Accurate measurement of aqueous solubility across a range of pH provides an ideal starting point for ultimately determining the distribution coefficient of a drug substance. Without first knowing the pH-solubility profile, the appropriate pH of the aqueous phase for the aqueous/organic bi-phasic mixture would be in question. The research presented here initially focuses on the development of an automated approach to determine pH-solubility profiles for a variety of drug substances with a wide range of physicochemical properties such as molecular weight, scaffolding, and tendencies for protonation/deprotonation. The experimental designs leveraged several HTE robotic platforms to enable the development of aqueous solubility profiles. Because of the efficiency of these automated platforms, the pH-solubility studies were conducted with minimal demand on resources for the investigators, so it was determined early in the project to include these studies as part of the experimental approach. At the onset of this portion of work, the investigators assumed that specific pH buffers would be required for each drug molecule, with the goal of being at least 3 pH away from the measured pKa in order to ensure that the molecule was fully dissolved in the aqueous phase. However, after the data was collected and analyzed, it was recognized that the distribution coefficient experiments could standardize on either pH 3 or pH 8 buffers as the aqueous phase, depending on the ionic state of each molecule.