title: Optimizing solubility: kinetic versus thermodynamic solubility temptations and risks.
abstract: The aim of this study was to assess the usefulness of kinetic and thermodynamic solubility data in guiding medicinal chemistry during lead optimization. The solubility of 465 research compounds was measured using a kinetic and a thermodynamic solubility assay. In the thermodynamic assay, polarized-light microscopy was used to investigate whether the result referred to the crystalline or to the amorphous compound. From the comparison of kinetic and thermodynamic solubility data it was noted that kinetic solubility measurements frequently yielded results which show considerably higher solubility compared to thermodynamic solubility. This observation is ascribed to the fact that a kinetic solubility assay typically delivers results which refer to the amorphous compound. In contrast, results from thermodynamic solubility determinations more frequently refer to a crystalline phase. Accordingly, thermodynamic solubility data--especially when used together with an assessment of the solid state form--are deemed to be more useful in guiding solubility optimization for research compounds.
authors.affiliation: Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany. christoph.saal@merckgroup.com
authors.forename: Christoph
authors.initials: C
authors.lastname: Saal
authors.forename: Anna Christine
authors.initials: AC
authors.lastname: Petereit
mesh_terms: D002626:Chemistry, Pharmaceutical; D007700:Kinetics; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations