(1035-B) Miniaturisation of an Aqueous Solubility assay using Acoustic Dispensing and 384-Well Based Workflows

Abstract: Drug discovery serves to optimize and qualify candidate drugs and requires concurrent optimization of physicochemical properties and metabolic stabilities alongside potency and efficacy on the intended target protein. A critical property that affects observed activities, as well as the ability to formulate a compound for in vivo studies, is aqueous solubility. There are significant challenges associated with accurate prediction of solubility values, speaking to the importance of robust and efficient methods for experimental determination of solubility. To achieve full impact in the drug discovery workflow, such assays must be available with sufficient throughput to support regular chemistry optimization. There are multiple challenges associated with assay miniaturization and automation of solubility assay workflows, but here we disclose what to the best of our knowledge is the first 384w-based dried-DMSO solubility assay. The new method requires only 6 µl of 10 mM DMSO stock solution with an assay capacity of 762 samples in each run. We achieve this assay efficiency by doing sample pooling prior to analysis with LC-MS. We demonstrate concordance between our data in the new 384w method for a validation set of well-known drugs as well as excellent correlation with historical values in previous 96-well based assay workflows. This robust method is run on a weekly basis as a part of an automated assay panel (DMPK Wave1), which is an integral part of the design-make-test-analysis cycle.