Yu Junguang, Henry Rodger F, Zhang Geoff G Z
School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, United States; Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States.
Structural Chemistry, Research and Development, AbbVie Inc., North Chicago, IL, 60064, United States.
J Pharm Sci. 2025 Jan;114(1):592-598. doi: 10.1016/j.xphs.2024.10.046. Epub 2024 Oct 28.
The rapid and efficient cocrystal screening, based on solution-mediated phase transformation (SMPT), was applied to the screening of cocrystals between ketoconazole (KTZ) and nine aliphatic dicarboxylic acids. Cocrystals formed successfully, in minutes, with a change of suspension characteristics, either a cake formation or the formation of large particles. Bulk cocrystals were characterized by powder X-ray diffraction, thermal analysis, and Raman spectroscopy. Single crystals were grown, and molecular structures were determined. Three previously reported cocrystals were reproduced, and six new cocrystals were discovered, including one that was reported as a failure in literature by solution or grinding method. Two hydrogen-bonded motifs are observed in these nine cocrystals: Most cocrystals form hydrogen bonded discrete tetramer with two KTZ and two acids molecules; while two cocrystals form infinite chain. This study demonstrated the high efficacy of cocrystal generation using the slurry screening method. It should be fully utilized in future cocrystal screening.
基于溶液介导的相变（SMPT）的快速高效共晶体筛选方法，被应用于酮康唑（KTZ）与九种脂肪族二元羧酸之间共晶体的筛选。几分钟内就成功形成了共晶体，悬浮特性发生了变化，要么形成块状物，要么形成大颗粒。通过粉末X射线衍射、热分析和拉曼光谱对大量共晶体进行了表征。生长出了单晶，并确定了分子结构。重现了三种先前报道的共晶体，发现了六种新的共晶体，其中包括一种在文献中通过溶液法或研磨法报道为未能形成的共晶体。在这九种共晶体中观察到两种氢键基序：大多数共晶体与两个KTZ分子和两个酸分子形成氢键离散四聚体；而两种共晶体形成无限链。本研究证明了使用浆料筛选法生成共晶体的高效性。在未来的共晶体筛选中应充分利用该方法。
