Yokoo Hidetomo, Tanaka Seiji, Yamamoto Eiichi, Tsuji Genichiro, Demizu Yosuke, Uchiyama Nahoko
National Institute of Health Sciences.
Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.
Chem Pharm Bull (Tokyo). 2023 Jan 1;71(1):58-63. doi: 10.1248/cpb.c22-00628. Epub 2022 Oct 27.
Understanding the characteristics of crystal polymorphism of active pharmaceutical ingredients and analyzing them with high sensitivity is important for quality of drug products, appropriate characterization strategies, and appropriate screening and selection processes. However, there are few methods to measure intra- and intermolecular correlations in crystals other than X-ray crystallography, for which it is sometimes difficult to obtain suitable single crystals. Recently, solid-state NMR has been recognized as a straightforward method for measuring molecular correlations. In this study, we selected ranitidine hydrochloride, which is known to exist in two forms, 1 and 2, as the model drug and investigated each form using solid-state NMR. In conducting the analysis, rotating the sample tube, which had a 1-mm inner diameter, increased the solid-state NMR resolution at 70 kHz. The H-N dipolar-based heteronuclear multiple quantum coherence (D-HMQC) analysis revealed the intermolecular correlation of Form 1 between the N atom of the nitro group and a proton of the furan moiety, which were closer than those of the intramolecular correlation reported using single X-ray crystal analysis. Thus, H-N D-HMQC analysis could be useful for characterizing intermolecular interaction in ranitidine hydrochloride crystals. In addition, we reassigned the C solid-state NMR signals of ranitidine hydrochloride according to the liquid-state and multiple solid-state NMR experiments.
了解活性药物成分的晶体多晶型特征并进行高灵敏度分析，对于药品质量、合适的表征策略以及合适的筛选和选择过程至关重要。然而，除了X射线晶体学外，测量晶体中分子内和分子间相关性的方法很少，而X射线晶体学有时难以获得合适的单晶。最近，固态核磁共振已被认为是一种测量分子相关性的直接方法。在本研究中，我们选择了已知存在两种晶型（晶型1和晶型2）的盐酸雷尼替丁作为模型药物，并使用固态核磁共振对每种晶型进行了研究。在进行分析时，旋转内径为1毫米的样品管提高了70kHz下的固态核磁共振分辨率。基于H-N偶极的异核多量子相干（D-HMQC）分析揭示了晶型1中硝基的N原子与呋喃部分的质子之间的分子间相关性，这比使用单晶X射线晶体分析报道的分子内相关性更紧密。因此，H-N D-HMQC分析可用于表征盐酸雷尼替丁晶体中的分子间相互作用。此外，我们根据液态和多固态核磁共振实验重新归属了盐酸雷尼替丁的C固态核磁共振信号。
