藥物晶型研究

1、2022-3-7.2022-3-7.提綱提綱F什么是晶體，多晶型？F多晶型研究對(duì)藥物開(kāi)發(fā)的重要性F如何篩選和選擇藥物的新晶型F多晶型的主要分析手段F晶型篩選實(shí)驗(yàn)的經(jīng)驗(yàn)分享-溶劑選擇2022-3-7.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 develope

2、d as crystallineStabilityProcessabilityIP protection 什么是晶體？什么是晶體？2022-3-7.什么是多晶型？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 are interested

3、in all the crystalline and amorphous phases for a chemical/pharmaceutical2022-3-7.2022-3-7.多晶型研究對(duì)藥物開(kāi)發(fā)的重要性2022-3-7.藥物多晶型研究的重要性藥物多晶型研究的重要性2022-3-7.2022-3-7.如何篩選和選擇藥物的新晶型2022-3-7.2022-3-7.2022-3-7.晶型的化學(xué)和物理分析手段晶型的化學(xué)和物理分析手段2022-3-7.2022-3-7.2022-3-7.Experience sharing on polymorph screening solvent selec

4、tion2022-3-7.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 identify as many new polymorphs (include solvate / hydrate) and amorphous for

5、m as possible - or to find the most stable form 2022-3-7.The method of polymorph screeningcrystallizationcrystallization from solution (slurry, anti-solvent precipitation , Solvent-thermal heating/coolingSlow/fast precipitation from saturated solutions)recrystallization from a neat compound (thermal

6、 heating/cooling, grinding , and high pressure )2022-3-7.polymorph screening crystallization from solutiondegree of supersaturation and Temperature are considered as the driving force of crystallisation diverse solvents result in the discovery of more polymorphs2022-3-7.crystallization from solution

7、 Solvent selectionSlurryAnti-solvent precipitation Solvent-thermal heating/cooling experiments Slow/fast precipitation from saturated solutions method SolventVisual solubility (mg/mL)MeOHEtOHIPA1-ButanolACNMEKMIBKEtOAciPrOAcMTBE2-MeTHFDMFNMPDMSOCH2Cl2Toluene1,4-DioxaneHeptaneTHFAcetoneWater2022-3-7.

8、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 solubility Solvent properties Polarity-different sort of solvents (alcohols, ethers,

9、 ester etc.) Boiling point Freezing point Toxicity miscibility ？2022-3-7.Slurry solvent selectionMake sure the sample is suspension solvent/mixed solvents solubility is poor2022-3-7.Anti-solvent precipitation solvent selection Prepare solvent good solubilityAnti-solvent selectionPoor solubilitypolar

10、itymiscibility miscibility Water DMF Heptane ACN 1,4-Dioxane MTBE DMSO2022-3-7.Solvent-thermal heating/cooling experimentschange temperature supersaturation good solubility Solvent selection solubility varies with the temperature freezing point of the solvent 2022-3-7.Slow/fast precipitation from saturated solutions method Evaporate the solvent supersaturation Slow/fast rate of crystallization Solvent selection low boiling point solventboiling pointDMF 152.8 CDMSO189 CNMP202 C2022-3-7.SummarySolvent selectionkey point of the method select appropr