Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution-a validation study

A novel potentiometric procedure has recently been described for rapid measurement of equilibrium aqueous solubility values of organic acids, bases, and ampholytes that form supersaturated solutions. In this procedure, the equilibrium solubility is actively sought by changing the concentration of the neutral form by adding HCl or KOH titrants and monitoring the rate of change of pH due to precipitation or dissolution in a process called Chasing Equilibrium. In this article, we seek to validate the procedure against a shake-flask protocol for solubility determination. A set of 16 small organic compounds, covering a wide range of solubilities was chosen for the study. Interestingly, while 10 compounds in the study were found to chase equilibrium, the others did not. Kinetic solubility data was also collected. It was noted that kinetic solubility was consistently higher than equilibrium solubility for chasers, but correlated well with equilibrium solubility for nonchasers. The ratio of kinetic to equilibrium solubility indicated a compound's ability to form supersaturated solutions. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association