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

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 ?h, 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.

SUBMITTER: Ravi M

PROVIDER: S-EPMC7828412 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Ravi Maharjan M Julu Tripathi T Kim Nam Ah NA Park Kyeung Eui KE Jeong Seong Hoon SH

Molecules (Basel, Switzerland) 20210113 2

The solubility and dissolution thermodynamics of new c-Met inhibitor, ABN401, were determined in eleven solvents and Transcutol<sup>®</sup> 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 <i>λh</i>, Yalkowsky, and Jouyban-Acree van't Hoff models. The experimental results were correlated and utilized further to investigate the feasibility of nanosuspension format ...[more]

PMID: 33450987

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Project description:BackgroundEfavirenz nanosuspensions (EZ-NSs) were developed by the wet milling method as the most promising top-down nanosizing technique. Different process and formulation parameters were studied and optimized to produce appropriate EZ-NS in suitable conditions to enhance drug dissolution.MethodsIn the preliminary studies, various polymeric stabilizers, including Pluronic F68, sodium carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), and polyvinyl alcohol (PVA), as well as different sizes and weight of milling beads were used to prepare NSs. The effect of sodium lauryl sulfate (SLS) concentration on the NS properties was also evaluated. The influence of other formulation and process parameters, including polymer concentration, milling speed, and milling time, on the particle size and distribution of NSs were investigated using Box-Behnken design. The optimized freeze-dried nanosuspension was characterized by redispersibility, physicochemical properties, and stability.ResultsA combination of PVA and SLS was selected as steric and electrostatic stabilizers. The optimum EZ-NS displayed a uniform size distribution with a mean particle size and zeta potential of 254.4 nm and 21.1 mV, respectively. The solidified nanosuspension was well redispersed to the original nanoparticles. Significantly enhanced aqueous solubility (about 11-fold) and accelerated dissolution rate were observed for the optimized formulation. This could be attributed to the reduced particle size and partial amorphization of EZ during the preparation process, studied by X-ray diffraction. Accelerated studies confirmed the stability of the optimum freeze-dried formulation over the examined period of three months.ConclusionsOptimization of different variables led to the formation of EZ-NSs with desired properties through wet milling in a very short time compared to the previous study and therefore reduced production costs. This formulation seems to be a suitable approach for solubility and dissolution enhancement of EZ and may have a great potential to improve the drug's oral bioavailability.

Dataset Information

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

Publications

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

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