Effect of environmental temperature on polymorphic solid-state transformation of indomethacin during grinding.

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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 .alpha. and .gamma. forms (metastable and stable forms) of IMC were ground at 4.degree. C and at 30 .+-. 0.5.degree. C, and the degree of crystallinity (Xc) of the ground products was measured by the X-ray diffractional internal standard method. The Xc of the .gamma. form ground at 4.degree. C decreased with increasing grinding time, and was 0% after 4 h, that is the .gamma. form had been converted to a noncrystalline solid. After grinding for 1 h at 30.degree. C, about 45% of .gamma. form of IMC was converted to noncrystalline solid, while the product ground for 10 h was transformed to the .alpha. form. The Xc of the .alpha. form ground for 2 h at 4.degree. C was 0%, that is, the .alpha. form had been converted to a noncrystalline solid within 2 h at 4.degree. C. The Xc of the .alpha. form ground at 30.degree. C decreased with increasing grinding time and the value after 10 h was about 60%. The solubility in distilled water at 35.degree. C of the .gamma. form ground for 10 h at 4.degree. C was about 60% larger than that of the intact .gamma. form. The solubilities of the .gamma. form ground for 10 h at 30.degree. C, the .alpha. form ground for 10 h at 4.degree. C and the .alpha. form ground for 10 h at 30.degree. C were all the same, 0.94 mg/100 ml, which is equal to that of the .alpha. form at 35.degree. C.

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