Revealing the dissolution behavior of letrozole (form I) in four binary solvent systems: Solubility determination, thermodynamic analysis and molecular simulations

Letrozole is a new aromatase inhibitor with extremely selective, which is widely used in the treatment of advanced postmenopausal breast cancer. This study focused on measuring the solubility of letrozole (form I) in four binary solvent systems (methanol + water, acetone + water, acetonitrile + water, methyl acetate + n-hexane) by the laser dynamic method at 0.1 MPa. The measured temperature ranged between 273.15 K and 323.15 K. It can be observed that when the composition of the binary solvents is constant, the solubility has a positive correlation with temperature. For methanol + water, acetone + water and methyl acetate + n-hexane binary solvent systems, a higher mass fraction of the positive solvent leads to an improvement in solubility. However, in the binary solvent system of acetonitrile + water, the co-solvency phenomena were detected. Five different models were applied to correlate the solubility data. The modified Apelblat equation demonstrated the most accurate fitting performance. The investigation of the Hirshfeld surface uncovered the intermolecular interactions in molecular crystals. For the sake of simulations, the electrostatic potentials (ESP) of the solvent and solute molecules were analyzed. The interactions between solute and solvent, as well as between the solvent and solvent, are crucial in determining the dissolution behavior, as demonstrated by the radial distribution function (RDF) analysis. The calculation of solvation free energy provides us a better insight into the dissolving characteristics of letrozole (form I). Furthermore, the apparent thermodynamic properties of the dissolution process of letrozole (form I) in four binary solvent systems were calculated, which indicates that the dissolution process is entropy-increasing and endothermic. Simple crystallization experiments were carried out, suggesting that acetone + water mixed solvent is the suitable solvent for letrozole anti-solvent crystallization. In summary, fundamental thermodynamic data for the design and optimization of the crystallization processes can be obtained from this study.