BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Gyeonggi 10326, Korea.
R&D Center, ABION Inc., Seoul 08394, Korea.
Molecules. 2021 Jan 13;26(2):390. doi: 10.3390/molecules26020390.
The solubility and dissolution thermodynamics of new c-Met inhibitor, ABN401, were determined in eleven solvents and Transcutol HP-water mixture (TWM) from 298.15 to 318.15 K. The experimental solubilities were validated using five mathematical models, namely modified Apelblat, van't Hoff, Buchowski-Ksiazaczak , Yalkowsky, and Jouyban-Acree van't Hoff models. The experimental results were correlated and utilized further to investigate the feasibility of nanosuspension formation using liquid anti-solvent precipitation. Thermodynamic solubility of ABN401 increased significantly with the increase in temperature and maximum solubility was obtained with Transcutol HP while low solubility in was obtained water. An activity coefficient study indicated that high molecular interaction was observed in ABN401-Transcutol HP (THP). The solubility increased proportionately as the mole fraction of Transcutol HP increased in TWM, which was also supported by a solvent effect study. The result suggested endothermic and entropy-driven dissolution. Based on the solubility, nanosuspension was designed with Transcutol HP as solvent, and water as anti-solvent. The mean particle size of nanosuspension decreased to 43.05 nm when the mole fraction of ABN401 in THP, and mole fraction of ABN401 in TWM mixture were decreased to 0.04 and 0.1. The ultrasonicated nanosuspension appeared to give comparatively higher dissolution than micronized nanosuspension and provide a candidate formulation for in vivo purposes.
新型 c-Met 抑制剂 ABN401 在 11 种溶剂和 Transcutol HP-水混合物（TWM）中的溶解度和溶解热力学从 298.15 至 318.15 K 进行了测定。实验溶解度用五种数学模型进行了验证，即修正的 Apelblat、van't Hoff、Buchowski-Ksiazaczak、Yalkowsky 和 Jouyban-Acree van't Hoff 模型。实验结果进行了关联，并进一步用于研究使用液体反溶剂沉淀形成纳米悬浮液的可行性。ABN401 的热力学溶解度随温度的升高而显著增加，在 Transcutol HP 中获得最大溶解度，而在水中溶解度较低。活度系数研究表明，ABN401-Transcutol HP（THP）中观察到高分子相互作用。在 TWM 中，随着 Transcutol HP 摩尔分数的增加，溶解度按比例增加，这也得到溶剂效应研究的支持。结果表明溶解是吸热和熵驱动的。基于溶解度，以 Transcutol HP 为溶剂，水为反溶剂设计了纳米混悬液。当 THP 中 ABN401 的摩尔分数和 TWM 混合物中 ABN401 的摩尔分数分别降至 0.04 和 0.1 时，纳米混悬液的平均粒径降至 43.05nm。超声纳米混悬液的溶解速度似乎比微米化纳米混悬液高，可为体内应用提供候选制剂。
