Solubility of letrozole in eight pure and five mixed solvents: Measurement, thermodynamic and molecular simulation analysis

In this work, the solubility of letrozole within eight single and five binary solvents was first systematically investigated at 283.15 K to 323.15 K via the gravimetric method. Subsequently, four thermodynamics formulas including modified Apelblat, λh, GSM and Jouyban-Acree were utilized to link the experimental outcomes of letrozole, all models achieved the good fitting performance and the ARD% was less than 2 %. The dissolvability of letrozole in chosen solvents exhibited a positive correlation with temperature, and co-solvency was observed in such mixed solvent systems as ethyl acetate + 1-propanol, and acetonitrile + 1-propanol. Furthermore, the sites of hydrogen bonding donor and acceptor of letrozole and solvents were analyzed through the molecular electrostatic potential surfaces (MEPs). Then solvent effect, solvation free energy and radial distribution function (RDF) analysis gained via molecular simulation were utilized to illuminate experimental phenomena, the outcomes manifested the polarity, cohesive energy density and other properties of solvents along with both solvent–solvent and solute–solvent interactions contributed differently to the dissolution processes. In the end, the apparent thermodynamic identities concerning letrozole within chosen solvent systems were computed under the van’t Hoff and Gibbs formulas, and outcomes showed that dissolution concerning letrozole was a procedure of endothermic and entropy mainly driven.