Rapid and accurate solubility determination of poorly soluble drug molecules by co-solvent extrapolation

Aqueous solubility is a critical parameter in drug design. Common methods to measure solubility are often too slow or too inaccurate to be routinely used. Measuring very low solubilities (10^-6 M and below) represents additional challenges. In this paper, we first describe a fast and reliable method to measure aqueous solubility of drug-like molecules in a 96-well plate format using only conventional laboratory equipment and a UV absorbance plate reader. The method was validated against the gold-standard saturation shake-flask on a set of 31 drug molecules and represents a practical improvement over already described high-throughput solubility determination methods. We then use this method to explore the solubility of six poorly soluble molecules in water-organic solvent mixtures. We discuss the relationship between solvent fraction and logarithmic solubility (logS), conditions to make this relationship linear, and how to use it to extrapolate solubility to 0 % cosolvent. We demonstrate that the MDM mixture (1:1:1 methanol, acetonitrile and dioxane) provides linear logS - cosolvent relationship for all tested compounds, and excellent extrapolation abilities. Our method opens the way to the systematic determination of very low solubilities at the very first stages of drug design programs, a valuable input for structure-property relationship studies.