Alelyunas Yun W, Liu Ruifeng, Pelosi-Kilby Luciana, Shen Cindy
CNS Chemistry and DMPK Department, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437, USA.
Eur J Pharm Sci. 2009 May 12;37(2):172-82. doi: 10.1016/j.ejps.2009.02.007. Epub 2009 Feb 24.
A rapid throughput equilibrium solubility measurement is described. The method utilizes central liquid storage where compounds are stored as 10mM solution in dimethyl sulfoxide (DMSO). The DMSO is subsequently removed to generate solid like material used for solubility measurement. A full range of available technologies is used including automated liquid handling, automated data collection using both HPLC/UV and LC/MS/MS. The method is fully validated and has been used to measure solubility for over 20,000 compounds across all phases of drug discovery. A detailed discussion on data interpretation and comparison to traditional solubility measurement using solid material is presented. An in-house solubility predictive model has been developed from the vast data set and has been employed successfully as part of compound design resulting in over 30% reduction in the number of poorly soluble compound synthesized.
本文描述了一种快速高通量平衡溶解度测量方法。该方法利用中央液体储存库，化合物以10mM的二甲基亚砜（DMSO）溶液形式储存。随后去除DMSO以生成用于溶解度测量的类固体物质。使用了一系列可用技术，包括自动液体处理、使用HPLC/UV和LC/MS/MS进行自动数据收集。该方法经过充分验证，已用于药物研发各阶段超过20000种化合物的溶解度测量。文中还详细讨论了数据解读以及与使用固体材料的传统溶解度测量方法的比较。已从大量数据集中开发出内部溶解度预测模型，并成功应用于化合物设计，使合成的难溶性化合物数量减少了30%以上。
