Thermodynamic analysis and molecular dynamic simulation of the solubility of vortioxetine hydrobromide in three binary solvent mixtures

The solubility of Vortioxetine hydrobromide (VORH) in three binary solvent mixtures of butanone + ethanol, butanone + n-propanol, and butanone + n-butanol was determined by the gravimetric method at temperatures ranging from (283.15 to 318.15) K. Surprisingly, the solubility displays a maximum at around 0.3 mol fraction of butanone in all three binary mixed solvents and this solvent composition was found to be independent of temperature. The solubility data was correlated by the modified Apelblat equation, lambda h equation, modified Jouyban-Acree model and NRTL model, and the modified Apelblat equation achieves the best fitting performance. Additionally, thermodynamic functions of mixing were derived, and the results suggest a spontaneous and entropy-driven mixing process. Molecular dynamic (MD) simulation was further employed to investigate solute-solvent and solvent-solvent interactions. Radial distribution function (RDF) analyses reveal that the rank of solute-solvent interactions correlates well with solubility order in binary solvent mixtures. The calculations of solvation free energy further confirm this correlation and the strongest interaction energy obtains at cosolvency composition in binary mixed solvents. Moreover, RDFS of solute-free binary solvent mixtures show that the composition of alcohols could alter the solvent (alcohol)-solvent (butanone) interactions and thereof influence interactions between VORH and butanone molecules in ternary system. The results thus indicate solvent- solvent interactions also play an important role in determining the solubility behavior. Therefore, both solute-solvent and solvent-solvent interactions were concluded to contribute to solubility behavior of VORH in three studied binary solvent mixtures. (C) 2018 Elsevier B.V. All rights reserved.