Dissecting the behavior of a promiscuous solvate former
Dissecting the behavior of a promiscuous solvate former
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DOI：
10.1002/anie.200503533
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Matzger, AJ
中科院分区：
文献类型：
--
作者：
Price, CP;Glick, GD;Matzger, AJ
溶剂合物形成在有机、有机金属和无机化合物中是常见的。其对药物的稳定性和生物利用度的影响导致了对溶剂化药物物质的大量研究。[1]一些化合物显示无差别的溶剂化物形成，而另一些则具有相当大的选择性。值得注意的是，导致这种或那种行为的结构特征尚未确定。因此，溶剂化物的发现需要经验方法。可以容易地设想倾向于有利于溶剂化物形成的两种情况。首先，其中潜在的分子间相互作用（例如氢键）在非溶剂化形式中不能很好地满足的化合物通常掺入溶剂分子以提供强的分子间相互作用，并且通常基于官能度选择性地溶剂化。另一种限制情况是溶剂夹杂物，以减少晶体中的空隙空间。大多数化合物具有来自这两种驱动力的贡献，这可以被视为主要分别通过静电和货车德瓦尔斯相互作用降低晶体自由能。易溶剂化的药物在文献中受到关注，两个突出的例子是磺胺噻唑和棉酚。磺胺噻唑是一种抗菌磺胺类药物，已知有100多种溶剂化物/共晶体和5种无溶剂多晶型物。[2-6]它与许多溶剂形成溶剂化物;然而，也有一些值得注意的例外，包括烃和卤化溶剂。溶剂化磺胺噻唑形成一组不同的晶体结构，以及几种同构溶剂合物。在某些情况下，溶剂的作用是填充晶格中的空隙空间（例如乙腈、二氧六环），而在其他晶体中，溶剂满足特定的分子间相互作用（例如N-甲酰基哌啶）。棉酚是一种天然产物，已被用作男性避孕药，它与近100个分子形成溶剂化物/共晶体。[7]溶剂化物可以从几乎所有常见的有机溶剂中产生。然而，它确实以无溶剂的形式从石油醚和己烷与乙醚的混合物中结晶。与磺胺噻唑类似，棉酚形成同构溶剂化物，其中溶剂填充结构中的空腔（例如四氯化碳、间二甲苯），以及棉酚与所包含溶剂之间具有特定氢键相互作用的溶剂化物（例如乙酸、2-丙醇）。
Solvate formation is a common occurrence among organic, organometallic, and inorganic compounds. Its impact on the stability and bioavailability of pharmaceuticals has led to considerable investigation of solvated drug substances.[1] Some compounds display indiscriminate solvate formation, while others are considerably more selective. Significantly, the structural features that lead to one behavior or another have not been identified. Hence, empirical approaches are required for the discovery of solvates. Two situations can readily be envisaged that would tend to favor solvate formation. First, compounds in which potential intermolecular interactions, such as hydrogen bonding, are not well satisfied in the unsolvated form generally incorporate solvent molecules to provide strong intermolecular interactions and often solvate selectively based on functionality. The other limiting case is solvent inclusion to decrease void space in the crystal. Most compounds have contributions from both of these driving forces, which can be viewed as lowering the crystal free energy primarily through electrostatic and van der Waals interactions, respectively. Readily solvated pharmaceuticals have received attention in the literature, two prominent examples are sulfathiazole and gossypol. Sulfathiazole is an antibacterial sulfa-drug known to crystallize in over 100 solvates/cocrystals and five solvent-free polymorphs.[2–6] It forms solvates with many solvents; however, there are some notable exceptions, which include hydrocarbon and halogenated solvents. Solvated sulfathiazole forms a diverse set of crystal structures, as well as several isostructural solvates. In some cases, the role of the solvent is to fill void space in the lattice (eg, acetonitrile, dioxane), while in other crystals the solvent satisfies specific intermolecular interactions (eg, N-formyl piperidine). Gossypol is a natural product that has been used as a male contraceptive and it forms solvates/cocrystals with nearly 100 molecules.[7] Solvates can be generated from nearly every common organic solvent. It does, however, crystallize in a solvent-free form from ligroin and mixtures of hexane and diethyl ether. Like sulfathiazole, gossypol forms isostructural solvates, in which the solvent fills a cavity in the structure (eg, carbon tetrachloride, m-xylene), as well as solvates with specific hydrogen-bonding interactions between gossypol and the included solvent (eg, acetic acid, 2-propanol).