Physicochemical characterization of indomethacin polymorphs and the transformation kinetics in ethanol.

Abstract

Methods for the preparation of polymorphs of indomethacin (IMC) were studied in order to obtain the pure polymorphs. The physicochemical properties of IMC polymorphs were measured by using X-ray diffraction analysis, infrared (IR) spectroscopy, differential thermal analysis (DTA) and differential scanning calorimetry (DSC), and two polymorphs (.alpha. and .gamma. forms) and one benzene solvate (.beta. form) were identified. The pure .alpha. form was obtained when distilled water at room temperature was poured into IMC ethanol solution at about 80.degree. C, and the precipitated crystals were filtered off and dried. The pure .beta. and .gamma. forms were obtained by recrystallization from benzene and ethyl ether, respectively, at room temperature. The melting points of the .alpha. and .gamma. forms were 148 and 154.degree. C, respectively, and their heats of fusion were 7.49 .+-. 0.27 and 8.64 .+-. 0.13 kcal/mol, respectively, as determined by DSC. A mixture of .alpha. and .gamma. forms was obtained by the method previously reported for .alpha. form preparation ("recrystallization method"), since the pure .alpha. form was transformed to the .gamma. form in ethanol at room temperature. The transformation of .alpha. form to .gamma. form in ethanol was analyzed by the kinetic method using 9 kinds of kinetic models. It was concluded that the transformation followed kinetics corresponding to two-dimensional growth of nuclei (Avrami equation), and the activation energy was calculated to be 14.2/mol from the Arrhenius plot. The solubilities of the .alpha. and .gamma. forms in distilled water were 0.87 and 0.69 mg/100 ml, respectively.