Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures

The dissolution profile and solubility of two polymorphic forms of mefenami c acid were studied in solvent mixtures of ethanol-water and ethyl acetate- ethanol. The solubility parameter (delta) was used to study the effect of p olarity on the solubility behavior of the two polymorphs. Differential scan ning calorimetry and infrared spectroscopy were performed on the original p owders and on the solid phases after contact with the solvent systems for t he characterization and identification of the polymorphs. The dissolution r ates of both polymorphs is greater in the less polar mixtures (ethyl acetat e-ethanol) of lower solubility parameter values. Form II showed larger diss olution rates and saturation concentrations than Form I in all the solvent systems studied. The solid phase of Form II converts totally to Form I afte r equilibration with the solvents. The rate of conversion was faster in the least polar mixtures. The solubility of both polymorphs reaches a single m aximum at 80% ethyl acetate in ethanol, delta = 20.09 MPa1/2. The modified extended Hildebrand method was used to predict the solubility profile of ea ch polymorph. A single equation was obtained for both polymorphs which incl udes the solubility parameter of the mixtures and the logarithm of the solu bility mole fraction of each polymorph in water. The Hildebrand solubility parameter of mefenamic acid is independent of the crystalline form and was determined from two methods giving quite similar values, delta(2) = 20-21 M Pa1/2. (C) 1999 Elsevier Science B.V. All rights reserved.