Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid/base titrations and calculated solubilities
Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid/base titrations and calculated solubilities
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DOI：
10.1002/jps.20212
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发表时间：
2005-01-01
影响因子：
3.8
通讯作者：
Dressman, JB
中科院分区：
文献类型：
--
作者：
Glomme, A;März, J;Dressman, JB
在药物发现过程中，溶解度是选择和优化先导化合物的重要参数之一。因此，它的决定应该在这一进程中尽早作出。由于所涉及的化合物数量很多，而在早期开发阶段可获得的每种化合物的量很少，因此非常希望用尽可能少的化合物来测量溶解度，并能够提高所用方法的吞吐量。本文建立了一种小型化的摇瓶法，并与半自动电位滴定和计算方法测定的21种难溶化合物的溶解度结果进行了比较，这些化合物的溶解度大多在0.03-30微克/毫升。电位法非常经济(需要大约100杯难溶化合物)，能够通过一次测定创建pH/溶解度曲线，但仅限于可电离的化合物。这种小型化的摇瓶方法可以用于所有化合物和各种介质。它的精密度和产量证明优于极难溶化合物的电位法。一套装置每周可以研究多达20种化合物。计算的溶解度数据似乎足以初步估计溶解度，但它们目前不能用作开发过程中关键决策点的实验测量的替代。(C)2004年Wiley-Liss公司
Solubility is one of the most important parameters for lead selection and optimization during drug discovery. Its determination should therefore take place as early as possible in the process. Because of the large numbers of compounds involved and the very low amounts of each compound available in the early development stage, it is highly desirable to measure the solubility with as little compound as possible and to be able to improve the throughput of the methods used. In this work, a miniaturized shake-flask method was developed and the solubility results were compared with those measured by semiautomated potentiometric acid/base titrations and computational methods for 21 poorly soluble compounds with solubilities mostly in the range 0.03-30 mug/ mL. The potentiometric method is very economical (approximately 100 mug of a poorly soluble compound is needed) and is able to create a pH/solubility profile with one single determination, but is limited to ionizable compounds. The miniaturized shake-flask method can be used for all compounds and a wide variety of media. Its precision and throughput proved superior to the potentiometric method for very poorly soluble compounds. Up to 20 compounds a week can be studied with one set-up. Calculated solubility data seem to be sufficient for a first estimate of the solubility, but they cannot currently be used as a substitute for experimental measurements at key decision points in the development process. (C) 2004 Wiley-Liss, Inc.