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1、2021/12/5,药物的多晶型研究,2021/12/5,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,2021/12/5,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 drugs are d
2、eveloped as crystallineStabilityProcessabilityIP protection,什么是晶体？,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 are interested in all the cry
3、stalline and amorphous phases for a chemical/pharmaceutical,2021/12/5,2021/12/5,2021/12/5,多晶型研究对药物开发的重要性,2021/12/5,药物多晶型研究的重要性,2021/12/5,2021/12/5,如何筛选和选择药物的新晶型,2021/12/5,2021/12/5,2021/12/5,晶型的化学和物理分析手段,2021/12/5,2021/12/5,2021/12/5,Experience sharing on polymorph screening solvent selection,2021/1
4、2/5,The purpose of polymorph screening,For 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 identify as many new polymorphs (include solvate / hydrate) and amorphous form as pos
5、sible - or to find the most stable form,The method of polymorph screening,2021/12/5,crystallization,crystallization from solution (slurry, anti-solvent precipitation , Solvent-thermal heating/coolingSlow/fast precipitation from saturated solutions),recrystallization from a neat compound (thermal hea
6、ting/cooling, grinding , and high pressure ),polymorph screening crystallization from solution,2021/12/5,degree of supersaturation and Temperature are considered as the driving force of crystallisation diverse solvents result in the discovery of more polymorphs,crystallization from solution Solvent
7、selection,2021/12/5,SlurryAnti-solvent precipitation Solvent-thermal heating/cooling experiments Slow/fast precipitation from saturated solutions method,crystallization from solution rational experimental design,2021/12/5,Limited resource How to find as many new polymorphs and amorphous form as poss
8、ible API properties different solubility in the solvent poor solubility or good solubility Solvent properties Polarity-different sort of solvents (alcohols, ethers, ester etc.) Boiling point Freezing point Toxicity miscibility,？,2021/12/5,Slurry solvent selection,Make sure the sample is suspension s
9、olvent/mixed solvents solubility is poor,2021/12/5,Anti-solvent precipitation solvent selection,Prepare solvent good solubility,Anti-solvent selection,Poor solubility,polarity,miscibility,miscibility Water DMF Heptane ACN 1,4-Dioxane MTBE DMSO,Solvent-thermal heating/cooling experiments,2021/12/5,ch
10、ange temperature supersaturation good solubility Solvent selection solubility varies with the temperature freezing point of the solvent,Slow/fast precipitation from saturated solutions method,2021/12/5,Evaporate the solvent supersaturationSlow/fast rate of crystallization Solvent selection low boiling point,SummarySolvent selection,2021/12/5,key point of the method select appropriate solvent,different solubility in the solvent,solvent properties,miscibilitybetween solvents,Polarity,boiling point,freezing point,Toxicity,