Department of Chemistry, Georgetown University, 37th and O Streets NW, Washington, District of Columbia 20057-1227, United States.
Mol Pharm. 2023 Nov 6;20(11):5554-5562. doi: 10.1021/acs.molpharmaceut.3c00481. Epub 2023 Oct 18.
The antiparasitic drug niclosamide (NCL) is notable for its ability to crystallize in multiple 1:1 channel solvate forms, none of which are isostructural. Here, using a combination of time-resolved synchrotron powder X-ray diffraction and thermogravimetry, the process-induced desolvation mechanisms of methanol and acetonitrile solvates are investigated. Structural changes in both solvates follow a complicated molecular-level trajectory characterized by a sudden shift in lattice parameters several degrees below the temperature where the desolvated phase first appears. Model fitting of kinetic data obtained under isothermal heating conditions suggests that the desolvation is rate-limited by the nucleation of the solvent-free product. The desolvation pathways identified in these systems stand in contrast to previous investigations of the NCL channel hydrate, where water loss by diffusion initially yields an anhydrous isomorph that converts to the thermodynamic polymorph at significantly higher temperatures. Taking the view that each solvate lattice is a unique "pre-organized" precursor, a comparison of the pathways from different starting topologies to the same final product provides the opportunity to reevaluate assumptions of how various factors (e.g., solvent binding strength, density) influence solid-state desolvation processes.
抗寄生虫药物硝氯酚（NCL）的一个显著特点是能够以多种 1:1 通道溶剂化物形式结晶，这些形式均非同构。在这里，我们使用时间分辨同步加速器粉末 X 射线衍射和热重分析相结合的方法，研究了甲醇和乙腈溶剂化物的过程诱导去溶剂化机制。两种溶剂化物的结构变化都遵循一个复杂的分子水平轨迹，其特征是在首先出现去溶剂化相的温度以下几度处晶格参数突然发生变化。在等温加热条件下获得的动力学数据的模型拟合表明，去溶剂化过程受到无溶剂产物成核的速率限制。在这些体系中确定的去溶剂化途径与之前对 NCL 通道水合物的研究形成对比，在之前的研究中，水通过扩散损失首先产生无水同构物，然后在更高的温度下转化为热力学多晶型物。从每个溶剂化物晶格都是独特的“预组织”前体的角度来看，比较不同起始拓扑结构到相同最终产物的途径，为重新评估各种因素（例如溶剂结合强度、密度）如何影响固态去溶剂化过程提供了机会。
