Department of Chemical Engineering, University of Chemistry and Technology, Technická 3, 166 28 Prague 6 - Dejvice, Czech Republic.
Department of Chemical Engineering, University of Chemistry and Technology, Technická 3, 166 28 Prague 6 - Dejvice, Czech Republic; Department of Structure Analysis, Institute of Physics of the Czech Academy of Sciences, Na Slovance 1999/2, 182 00 Praha 8, Czech Republic.
Int J Pharm. 2022 Jun 25;622:121854. doi: 10.1016/j.ijpharm.2022.121854. Epub 2022 May 25.
The aim of this study was to improve rivaroxaban water-solubility by cocrystal preparation and to understand this process. The screening with water-soluble coformers was performed via both mechanochemical and solution-mediated techniques. Two cocrystals of rivaroxaban with malonic acid and oxalic acid were prepared, and the structure of the cocrystal with oxalic acid was solved. Both cocrystals exhibit improved dissolution properties. The mechanism of the supersaturation maintenance was studied by in-situ Raman spectroscopy. The transformation into rivaroxaban dihydrate was identified as the critical step in the improved dissolution properties of both cocrystals. Moreover, the transformation kinetics and solubilization effects of the coformers were identified as responsible for the differences in the dissolution behavior of the cocrystals. In-vivo experiments proved that the use of cocrystal instead of form I of free API helped to increase the bioavailability ofrivaroxaban.
本研究旨在通过共晶制备来提高利伐沙班的水溶性，并深入了解这一过程。采用机械化学和溶液介导技术对水溶性共晶试剂进行筛选。制备了利伐沙班与丙二酸和草酸的两种共晶，并解析了草酸共晶的结构。两种共晶均表现出改善的溶解性能。通过原位拉曼光谱研究了过饱和度维持的机制。发现向利伐沙班二水合物的转化是两种共晶改善溶解性能的关键步骤。此外，共晶试剂的转化动力学和增溶作用被确定为影响共晶溶解行为差异的原因。体内实验证明，使用共晶代替游离 API 的 I 型晶有助于提高利伐沙班的生物利用度。
