Using the low-frequency Raman spectroscopy to analyze the crystallization of amorphous indomethacin

This paper gives a detailed analysis of the low-frequency Raman spectrum (LFRS) in the 5–250 cm−1 region, corresponding to collective vibrations, in the crystalline forms and in the amorphous state of indomethacin (IMC). This study points out the high sensitivity of the LFRS to detect, identify and evaluate the first traces of crystallization in comparison with high-frequency regions where internal vibration bands are detected. This analysis reveals that amorphous IMC prepared by cryogrinding instantaneously partially crystallizes at room temperature in the stable γ phase, well below Tg = 43 °C. A method based on the treatment of the LFRS to determine precise and very low volume of crystallized material within amorphous matrix is described and used to analyze the crystallization kinetics of ground amorphous IMC powder. This study demonstrates that Raman spectroscopy is also a well-adapted technique to point out small amount of amorphous state in crystalline matrix. Crystallization of ground IMC powder was also analyzed by isothermal microcalorimetry experiments, which is one of the most widely used methods to analyze isothermal crystallization and to evaluate crystallinity.