Understanding Solute-Hydrotrope Aggregation in Aqueous Solutions: A Molecular Dynamics Approach

Hydrotropy is a phenomenon where an amphiphilic molecule (i.e., the hydrotrope) is able to enhance the aqueous solubility of a hydrophobic solute. Understanding the molecular mechanisms behind this phenomenon is crucial to designing new hydrotropes aimed at enhancing the aqueous solubility of specific target solutes. This study investigates the hydrotropic behavior of 1,2-alkanediols in enhancing the aqueous solubility of syringic acid using molecular dynamics (MD) simulations. The analysis carried out here employs several computational methods, including Kirkwood-Buff integrals, solvation free energies, radial distribution functions, and hydrogen bonding number. The solvation free energy results reported in this work help explain the thermodynamic favorability of syringic acid solubilization in the presence of 1,2-alkanediols, aligning with experimental trends. In addition, MD simulations reveal a pronounced affinity between syringic acid and 1,2-alkanediols, particularly at low hydrotrope concentrations. This high affinity is driven by the alkyl chain of each hydrotrope when water is the main solvent, resulting in an increase in the solubility of the solute as the length of the hydrotrope alkyl chain increases. However, a shift in the solubilization mechanism is seen when water is no longer the main solvent, with the hydrogen bonding capabilities of the hydrotrope playing a larger role than its alkyl chains. Under low water concentration conditions, longer alkyl chains in the hydrotrope have difficulty forming hydrogen bonds, leading to an opposite trend compared to lower hydrotrope concentrations. This different behavior with composition results in a maximum solubility for systems with long alkyl chains at intermediate hydrotrope concentrations.