Development of a partially automated solubility screening (PASS) assay for early drug development

A medium‐throughput, compound‐saving, thermodynamic solubility assay for early drug development was developed. Solid compound suspended in heptane was used for simple, time‐saving, and flexible compound distribution into 96‐well plates, with minor risk to generate new physical forms during dispensing. Low volume, well‐stirred incubation vessels were generated by using a combination of V‐shaped wells, well caps, and vertically inserted stir bars. This allowed solubility determination up to 100 mg/mL in 40-80 µL volumes in aqueous and nonaqueous, low‐ and high‐viscosity solvents. After removal of residual solid through syringe filters mounted on microtiter plates, the filtrate was quantified by ultra performance liquid chromatography (UPLC) using a 1.2 min gradient. Combined with a robotic liquid handling system, throughput was 45 samples per hour and >600 solubility measurements per week. Results from the partially automated solubility screening (PASS) assay correlated well with reported solubility values (r2 = 0.882). The PASS assay is useful for compound‐saving, thermodynamic solubility measurement at the discovery-development interface where maximal solubility in many commonly used solvents needs to be determined. PASS results provide a basis for the identification of formulation strategies, the selection of appropriate excipients, and for the prediction of the potential in vivo behavior of compounds. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1748-1762, 2007