Influence mechanism of different organic solvents on API solvation behaviors: Molecular dynamics simulations

Abstract

Solubilities of active pharmaceutical ingredients (APIs) in different solvents are important fundamental properties and are of particular interest in purification (e.g. crystallization) of APIs in industry. Therefore, the objective of this work is to investigate the solvation mechanisms of the poorly soluble API ibuprofen in various organic solvents, by using molecular dynamics (MD) simulations. It was found that the solvation performance of ibuprofen in protic solvents mainly depend on van der Waals interaction, while that in aprotic solvents mainly depend on the ability of forming hydrogen bond (H-bond) of the solvents. Wherein, the strength of H-bond between ibuprofen and protic solvents mainly depends on the hydrogen bond donor (HBD) of the solvent, while hydrogen bond acceptor (HBA) ability of solvents directly determines the strength of H-bond between ibuprofen and aprotic solvents. This difference nature in solvation mechanism was due to the structural properties of protic solvents and aprotic solvents. Among them, protic solvents containing hydroxyl group have strong HBD and HBA characteristics, whereas aprotic solvents only show the characteristics of HBA, because it does not contain active hydrogen protons. In general, the MD simulation results revealed that the better solvation performance of ibuprofen in organic solvents corresponds to the higher polarizability of protic solvents or the stronger HBA ability of aprotic solvents. This work is expected to provide theoretical guidance for choosing appropriate solvents during API preparation and development.