertiesof
polymorphs,inANDAs,carefulattentionispaidtotheeffect
ofpolymorphisminthecontextofgenericdrugproduct
equivalency.
•Threedecisiontreesforsolidoraldosageformsorliquid
suspensionsareprovidedforevaluatingwhenandhow
polymorphsofdrugsubstancesshouldbemonitoredand
controlledinANDAsubmission.
•Forapprovalofanewdrug,US-FDAstatesthatappropriate
analyticalproceduresneedtobeusedtodetectpolymorphs,
hydrates,amorphousformsofthedrugsubstance.
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14. Commercial product based on
polymorphism
(ref: Hungarian Intellectual PropertyOffice)
Brand name API Patentee
Allegra Fexofenadin Sanofi
Cozaar Losartan Merck
Clarinex Desloratadine Schering-Plough
Epivir Lamivudine GSK
Geodon Ziprasidone Pfizer
Omnicef Cefdinir Abbott
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15. Polymorphism inseveral drugs
Drug Polymorphism
aspects
Bioavailabilityissues
Chloramphenicol
palmitate
Exist in 3 polymorphic
forms (A,B,C).
Stableform-A,
metastable form-B,
unstable form-C
Form B dissolves faster than
form A, and has a much higher
solubility. Low serum levelsfor
the stable polymorph A were
observed.
Carbamazepine 4 anhydrouspolymorphsRecent study reveals that
the were characterized initial dissolution rateof
(I,II,III,IV) carbamazepine was in the
order of form III>II>dihydrate,
while the order of AUC values
was form I>III>dihydrate. This
difference is due to rapid
transformation of form III to
dihydrate in GIfluids.
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16. Conclusion
•Differencesinthesolubilityandmeltingpointmustalsobeassessedandthena
decisioncanbemadetodeterminewhichformtoprogressthroughtothenext
stage.
•Metastableformmayleadtoapreferentialchoiceofapolymorphotherthan
stableform.
•Thelowestenergypolymorphisalmostalwaysthemostchemicallystableform,
andwillnotconverttoanotherpolymorphduringstorageasdrugproduct.
•Metastablecrystallinepolymorphsmaybelesschemicallystablecrystalline
formbutisoftenpossibletoimprovechemicalstabilityofsuchformsthrough
judiciouschoiceofexcipientsandformulationprocessasmetastableformhas
relativelyhighersolubility.
•Aspolymorphismcanhavesuchseriousconsequencesforthebioavailabilityof
drugswithlowaqueoussolubility.
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17. References
1.KadamK.P.andChavanR.P.,“EvaluationofVariousPolymorphsbyDifferent
TechniquesandTheirCharacterization-AReview”,TheInternationalJournalOf
EngineeringAndScience(IJES),Volume5,Issue6,Pages-29-34,2016.
2.EthirajT.andGaneshanV.,“Polymorphisminpharmaceuticalingredients-A
review”,WorldJournalofPharmacyandPharmaceuticalsciences,Volume3,
Issue3,621-633,2014.
3.SaurabhG. and KaushalC. “Pharmaceutical Solid Polymorphism in
Abbreviated New Drug Application (ANDA) –A Regulatory Perspective”, Journal
of Chemical and Pharmaceutical Research, 2011, 3(3):6-17.
4.BrittainH.G..,PolymorphisminPharmaceuticalSolids,MarcelDekker,Inc,Special
Indianedition,pp.7-19,2008.
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18. 5.BauerJ.F.,“Polymorphism—ACriticalConsiderationinPharmaceuticalDevelopment,
Manufacturing,andStability,”J.Valid.Technol.,pp.15–23,2008.
6KarpinskiP..H.,“PolymorphismofActivePharmaceuticalIngredients,”Chem.Eng.Technol.,
vol.29,no.2,pp.233–237,2006.
7SinghalD.andCuratoloW.,“Drugpolymorphismanddosageformdesign:apractical
perspective,”Adv.DrugDeliv.Rev.,vol.56,no.3,pp.335–347,2004.
8AguiarJ.andZelmer,J.E.“DissolutionbehaviorofpolymorphsofChloramphenicol
palmitateandMefenamicacid,”J.Pharm.Sci.,vol.58,no.8,pp.983–987,1969.
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