晶型与表面活性剂经典文献之九

InfluenceofImpuritiesontheSolution-MediatedPhaseTransformationofanActivePharmaceuticalIngredientTakashiMukuta,†,‡AlfredY.Lee,‡TakeshiKawakami,†andAllanS.Myerson*,‡ProcessChemistryLabs,AstellasPharmaInc.,160-2,Akahama,Takahagi-shi,Ibaraki,318-0001Japan,andDepartmentofChemicalandEnvironmentalEngineering,IllinoisInstituteofTechnology,Chicago,Illinois60616ReceivedOctober14,2004ABSTRACT:Thesolution-mediatedphasetransformationofthemetastableAformofanactivepharmaceuticalingredient(1)tothestableBformisinvestigatedin2-propanol.Thetransformationbehavior(orrate)isquantifiedusingpowderX-raydiffraction.Thestudiesshowthattherateoftransformationissensitivetothetailor-madeimpuritiesandthatthepresenceofcertaininhibitorsreducestherateoftransformation.Concurrentlymolecularmodelingstudiesareundertakentoinvestigatetheincorporationofthesestructurallyrelatedimpuritiesintothecrystallattice,anditisobservedthatthebuild-inapproachusedinmorphologypredictionsforadditive-hostsystemscanbeappliedtoevaluatetheextentofimpurityincorporation.Thebuild-inapproachemploystheattachmentenergymethodinwhichthehostmoleculesaresubstitutedbyimpuritymolecules,andtherelativeincorporationenergiesarecalculatedforvariouscrystalfaces.Theorderoftherelativeincorporationenergiesofthestructurallysimilarimpuritiesisidenticaltotheorderofthepercentagesoftheamountofimpuritiesincorporatedintothecrystallatticeasdeterminedbyhighperformanceliquidchromatography(HPLC).IntroductionPolymorphismistheabilityofachemicalentitytoexistinmorethanonedistinctcrystallineformasaresultofdifferencesinthepackingarrangementand/ormolecularconformation.1Thisphenomenonisoftenobservedinorganicmolecularcrystals2andisofpara-mountimportanceinthepharmaceuticalindustrywheredifferentsolidformsofthesamechemicalcompoundcanexhibitdifferentphysicalandchemicalpropertiesaswellasdifferentsolubilityanddissolution,whichinturnaffectsthebioavailabilityandstabilityofthedrugsubstance.PharmaceuticalmanufacturersarerequiredbytheFoodandDrugAdministrationtoconsistentlyproducethedesiredpolymorphofadrug.3-5Discoveryandcharacterizationofpolymorphsarecrucialintheearlystagesofthedevelopmentofthedrugproduct,asunanticipatedappearanceordisappearance6ofapoly-morphcanimpactthetimetomarketforadrug,orinthecaseofritonavir7,8itcanresultinawithdrawalofacommercialpharmaceuticalproduct.Asaresult,polymorphscreening,inwhichacompoundiscrystal-lizedinvariousprocessconditionsunderavarietyofcrystallizationmethods(e.g.,sublimation,crystalliza-tionfromthemelt,vapordiffusion,thermaltreatment,andcrystallizationfromasinglesolventorcombinationsofsolvents),hasbeenparticularlyimportant.9Morerecently,high-throughputcrystallizationscreenshavebeendevelopedusingacombinatorialapproachtocapturecrystalformdiversity.10-14Thisapproachen-ablesamorecomprehensiveexplorationofsolidformsandhasbeenappliedtovarioushighlypolymorphicpharmaceuticalcompoundssuchasacetaminophen,15MK-996,16ritonavir,17andsertralineHCl.16,18Itisimportanttoidentifythemoststablepolymorphaswellastofullyunderstandandcontroltheconditionstoobtainthedesiredsolidform.Numerousmethodsandstrategieshavebeenusedtocontrolpolymorphism,includingcapillarycrystallization,19-21laser-inducednucleation,22,23solvent-dropgrinding,24spraydrying,25supercriticalfluidcrystallization,26self-assembledmono-layers,27,28surfacesofmetastablecrystalforms,29nano-porouspolymermonolithsandglassmatrixes,30polymerheteronuclei,31andorganicsingle-crystalsurfacesthatdirecttheselectivityofpolymorphsthroughepitaxialmatching.32,33Inaddition,designeradditiveshavebeenshowntoinhibittheformationofonepolymorph,inturnpromotingthecrystallizationofanotherpolymorph.34,35Theseadditiveshavealsobeenexploitedtoengineercrystalmorphology36,37andkineticallyresolvechiralmolecules.38,39Similarly,impuritiesandsynthesisbyprod-uctscaninfluencethenucleationandgrowthofpoly-morphsascanbeseeninthecaseofterephthalicacidwhereanimpurityinducedtwinningandinhibitedasolid-statetransformation,leadingtothestabilizationofthemetastableform.40Recentworkshaveutilizedadditivesorimpuritiesinmanipulatingthepolymorphicoutcome.41-45Structurallyrelatedadditivesorimpuritiesmaybeincorporatedintothehostcrystallatticeascrystalfacesaresometimesunabletodiscriminatebetweenthehostandtheadditive/impuritymolecule.46Thiscanleadtosevereconsequencesasincorporatedimpuritiescanalterthephysicalandchemicalpropertiesofthecrystalsandquitepossiblyhavetoxicologicaleffects.Thus,controlandminimizationoftheimpuritycontentinpharmaceuticalproductsareofutmostimportance.Molecularmodelingtechniquesemployingtheattach-mentenergymethodhaveshownthatimpurity-modifiedcrystalhabitcanbesuccessfullypredicted47-52andthatrelativeincorporationenergiescanbeusedasanindicatorforthelikelihoodofimpurityincorporationoncrystalsurfaces.51,52Inmostcases,thecrystallizationofpolymorphsoftenobeysOstwald’sLawofStages53wherethekinetically*Towhomcorrespondenceshouldbeaddressed.Phone:[phone].Fax:[phone].E-mail:[e-mail].†AstellasPharmaInc.‡IllinoisInstituteofTechnology.CRYSTALGROWTH&DESIGN2005VOL.5,NO.41429-1436