药物晶型研究

1、2022/9/25药物的多晶型研究2022/9/25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2022/9/25Crystal 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 develop

2、ed 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 crystallin

3、e and amorphous phases for a chemical/pharmaceutical2022/9/252022/9/252022/9/25多晶型研究对药物开发的重要性2022/9/25药物多晶型研究的重要性2022/9/252022/9/25如何筛选和选择药物的新晶型2022/9/252022/9/252022/9/25晶型的化学和物理分析手段2022/9/252022/9/252022/9/25Experience sharing on polymorph screening solvent selection2022/9/25The purpose of polymor

4、ph 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 identify as many new polymorphs (include solvate / hydrate) and amorphous form as possible - or to find the most

5、 stable form The method of polymorph screening2022/9/25crystallizationcrystallization from solution (slurry, anti-solvent precipitation , Solvent-thermal heating/coolingSlow/fast precipitation from saturated solutions)recrystallization from a neat compound (thermal heating/cooling, grinding , and hi

6、gh pressure )polymorph screening crystallization from solution2022/9/25degree of supersaturation and Temperature are considered as the driving force of crystallisation diverse solvents result in the discovery of more polymorphscrystallization from solution Solvent selection2022/9/25SlurryAnti-solven

7、t precipitation Solvent-thermal heating/cooling experiments Slow/fast precipitation from saturated solutions method SolventVisual solubility (mg/mL)MeOHEtOHIPA1-ButanolACNMEKMIBKEtOAciPrOAcMTBE2-MeTHFDMFNMPDMSOCH2Cl2Toluene1,4-DioxaneHeptaneTHFAcetoneWatercrystallization from solution rational exper

8、imental design2022/9/25Limited resource How to find as many new polymorphs and amorphous form as possible 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

9、 point Toxicity miscibility ？2022/9/25Slurry solvent selectionMake sure the sample is suspension solvent/mixed solvents solubility is poor2022/9/25Anti-solvent precipitation solvent selection Prepare solvent good solubilityAnti-solvent selectionPoor solubilitypolaritymiscibility miscibility Water DM

10、F Heptane ACN 1,4-Dioxane MTBE DMSOSolvent-thermal heating/cooling experiments2022/9/25change temperature supersaturation good solubility Solvent selection solubility varies with the temperature freezing point of the solvent Slow/fast precipitation from saturated solutions method2022/9/25Evaporate the solvent supersaturationSlow/fast rate of crystallization Solvent selection low boiling point solventboiling pointDMF 152.8 CDMSO189 CNMP202 CSummarySolvent selection2022/9/25key poin