Abstract
The dissolution behavior of an active pharmaceutical ingredient (API) in different solvents is of great importance for the design and optimization of its crystallization process. In this study, the solubility of letrozole in fourteen pure solvents was determined using a gravimetric method within the temperature range of 283.15–323.15 K at atmospheric pressure. The results demonstrate a significant correlation between letrozole’s dissolution behavior and the molecular structure (carbon chain length and presence of branched chains) and properties (dielectric constant and cohesive energy density) of the solvent. Solubility analysis and simple crystallization experiments suggest that acetonitrile may serve as a suitable solvent for the cooling crystallization of letrozole. To enhance the applicability of solubility data, five mathematical models were employed for data fitting. In addition, the Van’t Hoff equation was utilized to calculate the apparent thermodynamic properties of the letrozole dissolution process. Furthermore, molecular simulations were conducted to investigate the dissolution behavior of letrozole in different solvents, revealing distinct patterns of interaction between solute and solvent molecules. Specifically, in alcohol solvents, alcohol ether solvents, and acetonitrile, solute molecules interact with solvent molecules primarily as hydrogen bond acceptors, whereas the opposite behavior is observed in ester solvents and acetone. Binding energy, radial distribution function (RDF), and coordination number (CN) analyses effectively elucidate the dissolution behavior of letrozole in solvents of the same category, indicating that stronger solute–solvent interactions result in higher solubility. A comprehensive examination of solute–solvent and solvent–solvent interactions offers a rational explanation for letrozole’s dissolution behavior in solvents of different categories, highlighting the decisive impact of solvent–solvent interactions, particularly in alcohol solvents and acetone.
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