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1、药物的多晶型研究药物的多晶型研究2024/5/9 周四1.提纲提纲F什么是晶体，多晶型？F多晶型研究对药物开发的重要性F如何筛选和选择药物的新晶型F多晶型的主要分析手段F晶型筛选实验的经验分享-溶剂选择2024/5/9 周四2.Crystal A solid material whose constituent atoms,molecules,or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions.Pharmaceutical crystals Most dru
2、gs are developed as crystallineStabilityProcessabilityIP protection 什么是晶体？什么是晶体？2024/5/9 周四3.什么是多晶型？什么是多晶型？Polymorphism is the ability of a solid material to exist in more than one form or crystal structure.Polymorphs Sold phaseSame chemical compositionDifferent molecular arrangements In practice,we
3、 are interested in all the crystalline and amorphous phases for a chemical/pharmaceutical2024/5/9 周四4.2024/5/9 周四5.多晶型研究对药物开发的重要性2024/5/9 周四6.药物多晶型研究的重要性药物多晶型研究的重要性2024/5/9 周四7.2024/5/9 周四8.2024/5/9 周四9.如何筛选和选择药物的新晶型10.2024/5/9 周四11.2024/5/9 周四12.晶型的化学和物理分析手段晶型的化学和物理分析手段2024/5/9 周四13.2024/5/9 周四14.2
4、024/5/9 周四15.Experience sharing on polymorph screening solvent selection2024/5/9 周四16.The purpose of polymorph screeningFor Innovator companies -select the optimal solid-state of API for development -study relevant polymorphs for IP protectionFor CRO companies based on the customers needs -to identi
5、fy as many new polymorphs(include solvate/hydrate)and amorphous form as possible -or to find the most stable form 2024/5/9 周四17.The method of polymorph screeningcrystallizationcrystallization from solution(slurry,anti-solvent precipitation,Solvent-thermal heating/coolingSlow/fast precipitation from
6、saturated solutions)recrystallization from a neat compound(thermal heating/cooling,grinding,and high pressure)2024/5/9 周四18.polymorph screening crystallization from solutiondegree of supersaturation and Temperature are considered as the driving force of crystallisation diverse solvents result in the
7、 discovery of more polymorphs2024/5/9 周四19.crystallization from solution Solvent selectionSlurryAnti-solvent precipitation Solvent-thermal heating/cooling experiments Slow/fast precipitation from saturated solutions method SolventVisual solubility(mg/mL)MeOHEtOHIPA1-ButanolACNMEKMIBKEtOAciPrOAcMTBE2
8、MeTHFDMFNMPDMSOCH2Cl2Toluene1,4-DioxaneHeptaneTHFAcetoneWater2024/5/9 周四20.crystallization from solution rational experimental designLimited resource How to find as many new polymorphs and amorphous form as possible API properties different solubility in the solvent poor solubility or good solubili
9、ty Solvent properties Polarity-different sort of solvents(alcohols,ethers,ester etc.)Boiling point Freezing point Toxicity miscibility？2024/5/9 周四21.Slurry solvent selectionMake sure the sample is suspension solvent/mixed solvents solubility is poor2024/5/9 周四22.Anti-solvent precipitation solvent se
10、lection Prepare solvent good solubilityAnti-solvent selectionPoor solubilitypolaritymiscibility miscibility Water DMF Heptane ACN 1,4-Dioxane MTBE DMSO2024/5/9 周四23.Solvent-thermal heating/cooling experimentschange temperature supersaturation good solubility Solvent selection solubility varies with
11、the temperature freezing point of the solvent 2024/5/9 周四24.Slow/fast precipitation from saturated solutions methodEvaporate the solvent supersaturationSlow/fast rate of crystallization Solvent selection low boiling point solventboiling pointDMF 152.8 CDMSO189 CNMP202 C2024/5/9 周四25.SummarySolvent selectionkey point of the method select appropriate solvent different solubility in the solventsolvent propertiesmiscibilitybetween solvents Polarityboiling pointfreezing pointToxicity2024/5/9 周四26.
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