Solubility Determination of c-Met Inhibitor in Solvent Mixtures and Mathematical Modeling to Develop Nanosuspension Formulation

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 2; p. 390
• Main Authors: Ravi, Maharjan, Julu, Tripathi, Kim, Nam Ah, Park, Kyeung Eui, Jeong, Seong Hoon
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 13.01.2021; MDPI AG
• Subjects: mathematical models; nanosuspension; precipitation; solubility; thermodynamics; transcutol® HP; thermodynamics; transcutol® HP; precipitation; solubility; nanosuspension; mathematical models
• ISSN: 1420-3049; 1420-3049
• 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.