Abstract
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 λh, 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.
Highlights
ABN401, (Figure 1, 4-[5-[4-[(4-Methylpiperazin-1-yl)methyl]phenyl]pyrimidin-2-yl]-2[[5-(1-methylpyrazol-4-yl)triazolo[4,5-b]pyrazin-3-yl]methyl]morpholine, PubChem CID118364782, C29 H34 N12 O, molar mass 566.66 g·mol−1 ), is a generation synthetic tyrosine kinase c-Met inhibitor, and showed its therapeutic potential in the treatment of non-small cell lung cancer by patient-derived xenograft model [1]
The solubility of the drug was determined in eleven solvents and in Transcutol® HP–water mixture (TWM) mixture using a static equilibrium method and correlated with various models, and modified
The solubility of the drug increased with an increase in temperature for all solvents including the TWM mixture
Summary
Because of its low toxicity, enhanced solubilizing capacity, physiological compatibility, and being listed as excipient in the United States pharmacopoeia national formulary (USP NF), its application in pharmaceutical, cosmeceutical, and nutraceutical field is expanding [32,34] It can be added as a co-solvent in the aqueous mixture to increase the solubility of drugs, which is very important in developing liquid based formulation [29,30,31]. Based on the solubility data of ABN401 on various solvents, the least soluble (water) and the most soluble (THP) solvents were chosen to develop a stable nanosuspension using liquid anti-solvent precipitation [29,34,36] It was a combination process of precipitation followed by microfluidization or ultrasonication. It resulted in nanocrystals, termed as nanosuspension, and their various properties including dissolution profile, particle size, and stability were evaluated
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