Effect of Environmental Temperature on Polymorphic Solid-State Transformation of Indomethacin during Grinding

Abstract

The effect of grinding in an agate centrifugal ball mill at 200 rpm on the physicochemical properties of indomethacin (IMC) polymorphs was studied by means of X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry. The a and y forms (metastable and stable forms) of IMC were ground at 4°C and at 30±0.5°C, and the degree of crystallinity (Xc) of the ground products was measured by the X-ray diffractional internal standard method. The Xcof the y form ground at 4 °C decreased with increasing grinding time, and was 0% after 4h, that is, the y form had been converted to a noncrystalline solid. After grinding for 1 h at 30 °C, about 45% of y form of IMC was converted to noncrystalline solid, while the product ground for 10 h was transformed to the a form. The Xcof the a form ground for 2 h at 4 °C was 0%, that is, the a form had been converted to a noncrystalline solid within 2h at 4°C. The Xcof the a form ground at 30 °C decreased with increasing grinding time and the value after 10 h was about 60%. The solubility in distilled water at 35 °C of the y form ground for 10 h at 4°C was about 60% larger than that of the intact y form. The solubilities of the y form ground for 10 h at 30 °C, the a form ground for 10 h at 4°C and the α form ground for 10 h at 30 °C were all the same, 0.94 mg/100 ml, which is equal to that of the a form at 35 °C. © 1986, The Pharmaceutical Society of Japan. All rights reserved.