活性药物成分的水合物:35Cl和2H固态核磁共振和DFT研究

IF 1.8 3区 化学 Q4 CHEMISTRY, PHYSICAL Solid state nuclear magnetic resonance Pub Date : 2022-12-01 DOI:10.1016/j.ssnmr.2022.101837
Sean T. Holmes , Cameron S. Vojvodin , Natan Veinberg , Emilia M. Iacobelli , David A. Hirsh , Robert W. Schurko
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引用次数: 1

摘要

本研究采用35Cl和2H固体核磁共振(SSNMR)光谱和色散校正平面波密度泛函理论(DFT)计算来表征活性药物成分(api)水合物的分子水平结构和动力学。我们使用35Cl SSNMR测量氯离子的EFG张量来表征原料药盐酸盐的水合形式,以及两种相应的无水形式。DFT计算用于改进原料药的晶体结构,并确定35Cl EFG张量与近似氢键的空间排列之间的关系,这种关系特别受与水分子相互作用的影响。我们发现35Cl EFG张量与局部氢键几何形状之间的关系是复杂的,但通过使用DFT计算可以获得有意义的结构/性质关系。具体来说,对于每一种可以进行这种比较的情况,我们发现水合物的CQ值比相应的无水形式的CQ值要小,这表明前者是一个具有更高球对称性基态电子密度的氯离子环境。最后,在API盐酸西米替丁一水合物氘交换样品上进行了35Cl和2H变温SSNMR实验,以监测35Cl和2H EFG张量的运动影响对光谱的温度依赖性影响。从2H SSNMR光谱中,我们确定水分子的运动是以围绕其C2自转轴的跳状运动为特征的,这种运动发生在不太可能影响35Cl中心转移(+1/2↔︎−1/2)粉末模式的时间尺度上(35Cl SSNMR证实了这一点)。总之,这些方法在原料药的散装和剂型的未来研究中显示出巨大的希望,特别是在可变水合物中,晶体水含量随外部条件(如湿度)而变化。
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Hydrates of active pharmaceutical ingredients: A 35Cl and 2H solid-state NMR and DFT study

This study uses 35Cl and 2H solid-state NMR (SSNMR) spectroscopy and dispersion-corrected plane-wave density functional theory (DFT) calculations to characterize the molecular-level structures and dynamics of hydrates of active pharmaceutical ingredients (APIs). We use 35Cl SSNMR to measure the EFG tensors of the chloride ions to characterize hydrated forms of hydrochloride salts of APIs, along with two corresponding anhydrous forms. DFT calculations are used to refine the crystal structures of the APIs and determine relationships between the 35Cl EFG tensors and the spatial arrangements of proximate hydrogen bonds, which are particularly influenced by interactions with water molecules. We find that the relationship between 35Cl EFG tensors and local hydrogen bonding geometries is complex, but meaningful structure/property relationships can be garnered through use of DFT calculations. Specifically, for every case in which such a comparison could be made, we find that the hydrate has a smaller magnitude of CQ than the corresponding anhydrous form, indicating a chloride ion environment with a ground-state electron density of higher spherical symmetry in the former. Finally, variable-temperature 35Cl and 2H SSNMR experiments on a deuterium-exchanged sample of the API cimetidine hydrochloride monohydrate are used to monitor temperature-dependent influences on the spectra that may arise from motional influences on the 35Cl and 2H EFG tensors. From the 2H SSNMR spectra, we determine that the motions of water molecules are characterized by jump-like motions about their C2 rotational axes that occur on timescales that are unlikely to influence the 35Cl central-transition (+1/2 ↔︎ −1/2) powder patterns (this is confirmed by 35Cl SSNMR). Together, these methods show great promise for the future study of APIs in their bulk and dosage forms, especially variable hydrates in which crystallographic water content varies with external conditions such as humidity.

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来源期刊
CiteScore
5.30
自引率
9.40%
发文量
42
审稿时长
72 days
期刊介绍: The journal Solid State Nuclear Magnetic Resonance publishes original manuscripts of high scientific quality dealing with all experimental and theoretical aspects of solid state NMR. This includes advances in instrumentation, development of new experimental techniques and methodology, new theoretical insights, new data processing and simulation methods, and original applications of established or novel methods to scientific problems.
期刊最新文献
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