Molecular Mechanism of the Cosolvency Effect in Organic Solutes with Similar Structures

Cosolvency is an interesting and important solubilization strategy that can be reasonably utilized in the pharmaceutical industry and other industries. However, the molecular mechanism is not well understood. To explore the microscopic mechanism of the cosolvency, two organic small molecules (l-hydroxyproline and d-pipecolic acid) with very similar structures were selected as model compounds. Their solubility in three binary mixed solvents of alcohol + acetone (methanol + acetone, ethanol + acetone, and 1-propanol + acetone) was measured using the isothermal equilibrium method. And it was found that l-hydroxyproline exhibits significant cosolvency behavior while d-pipecolic acid exhibits a general solubility trend. Moreover, molecular dynamics simulation, attenuated total reflection Fourier transform infrared spectrometry, high-resolution mass spectrometry, 1H nuclear magnetic resonance spectra, and other methods were applied to systematically investigate the effects of solute molecular aggregation and interactions on the cosolvency phenomenon. The results indicate that the aggregation form of solute molecules undergoes transformations with changes in solvent composition, accompanied by alterations in solute–solvent interactions, which ultimately lead to the occurrence of cosolvency.