Rapid throughput screening of apparent KSP values for weakly basic drugs using 96-well format

Journal of Pharmaceutical Sciences
Jeremy GuoJames N Herron


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 <1 M) to yield final total drug concentrations around 2.5 mM. The plate is checked for precipitation. Filtrates from only those precipitated wells were subjected to rapid gradient HPLC analysis. An iterative procedure is employed to calculate all species concentrations based on mass and charge balance equations. The apparent 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 <10%. Conventional apparent 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 pr...Continue Reading


Dec 1, 1972·Journal of Pharmaceutical Sciences·S F Kramer, G L Flynn
Jul 8, 1998·Pharmaceutical Development and Technology·W Q Tong, G Whitesell
Dec 8, 2000·Pharmaceutical Development and Technology·M Sacchetti
May 29, 2003·Combinatorial Chemistry & High Throughput Screening·Ge WuBill Janzen
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Feb 17, 2015·The Journal of Pharmacy and Pharmacology·Ana Fernández CasaresMarcel Hoffmann
Nov 4, 2017·Journal of Pharmaceutical Sciences·Katie L CavanaghNaír Rodríguez-Hornedo

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