药物晶型研究课件

提纲什么是晶体，多晶型？多晶型研究对药物开发的重要性如何筛选和选择药物的新晶型多晶型的主要分析手段晶型筛选实验的经验分享----溶剂选择2023/10/3提纲什么是晶体，多晶型？2023/8/21Crystal

Asolidmaterialwhoseconstituentatoms,molecules,orionsarearrangedinanorderlyrepeatingpatternextendinginallthreespatialdimensions.PharmaceuticalcrystalsMostdrugsaredevelopedascrystallineStabilityProcessabilityIPprotection什么是晶体？2023/10/3Crystal什么是晶体？2023/8/22什么是多晶型？Polymorphismistheabilityofasolidmaterialtoexistinmorethanoneformorcrystalstructure.PolymorphsSoldphaseSamechemicalcompositionDifferentmoleculararrangementsInpractice,weareinterestedinallthecrystallineandamorphousphasesforachemical/pharmaceutical2023/10/3什么是多晶型？Polymorphismistheab32023/10/32023/8/24多晶型研究对药物开发的重要性2023/10/32023/8/25药物多晶型研究的重要性2023/10/3药物多晶型研究的重要性2023/8/262023/10/32023/8/272023/10/32023/8/28如何筛选和选择药物的新晶型如何筛选和选择药物的新晶型92023/10/32023/8/2102023/10/32023/8/211晶型的化学和物理分析手段2023/10/3晶型的化学和物理分析手段2023/8/2122023/10/32023/8/2132023/10/32023/8/214Experiencesharingonpolymorphscreening——solventselection2023/10/3Experiencesharingonpolymorp15ThepurposeofpolymorphscreeningForInnovatorcompanies-selecttheoptimalsolid-stateofAPIfordevelopment-studyrelevantpolymorphsforIPprotectionForCROcompaniesbasedonthecustomersneeds-toidentifyasmanynewpolymorphs(includesolvate/hydrate)andamorphousformaspossible-ortofindthemoststableform

2023/10/3Thepurposeofpolymorphscree16Themethodofpolymorphscreeningcrystallizationcrystallizationfromsolution(slurry,anti-solventprecipitation,Solvent-thermalheating/coolingSlow/fastprecipitationfromsaturatedsolutions)recrystallizationfromaneatcompound(thermalheating/cooling,grinding,andhighpressure)2023/10/3Themethodofpolymorphscreen17polymorphscreening——

crystallizationfromsolutiondegreeofsupersaturationandTemperatureareconsideredasthedrivingforceofcrystallisationdiversesolventsresultinthediscoveryofmorepolymorphs2023/10/3polymorphscreening——

18crystallizationfromsolution——SolventselectionSlurryAnti-solventprecipitationSolvent-thermalheating/coolingexperimentsSlow/fastprecipitationfromsaturatedsolutionsmethodSolventVisualsolubility(mg/mL)MeOH

EtOH

IPA

1-Butanol

ACN

MEK

MIBK

EtOAc

iPrOAc

MTBE

2-MeTHF

DMF

NMP

DMSO

CH2Cl2

Toluene

1,4-Dioxane

Heptane

THF

Acetone

Water

2023/10/3crystallizationfromsolution19crystallizationfromsolution——

rationalexperimentaldesignLimitedresource

Howtofindasmanynewpolymorphsand

amorphousformaspossibleAPIpropertiesdifferentsolubilityinthesolvent

poorsolubilityorgoodsolubilitySolventproperties

Polarity-differentsortofsolvents(alcohols,ethers,esteretc.)BoilingpointFreezingpointToxicitymiscibility？2023/10/3crystallizationfromsolution20Slurry——solventselectionMakesurethesampleissuspension

solvent/mixedsolventssolubilityispoor2023/10/3Slurry——solv21Anti-solventprecipitation

—solventselectionPreparesolventgoodsolubilityAnti-solventselectionPoorsolubilitypolaritymiscibility

miscibilityWaterDMFHeptaneACN1,4-DioxaneMTBEDMSO2023/10/3Anti-solventprecipitation

22Solvent-thermal

heating/coolingexperimentschangetemperaturesupersaturation

goodsolubilitySolventselectionsolubilityvarieswiththetemperature

freezingpointofthesolvent2023/10/3Solvent-thermal

heating/cool23Slow/fastprecipitationfromsaturatedsolutionsmethodEvaporatethesolventsupersaturationSlow/fastrateofcrystallization

SolventselectionlowboilingpointsolventboilingpointDMF152.8ºCDMSO189ºCNMP202ºC2023/10/3Slow/fastprecipitationfroms24Summary—Solventsel