Suzuki Hironori, Matsushima Masahito, Ito Masataka, Noguchi Shuji
Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba274-8514, Japan.
Mol Pharm. 2023 Feb 6;20(2):1213-1221. doi: 10.1021/acs.molpharmaceut.2c00886. Epub 2022 Dec 23.
Sulfur K-edge X-ray absorption near-edge spectroscopy (XANES) measurements were performed to characterize the crystal polymorphs of the active pharmaceutical ingredients (APIs) containing sulfur atoms. Cimetidine (CIM) was used as a model API. Each crystal form of CIM has its own XANES spectrum, so we can discriminate the crystal form by its spectrum. The analysis of the crystal structure of CIM revealed that the difference in the shape of XANES spectra was ascribable to the difference in the C-S-C bond angle of CIM molecules and the intermolecular hydrogen bonds, such as C-H···S and N-H···S, and S-S interaction. It was found that the peak shape of the XANES spectrum is gentle when the C-S-C bond angle is large, while the peak shape can be steep when the C-S-C bond angle is small. Furthermore, it was found that the peak energy values varied depending on the hydrogen bonds and S-S interaction. By linear combination fitting using XANES spectra, it was possible to quantify the ratio of CIM form A crystal in mixed powders of form A and monohydrate crystals. These results indicate that XANES measurements can be a useful technique to evaluate the crystal polymorphism of APIs containing S atom in pharmaceutical formulation.
进行了硫 K 边 X 射线吸收近边光谱（XANES）测量，以表征含硫原子的活性药物成分（API）的晶体多晶型物。西咪替丁（CIM）用作模型 API。CIM 的每种晶型都有其自身的 XANES 光谱，因此我们可以通过其光谱来区分晶型。对 CIM 晶体结构的分析表明，XANES 光谱形状的差异归因于 CIM 分子的 C-S-C 键角以及分子间氢键（如 C-H···S 和 N-H···S）和 S-S 相互作用的差异。发现当 C-S-C 键角较大时，XANES 光谱的峰形较平缓，而当 C-S-C 键角较小时，峰形可能较陡峭。此外，发现峰能量值随氢键和 S-S 相互作用而变化。通过使用 XANES 光谱进行线性组合拟合，可以量化 A 型晶体和一水合物晶体混合粉末中 A 型 CIM 晶体的比例。这些结果表明，XANES 测量可以成为评估药物制剂中含 S 原子 API 晶体多晶型的有用技术。
