Comparison of chromatographic and spectroscopic methods used to rank compounds for aqueous solubility

Rapid methods for ranking the solubility of compounds in aqueous media usin g commercial, 96-well ultraviolet-visible (UV-vis) and nephelometric plate readers are described. The methods were evaluated using commercially availa ble compounds from a variety of structural classes as well as a series of s tructurally related compounds derived from combinatorial synthesis. Samples were predissolved in dimethyl sulfoxide (DMSO) and then added to the study solvent to attain a final concentration of DMSO in the aqueous solution of 5%. Comparison of filtration of the samples through nylon and poly(tetrafl uoroethylene) (PTFE) membranes is also described. The solubility of the com pounds determined using the UV-vis plate reader in the absorption mode (wit h samples filtered with the PTFE filter) as well as in the light scattering mode was in good agreement with that determined by high-performance liquid chromatography, with an average correlation of 0.95. Solubility data obtai ned using a 96-well nephelometer was also comparable (r(2) = 0.97). The non equilibrium methods described in this study can be used to rapidly rank com pounds from combinatorial libraries for solubility and can also give a gene ral assessment of solubility prior to running additional high throughput sc reens in a drug discovery environment. (C) 2001 Wiley-Liss, Inc. and the Am erican Pharmaceutical Association J Pharm Sci 90:521-529, 2001.