Sean T. Holmes , Cameron S. Vojvodin , Natan Veinberg , Emilia M. Iacobelli , David A. Hirsh , Robert W. Schurko
{"title":"活性药物成分的水合物:35Cl和2H固态核磁共振和DFT研究","authors":"Sean T. Holmes , Cameron S. Vojvodin , Natan Veinberg , Emilia M. Iacobelli , David A. Hirsh , Robert W. Schurko","doi":"10.1016/j.ssnmr.2022.101837","DOIUrl":null,"url":null,"abstract":"<div><p>This study uses <sup>35</sup>Cl and <sup>2</sup>H 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 <sup>35</sup><span><span>Cl SSNMR to measure the EFG tensors of the </span>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 </span><sup>35</sup><span>Cl 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 </span><sup>35</sup>Cl 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 <em>C</em><sub>Q</sub> 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 <sup>35</sup>Cl and <sup>2</sup>H 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 <sup>35</sup>Cl and <sup>2</sup>H EFG tensors. From the <sup>2</sup>H SSNMR spectra, we determine that the motions of water molecules are characterized by jump-like motions about their <em>C</em><sub>2</sub> rotational axes that occur on timescales that are unlikely to influence the <sup>35</sup>Cl central-transition (+1/2 ↔︎ −1/2) powder patterns (this is confirmed by <sup>35</sup>Cl 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.</p></div>","PeriodicalId":21937,"journal":{"name":"Solid state nuclear magnetic resonance","volume":null,"pages":null},"PeriodicalIF":1.8000,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Hydrates of active pharmaceutical ingredients: A 35Cl and 2H solid-state NMR and DFT study\",\"authors\":\"Sean T. Holmes , Cameron S. Vojvodin , Natan Veinberg , Emilia M. Iacobelli , David A. Hirsh , Robert W. Schurko\",\"doi\":\"10.1016/j.ssnmr.2022.101837\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>This study uses <sup>35</sup>Cl and <sup>2</sup>H 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 <sup>35</sup><span><span>Cl SSNMR to measure the EFG tensors of the </span>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 </span><sup>35</sup><span>Cl 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 </span><sup>35</sup>Cl 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 <em>C</em><sub>Q</sub> 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 <sup>35</sup>Cl and <sup>2</sup>H 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 <sup>35</sup>Cl and <sup>2</sup>H EFG tensors. From the <sup>2</sup>H SSNMR spectra, we determine that the motions of water molecules are characterized by jump-like motions about their <em>C</em><sub>2</sub> rotational axes that occur on timescales that are unlikely to influence the <sup>35</sup>Cl central-transition (+1/2 ↔︎ −1/2) powder patterns (this is confirmed by <sup>35</sup>Cl 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.</p></div>\",\"PeriodicalId\":21937,\"journal\":{\"name\":\"Solid state nuclear magnetic resonance\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2022-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Solid state nuclear magnetic resonance\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0926204022000662\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Solid state nuclear magnetic resonance","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0926204022000662","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
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.
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.