1、2020/6/19,藥物的多晶型研究,2020/6/19,提綱,什么是晶體，多晶型？ 多晶型研究對(duì)藥物開發(fā)的重要性 如何篩選和選擇藥物的新晶型 多晶型的主要分析手段 晶型篩選實(shí)驗(yàn)的經(jīng)驗(yàn)分享-溶劑選擇,2020/6/19,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

2、 are developed as crystalline Stability Processability IP protection,什么是晶體？,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 phase Same chemical composition Different molecular arrangements In practice, we are interested in

3、all the crystalline and amorphous phases for a chemical/pharmaceutical,2020/6/19,2020/6/19,2020/6/19,多晶型研究對(duì)藥物開發(fā)的重要性,2020/6/19,藥物多晶型研究的重要性,2020/6/19,2020/6/19,如何篩選和選擇藥物的新晶型,2020/6/19,2020/6/19,2020/6/19,晶型的化學(xué)和物理分析手段,2020/6/19,2020/6/19,2020/6/19,Experience sharing on polymorph screening solvent selec

4、tion,2020/6/19,The purpose of polymorph screening,For Innovator companies - select the optimal solid-state of API for development -study relevant polymorphs for IP protection For CRO companies based on the customers needs - to identify as many new polymorphs (include solvate / hydrate) and amorphous

5、 form as possible - or to find the most stable form,The method of polymorph screening,2020/6/19,crystallization,crystallization from solution (slurry, anti-solvent precipitation , Solvent-thermal heating/cooling Slow/fast precipitation from saturated solutions),recrystallization from a neat compound

6、 (thermal heating/cooling, grinding , and high pressure ),polymorph screening crystallization from solution,2020/6/19,degree of supersaturation and Temperature are considered as the driving force of crystallisation diverse solvents result in the discovery of more polymorphs,crystallization from solu

7、tion Solvent selection,2020/6/19,Slurry Anti-solvent precipitation Solvent-thermal heating/cooling experiments Slow/fast precipitation from saturated solutions method,crystallization from solution rational experimental design,2020/6/19,Limited resource How to find as many new polymorphs and amorphou

8、s 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 point Toxicity miscibility,？,2020/6/19,Slurry solvent selection,Make sure the sample i

9、s suspension solvent/mixed solvents solubility is poor,2020/6/19,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 experiment

10、s,2020/6/19,change temperature supersaturation good solubility Solvent selection solubility varies with the temperature freezing point of the solvent,Slow/fast precipitation from saturated solutions method,2020/6/19,Evaporate the solvent supersaturation Slow/fast rate of crystallization Solvent selection low boiling point,SummarySolvent selection,2020/6/19,key point of the met