Low- versus Mid-frequency Raman Spectroscopy for in Situ Analysis of Crystallization in Slurries.

Slurry studies are useful for exhaustive polymorph and solid-state stability screening of drug compounds. Raman spectroscopy is convenient for monitoring crystallization in such slurries, as the measurements can be performed even in aqueous environments. While the mid-frequency region (400-4000 cm) is dominated by intramolecular vibrations and has traditionally been used for such studies, the low-frequency spectral region (<200 cm) probes solid-state related lattice vibrations and is potentially more valuable for understanding subtle and/or complex crystallization behavior. The aim of the study was to investigate low-frequency Raman spectroscopy for monitoring of crystallization of an amorphous pharmaceutical in slurries for the first time and directly compare the results with those simultaneously obtained with mid-frequency Raman spectroscopy. Amorphous indomethacin (IND) slurries were prepared at pH 1.2 and continuously monitored at 5 and 25 °C with both low- and mid-frequency Raman spectroscopy. At 25 °C, both spectral regions profiled amorphous IND in slurries as converting directly from the amorphous form toward the α crystalline form. In contrast, at 5 °C, principal component analysis revealed a divergence in the detected conversion profiles: the mid-frequency Raman suggested a direct conversion to the α crystalline form, but the low-frequency region showed additional transition points. These were attributed to the appearance of minor amounts of the ε-form. The additional solid-state sensitivity of the low-frequency region was attributed to the better signal-to-noise ratio and more consistent spectra in this region. Finally, the low-frequency Raman spectrum of the ε-form of IND is reported for the first time.