A High Energy X-ray Diffraction Study of Amorphous Indomethacin
A High Energy X-ray Diffraction Study of Amorphous Indomethacin
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DOI：
10.1016/j.xphs.2021.12.003
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发表时间：
2022-03-04
影响因子：
3.8
通讯作者：
Weber, J. K. R.
中科院分区：
文献类型：
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作者：
Benmore, C. J.;Benmore, S. R.;Weber, J. K. R.
无定形药物通常具有广泛的分子构象和成键能力。X射线对分布函数（PDF）方法是表征分子内和分子间堆积排列变化的有力技术。在这里，无定形吲哚美辛的X-射线PDF被证明是特别敏感的结晶状态的异构体中发现的氯苄基环的优选取向。在某些情况下，氯苄基环在无定形形式中没有优选的扭转角，而在其他情况下观察到不同的异构体取向的证据。发现氯苄基环没有优选扭转角的无定形样品有利于增强分子间氢键，这反映在第一尖锐衍射峰的强度上。这些结构上的显著变化排除了无定形吲哚美辛作为X射线PDF测量的可能标准。在高湿度下，>40小时的时间分辨PDF显示水分子与吲哚美辛分子形成氢键。一个简单的线性氢键模型表明，湿的无定形形式的水分子具有类似的氢键强度之间发现的吲哚美辛二聚体或链在干燥的无定形形式。(c)2021年美国药学协会。爱思唯尔公司出版All rights reserved.
Amorphous pharmaceuticals often possess a wide range of molecular conformations and bonding arrange-ments. The x-ray pair distribution function (PDF) method is a powerful technique for the characterization of variations in both intra-molecular and inter-molecular packing arrangements. Here, the x-ray PDF of amor-phous Indomethacin is shown to be particularly sensitive to the preferred orientations of the chlorobenzyl ring found in isomers in the crystalline state. In some cases, the chlorobenzyl ring has no preferred torsional angle in the amorphous form, while in others evidence of distinct isomer orientations are observed. Amor-phous samples with no preferred torsion angles of the chlorobenzyl ring are found to favor enhanced inter-molecular hydrogen bonding, and this is reflected in the intensity of the first sharp diffraction peak. These significant variations in structure rule out amorphous Indomethacin as a possible standard for x-ray PDF measurements. At high humidity, time resolved PDF's for >40 h reveal water molecules forming hydrogen bonds with Indomethacin molecules. A simple linear hydrogen bond model indicates that water molecules in the wet amorphous form have similar hydrogen bond strengths to those found between Indomethacin dimers or chains in the dry amorphous form. (c) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.