Molecular conformations of the polymorphic forms of cimetidine from 13C solid-state NMR distance and angle measurements
Molecular conformations of the polymorphic forms of cimetidine from 13C solid-state NMR distance and angle measurements
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DOI：
10.1021/ja993067z
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发表时间：
2000-02-16
影响因子：
15
通讯作者：
Saunders, D
中科院分区：
文献类型：
--
作者：
Middleton, DA;Le Duff, CS;Saunders, D
合成了多晶型药物化合物西咪替丁（一种组胺 H-2 受体拮抗剂），其在咪唑次甲基碳 C2 和胍甲基碳 C16 处含有 C-13 富集位点。使用 C-13 交叉偏振魔角旋转 (CPMAS) NMR 方法检查了双 C-13 标记的西咪替丁、三种无水物（A、B 和 C）和一水合物 (M1) 的四种晶型的结构。对于形式A和M1获得的旋转共振磁化强度交换曲线与从它们的晶体结构测量的3.78和3.82埃的C2-C16原子间距离一致。尚未获得晶体结构的晶型 B 和 C 的交换曲线表明，在这两种情况下，C2-C16 原子间距离均在 5.2 至 5.8 埃之间，表明西咪替丁在这些晶型中采用部分延伸的构象。此外，使用双量子异核局域场 (2Q-HLF) NMR 确定两个 C-13 标记位点处 C-13-H 键的相对方向。实验数据与 A 型和 M1 型的已知几何形状一致，并且就 C 型而言，与有限数量的可能结构一致。 C 型能量有利的分子构象与距离和角度测量结果一致，仅分为六个不同的簇。这些结果证明了使用 CP-MAS NMR 结合最小同位素标记策略来确定药物化合物和其他不适合晶体学的材料的完整固态结构的可行性。
The polymorphic drug compound cimetidine, a histamine H-2 receptor antagonist, was synthesized containing sites of C-13 enrichment at the imidazolium methine carbon C2 and at the guanidinium methyl carbon C16. The structures of four crystalline forms of double C-13-labeled cimetidine, three anhydrates (A, B, and C) and a monohydrate (M1), were examined using C-13 cross polarization magic angle spinning (CPMAS) NMR methods. Rotational resonance magnetization exchange curves obtained for forms A and M1 were consistent with C2-C16 interatomic distances of 3.78 and 3.82 Angstrom as measured from their crystal structures. Exchange curves for forms B and C, for which crystal structures have not been obtained, indicated that in both cases the C2-C16 interatomic distance lies between 5.2 and 5.8 Angstrom, suggesting that cimetidine adopts a partially extended conformation in these forms. In addition, double quantum heteronuclear local field (2Q-HLF) NMR was used to determine the relative orientations of the C-13-H bonds at the two C-13-labeled sites. The experimental data were consistent with the known geometry of forms A and M1 and, in the case of form C, with a limited number of possible structures. Energetically favorable molecular conformations of form C, which were in agreement with the distance and angle measurements, fell into just six distinct clusters. These results demonstrate the feasibility of determining the complete solid-state structures of pharmaceutical compounds, and other materials not amenable to crystallography, using CP-MAS NMR combined with a minimal isotope labeling strategy.