Parallel stacking of caffeine with riboflavin in aqueous solutions: The potential mechanism for hydrotropic solubilization of riboflavin

Hydrotropy is a phenomenon where the presence of a large quantity of one solute enhances the solubility of another solute. The mechanism of this phenomenon remains elusive and a topic of debate. This study employed molecular dynamics simulation to investigate solute interactions of a model system consisting of a hydrotropic agent, caffeine (CAF), a poorly water-soluble solute, riboflavin (RBF), and water. The study demonstrates that CAF and RBF undergo molecular parallel stacking in the aqueous solution, a result correlating closely to the self-stacking of CAF under the same conditions. The correlations are found both structurally and dynamically, suggesting that the self-stacking of CAF is the primary effect, and incorporation of RBF is the secondary effect. The solute stacking gives rise to the partitioning of solutes and water, which helps restoring the normal water structure and drives down the system energy. The interactions between the solutes are found insignificant to the solute clustering. The dynamic data confirm that the solute stacks are dynamically active. These results suggest that hydrotropic effect of CAF may be attributed to solute parallel stacking.