Raman spectroscopy using the mid-frequency (1800-1500 cm−1) and low-frequency (200-8 cm−1) spectral regions is used to study the transformation of amorphous indomethacin (IND) to the γ-crystalline form. The low-frequency spectral region provides access to collective vibrations of molecules in the crystalline and amorphous state, while the mid-frequency spectral region provides access to the molecular vibrations that are sensitive to the local functional group environment. Both spectral regions provide distinct Raman bands for the amorphous and crystalline forms of IND. The more intense low-frequency Raman bands provide greater sensitivity for detecting the onset of crystallization in an amorphous matrix. Subtle differences in the behavior of the initial crystalline process of IND are observed between the low-frequency and mid-frequency Raman bands. These observations suggest that different responses for mid- and low-frequency Raman bands occur for the microcrystalline domains present during the initial crystallization process. The suitability of low-frequency Raman spectroscopy to monitor IND in a suspension was demonstrated. This suggests that the technique will be a valuable tool for at-line and on-line monitoring of active pharmaceutical ingredient crystallization.
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