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 microL 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.