Solid-liquid equilibrium of ropivacaine in fourteen organic solvents: An experimental and molecular simulation study

Abstract

The solubility of ropivacaine in fourteen pure solvents at 283.15 K to 323.15 K was determined via the gravimetric method and was well correlated with three thermodynamic models, including the Apelblat, λh, and NRTL models. Among all experimental solvents, the solubility of ropivacaine was found to be highest in pure THF and lowest in acetonitrile. In alcohol solvents, the maximum solubility was observed in amyl alcohol followed by 1-butanol, while the minimum value was observed in 1-propanol. The thermodynamic properties of mixing were calculated based on the NRTL equation, indicating that the mixing processes are spontaneous and entropy-driven. In addition, the crystal structure of ropivacaine was obtained and investigated by Hirshfeld surface analysis and molecular electrostatic potential surface analysis. The physicochemical properties of solvents, such as polarity, cohesive energy density and dielectric constant, were analyzed to explain the solid–liquid behavior of ropivacaine. Finally, a molecular dynamics simulation and radial distribution function analysis were performed. The results indicated that ropivacaine could interact with organic solvents via van der Waals interactions, electrostatic interactions, and hydrogen bonding.