Molecular simulation and solubilities of (R,S)- and (S)-tetramisole hydrochloride in two binary solvents

Abstract

In this article, the molar fraction solubility of (R,S)- and (S)-tetramisole hydrochloride in two binary solvents (methanol + ethanol and methanol + toluene) was measured by experiments between 283.15 K and 323.15 K. Then four different equations including Apelblat equation, λh equation, GSM equation, Jouyban-Acree equation were applied to connect the measured solubility data of (R,S)- and (S)-tetramisole hydrochloride, where Apelblat equation had the minimum ARD%. The crystal structures together with intermolecular interactions of (R,S)- and (S)-tetramisole hydrochloride were then analyzed. In addition, the infrared spectra were also simulated using dimer configurations. Furthermore, molecular dynamic simulations including radial distribution function (RDF) combined with solvation free energy were performed to explore solvent–solvent interactions along with solute–solvent interactions. The results showed that there was co-solvency in methanol + toluene binary solvent. According to simulation results, both solvent–solvent interactions and solute–solvent interactions played an important role in affecting the solubilities of (R,S)- and (S)-tetramisole hydrochloride. In the end, combining solid state characterization and ternary phase diagrams, (R,S)-tetramisole hydrochloride was determined to be a racemic compound. All the results in this paper can provide theoretical support for enhancing crystallization resolution techniques for chiral drugs.