诺华制药资料：药物成盐的原理、策略和知识产权保护

SaltScreeningandSelection:NewChallengesandConsiderationsintheModernPharmaceuticalR&DParadigmWei-Qin(Tony)Tong,Ph.D.NovartisPharmaceuticalsCorporationIntegratedDrugProductDevelopmentProcess(3day-course),UniversityofUtahJuly17-19,2006PresentationOutline•Introduction•TheoreticalConsiderations•pH-solubilityprofiles,pKaandsaltformation•Predictionofsaltsolubility•Solubilityproductandinsitusaltscreening•Solubility/dissolutionrateofsalts•DissolutionofsaltsintheGIfluids•Saltsandothersolubilizationtechniques•Effectofsaltsonchemicalstability•PracticalConsiderations•Dosageformconsiderations•Toxicityconsiderations•Saltandformselectionstrategies•Impactofsaltonintellectualproperty(IP)andlifecyclemanagement(LCM)•Automationandhighthroughout•CaseStudies•SummaryIntroductionModernR&DParadigm•Combinatorialchemistryandhigh-throughputscreeningresultinmanymorehitsandmoredevelopmentcandidates.•PropertiesofNCEsbecomelessfavorablefordevelopment:-40%compoundsbelongtoclassIIandIV(FDAbiopharmaceuticalclassificationsystem)•GapbetweenResearchandDevelopmentisdisappearing:-Profilingofpharmaceuticalpropertiesofdrugcandidatesbecomesaroutinepractice•Successratehasnotimproved.•Competitionisintensifying:-FastertomarketandprotectionofintellectualpropertiesarebecominganecessityNewChallengesforDevelopmentScientists:howdothesechallengesaffectsaltscreeningandselection?•Considerationofpharmaceuticalpropertiesindrugdesign-developabilityassessment:Needtoconsidertheimpactofsaltsondevelopability•Shorterdevelopmenttimeline:Needtoselecttherightsaltthefirsttime•Increasedneedforspecialdrugdeliverysystems:Needtoevaluatetheimpactofsaltsonthesolubilityandstabilityinthesesystems•Impactonpharmaceuticalpropertiesrequiredforasuccessfuldosageform:-bioavailability-stability(bothchemicalandphysical)-manufacturability•Impactonphysicochemicalpropertiesofthedrugsubstance:-Solubility-Dissolutionrate-hygroscopicity-Chemicalstability-Crystalform-MechanicalpropertiesImpactofSalts“Changingthesalt,changingthedrug”TheoreticalConsiderationsSolubilityofsaltofsaltpHpHmaxmaxSolubilitySolubilitypHpHMonobasicCompoundSolubilityoffreebaseSolidPhase:SaltSolidPhase:SaltSolidPhase:BaseSolidPhase:BaseRef:Serajuddin&Pudipeddi,inHandbookofPharmaceuticalSaltsRef:Serajuddin&Pudipeddi,inHandbookofPharmaceuticalSalts,IUPAC,2002,IUPAC,2002pH-SolubilityProfileTheRoleofpKa•Forstablesaltformationtobecomplete,ionizationmustbeeffectivelycompletesuchthatasingleionizationstateisform.•2pHunitsdifferencebetweenthepKasofthebaseandtheacidtypicallynecessary•Withcounterionsthatcorrespondtovolatileacidsorbases,thepKarequirementmaybedifferent,e.g.-pKa1.8–2.2(triazoleantifungalagentsofthea-styrylcarbinol)-CrystallineHClsalt(pKa-6.1):12%lossofchlorideafter6hrsat60ºC-Crystallinemesylatesalt(pKa-1.2):stableafter3weeksstorageat60ºCPredictionofSaltSolubility•Contributingfactorstosaltsolubility:-solvationenergy/heatofsolvation-crystallinity/heatoffusion•Solubilityofsaltsarestilllargelyunpredictableexceptforsomegeneraltrends•MostoftheempiricalmethodsrequiresmeltingpointthatisdifficulttoobtainwithoutmakingtheactualsaltSolubilityProductandInSituSaltScreening•Iffreebaseisaddedtoacertainconcentrationofacid,withtheacidconcentrationhighenoughtoensurethepHofthesolutionislowerthanpHmax,thebasewillformthecorrespondingsaltwiththeacid.•Thesolubilityproduct(Ksp)andthesolubilityofthesaltformedinsitucanbecalculated.•Multiplecounter-ions,addedinpredeterminedamountssoasnottoexceedtheKspofanysalt,canprovidesignificantlyhighersolubilitythansinglecounter-ion.Ref:TongW.Q.andWhitesellG.,Pharm.Dev.Tech.,3,215-223,(1998).Marra-FeilM.andAndersonB.D.,PharSci.,1,S-400,(1998).SolubilityandDissolutionRateofSalts•ItisonlyatapHvaluelessthanpHmaxthatthesolubilityofthesaltcanbedetermined•Saturatedsolutioninthepresenceofbufferspecies:saltconversionmayoccur•EffectofsolubilityandmicroenvironmentpHondissolutionrate:self-bufferingeffect•IntrinsicdissolutionrateofbupivacaineanditsHClsaltasafunctionofthepHofthedissolutionmediumRef:Pudipeddiet.al,inHandbookofPharmaceuticalSalts,IUPARef:Pudipeddiet.al,inHandbookofPharmaceuticalSalts,IUPAC,2002,C,2002,Originalref:ShahJ.C.andManiarJ.,J.Contr.Rel.,23,261Originalref:ShahJ.C.andManiarJ.,J.Contr.Rel.,23,261--270,(1993).270,(1993).SolubilityandDissolutionRateofSaltssaltofanbasicdrugStomach(pH1-3)DissolvedDrugRemaininsolutionSmallIntestine(pH5-7)PrecipitateasHClsalt(crystallineoramorphous)DissolutionProcessoftheSaltofBasicDrugsDissolvedDrugPrecipitateasfreebase(crystallineoramorphous)DissolveorconverttofreebaseanddissolveDissolveorconverttofreebaseanddissolveEntericCoatingBasicsaltofanacidicdrugStomach(pH1-3)Microenvironmentofdiffusionlayer(pH5-6)DissolvedDrugEmptytosmallintestineforabsorptionSmallIntestine(pH5-7)Precipitateasfreeacid(crystallineoramorphous)EmptytosmallintestineandredissolveathigherpHDissolutionProcessoftheSaltofAcidicDrugsSaltsandOtherSolubilizationTechniques•Effectofsaltsoncomplexation•Effectofsaltsonsolubizationbysurfactants•Solubilityofsaltsinnon-aqueoussolvents•Effectofsaltsonamorphous/soliddisp