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首页> 外文期刊>Crystal growth & design >Isomorphism, disorder, and hydration in the crystal structures of racemic and single-enantiomer carvedilol phosphate
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Isomorphism, disorder, and hydration in the crystal structures of racemic and single-enantiomer carvedilol phosphate

机译：外消旋和单对映体磷酸卡维地洛的晶体结构的同构，无序和水合作用

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摘要

Understanding the crystalline structure of racemic carvedilol phosphate hemihydrate presents several challenges that were overcome using a combination of single-crystal X-ray diffraction, solid-state NMR (SSNMR), and other analytical techniques. Initial attempts to obtain a crystal structure were hampered by difficulties with twinning and problematic disorder in the final refinements. Multinuclear SSNMR analysis localized the disorder to portions of the molecule near the chiral center. As a result, single-enantiomer carvedilol phosphate was prepared and was found to crystallize in a phase that was isomorphous with the racemate, while SSNMR spectra of the single enantiomers did not contain the disorder observed in the racemate. The single-crystal X-ray structure of the (R)-enantiomer was solved and used as a starting point to successfully progress the solution of the disordered racemic crystal structure. Thermal analysis and construction of a phase diagram, along with crystallographic and spectroscopic analysis, found the crystal structure of the racemate to be a solid solution of (R)- and (S)-enantiomers, with the conformation of the molecule adjusting to fit. The crystal structures show the stoichiometry of the both the racemate and (R)-enantiomer to be a hemihydrate. The phase isomorphically dehydrates below relative humidity values of 1% and above temperatures of 125 °C as assessed by water vapor sorption studies, powder X-ray diffraction, and SSNMR. Single-crystal diffraction detected significant changes in the unit cell dimensions as the phase dehydrated, which was related to the visual appearance of opacity in a single crystal of the (R)-enantiomer. The mechanism of water incorporation was further probed spectroscopically via exchange with deuterium, ~(17)O-, and ~(18)O-labeled water; the results suggest that dehydration and rehydration likely proceed via narrow tunnels in the crystal structure, combined with the formation of fissures in the crystal. ~2H SSNMR experiments showed that the water does not engage in solid-state jump motion even at higher temperatures.
机译：了解外消旋卡维地洛磷酸半水合物的晶体结构提出了一些挑战，这些挑战可以通过结合使用单晶X射线衍射，固态NMR（SSNMR）和其他分析技术来克服。在最终精制中，孪晶和成问题的困难阻碍了获得晶体结构的最初尝试。多核SSNMR分析将疾病定位于手性中心附近的分子部分。结果，制备了单对映异构体磷酸卡维地洛磷酸酯，发现其在与外消旋体同晶的相中结晶，而单个对映异构体的SSNMR光谱不包含在外消旋体中观察到的无序。解决了（R）-对映异构体的单晶X射线结构，并将其用作成功解决无序外消旋晶体结构的起点。通过热分析和相图的构建以及晶体学和光谱学分析，发现外消旋体的晶体结构为（R）-和（S）-对映体的固溶体，分子的构型调整为适合。晶体结构显示外消旋体和（R）-对映异构体均为半水合物的化学计量。通过水蒸气吸附研究，粉末X射线衍射和SSNMR评估，相在低于1％的相对湿度值和高于125°C的温度下同晶脱水。当脱水相时，单晶衍射检测到晶胞尺寸的显着变化，这与（R）-对映异构体单晶的不透明外观有关。通过与氘，〜（17）O-和〜（18）O标记的水交换，进一步用光谱法研究了水的结合机理。结果表明，脱水和再水化可能是通过晶体结构中狭窄的隧道进行的，再加上晶体中裂缝的形成。 〜2H SSNMR实验表明，即使在较高温度下，水也不会发生固态跳跃运动。

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