Study on the liquid–liquid phase separation phenomenon of iohexol in a binary mixed solvent of methanol and n-butanol: Thermodynamic behavior and molecular dynamics calculation

Abstract

The impact of oiling-out on the control of the crystallization purification process during iohexol crystallization is significant. Thus, the solubility of iohexol and its oiling-out behavior in a binary solvent mixture of methanol and n-butanol was investigated in this study. The solubility was determined using the equilibrium method at temperatures ranging from 273.15 K to 303.15 K under atmospheric pressure, revealing that solubility increases with temperature and methanol concentration. Four models were employed to model the solubility data, with the CNIBS/R-K model demonstrating the highest correlation. The van't Hoff equation was utilized to calculate the thermodynamic properties, the result indicating that enthalpy predominates in the dissolution process. Furthermore, ternary phase diagrams were constructed to elucidate the nucleation mechanism of iohexol, identifying nucleation sites and performing kinetic simulations from a molecular perspective. These analyses indicated that lower temperatures are favor the control of oiling-out phenomena. The nucleation of iohexol is characterized by a two-step mechanism, initiating with liquid–liquid separation, followed by nucleation and crystal growth. Solubility parameters, derived using Materials Studio, suggest enhanced interactions between iohexol and methanol, which is also corroborated by the solvation energy data from Gaussian software. This interaction explains the tendency of iohexol to oiling out in mixed solvents. Radial distribution function (RDF) analysis illustrates that methanol-iohexol interactions intensify prior to oiling-out, reach a peak during oiling-out, and diminish after nucleation due to desolvation. The occurrence of oiling-out can lead to challenges such as diminished product quality, reduced yields, and difficulties in reprocessing. Therefore, understanding the mechanism of oiling-out is fundamental to addressing these issues, rendering these insights invaluable for the study of crystallization processes and oiling out phenomena in other small organic molecules.