Hydrotropic Action of Cationic Hydrotrope p-Toluidinium Chloride on the Solubility of Sparingly Soluble Gliclazide Drug Molecule: A Computational Study

Abstract

We perform classical molecular dynamics simulations of sparingly soluble drug gliclazide (GLC) and hydrotrope p-toluidinium chloride (PTOL) in water with a regime of PTOL concentrations. Our results demonstrate that PTOL starts to self-aggregate above its minimum hydrotrope concentration (MHC). Further, these PTOL aggregates create a mixed micellar-like framework in which the hydrophobic small tail part of most of the PTOL molecules direct toward the inside, whereas in order to make favorable contact with water molecules its hydrophilic ammonium group points outward. But, in order to make hydrogen bonds with GLC molecules, the polar groups of a few of the hydrotropes direct inward also. This provides an environment for the incorporation of the drug molecules into the mixed environment (hydrophobic as well as hydrophilic core) of PTOL clusters. The average number of hydrogen bond calculations indicates that PTOL aggregate does not have much effect on the average number of water-PTOL hydrogen bonds, but it has an influence on the average number of water-GLC, GLC-GLC, and GLC-PTOL hydrogen bonds. Both electrostatic and van der Waals energy components of drug and hydrotrope interactions play vital roles in the solubilization process. Furthermore, the estimation of Flory-Huggins interaction parameters also suggests favorable interactions between hydrotrope PTOL and GLC drug molecules.