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Solubility

A complex but vital parameter in drug design

Throughout the life cycle of drugs in development, there are many reasons why it is important to know their solubility. In discovery and lead optimization, it helps for the identification of potential screening and bioavailability issues and it is valuable in planning chemistry changes. During biopharmaceutical evaluation, knowledge of solubility is important for the confirmation of bioavailability issues, while during early trials of drugs it is used in the design of animal and human formulations. In drug development, solubility knowledge is needed for biopharmaceutical classification, biowaivers and bioequivalence. It is also required for formulation optimization and salt selection. In manufacturing, solubility affects the optimization of manufacturing processes.

Equilibrium solubility (the concentration of compound in a saturated solution when excess solid is present, and solution and solid are at equilibrium) is traditionally measured by the shake-flask method, and while this method is accurate when performed to a high standard, it is slow. Kinetic solubility (the solubility at the time when an induced precipitate first appears in a solution) can also be measured, and while the measurements are much faster than equilibrium solubility by shake-flask, the kinetic solubilities obtained are often much higher than measured equilibrium solubilities.

The pH-metric methods available as add-ons to Sirius RefinementPro software (CheqSol, Bjerrum) get accurate results quickly for solubility of ionizable compounds, as well as providing insight into solubility-related phenomena including supersaturation, precipitation rates and polymorph creation under aqueous conditions. Notably, plots of measured equilibrium solubility values vs. measured logP provide a quick guide to BCS Class.