Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland.
The Dodd-Walls Centre for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9054, New Zealand.
Mol Pharm. 2022 Jul 4;19(7):2316-2326. doi: 10.1021/acs.molpharmaceut.2c00126. Epub 2022 May 3.
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.
浆液研究对于药物化合物的详尽多晶型和固态稳定性筛选很有用。拉曼光谱法便于监测此类浆液中的结晶过程，因为即使在水相环境中也可以进行测量。虽然中频区域（400-4000cm）主要由分子内振动主导，并且传统上用于此类研究，但低频光谱区域（<200cm）探测与固态相关的晶格振动，对于理解微妙和/或复杂的结晶行为可能更有价值。该研究的目的是首次调查低频拉曼光谱法在浆液中监测无定形药物结晶的情况，并将结果与中频拉曼光谱法同时获得的结果进行直接比较。在 pH 1.2 下制备无定形吲哚美辛（IND）浆液，并分别在 5°C 和 25°C 下使用低频和中频拉曼光谱连续监测。在 25°C 下，两个光谱区域都将浆液中的无定形 IND 描绘为直接从无定形形式转化为α晶形式。相比之下，在 5°C 时，主成分分析显示出检测到的转化曲线的差异：中频拉曼表明直接转化为α晶形式，但低频区域显示出额外的转变点。这些归因于少量 ε-形式的出现。低频区域的额外固态灵敏度归因于该区域中更好的信噪比和更一致的光谱。最后，首次报道了 IND 的 ε-形式的低频拉曼光谱。
