The solution properties of mefenamic acid and a closely related analogue are indistinguishable in polar solvents but significantly different in nonpolar environments

Abstract

This study investigates the cosolute effects of mefenamic acid (XA) and flufenamic acid (FA). These compounds serve as model of a drug discovery lead compound and a structural analogue. The activity coefficients of XA and FA in different solvents were obtained from solubility measurements at 25 degrees C. The effect of varying concentrations of FA on the solubility of XA in four different solvents, including toluene, cyclohexane, ethanol, and an ethanolwater mixture (80:20, v/v), was investigated. The magnitude of change in the activity coefficient of XA in the presence of FA in different solvents was used to elucidate the thermodynamic effect of FA on the solubility of XA. Nuclear magnetic resonance and Fourier-transform infrared spectroscopy were used to obtain molecular level information about the interactions of the compounds in solution. The presence of FA increases XA solubility in toluene and in cyclohexane as much as seven-fold. Conversely, in ethanol and the ethanolwater mixture, similar levels of FA have essentially no effect on the solubility of XA. The solution properties investigated show that despite the close structural similarity between XA and FA, the two compounds are strongly distinguishable in nonpolar solvents. Conversely, the solution properties of the same two solutes are indistinguishable in polar solvents. A solubilization model based on solute-cosolute interactions is presented. (c) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:45294539, 2012