Rapid Throughput Screening of Apparent KSP Values for Weakly Basic Drugs Using 96-Well Format

Abstract A rapid-throughput screening assay was developed to estimate the salt solubility parameter, K SP , with a minimal quantity of drug. This assay allows for early evaluation of salt limited solubility with a large number of counter-ions and biologically promising drug leads. Drugs dissolved (typically 10 mM) in DMSO are robotically distributed to a 96-well plate. DMSO is evaporated, and drugs are equilibrated with various acids at different concentrations (typically K SP values assuming 1:1 stoichiometry are determined from counter-ion and ionized drug activities. A correlation coefficient >0.975 for eight drugs totaling 16 salts is reported. Intra-day and inter-day reproducibility was K SP measurements were translated to 96-well format for increased throughput and minimal drug consumption (typically 10 mg) to evaluate at least eight different counter-ions. Although the current protocol estimates K SP from 10 −3 to 10 −7 M, the dynamic range of the assay could be expanded by adjusting drug and counter-ion concentrations.