Revealing water structure modification by a sodium–glucose cotransporter-2 inhibitor-type antidiabetic drug with <scp>d</scp>-(+)-glucose in aqueous media

In this work, volumetric, acoustic, viscometric, and photon correlation spectroscopic studies of an antidiabetic drug, ertugliflozin L-pyroglutamic acid (E.L-PGA) have been performed in aqueous medium in absence and presence of D-(+)-glucose. E.L-PGA serves as a structure-maker at intermediate concentrations (<i>ca.</i> 2.0 × 10^-4 mol kg^-1) while as a structure-breaker at low ((0.5-2.0) × 10^-4 mol kg^-1) and high ((2.0-3.5) × 10^-4 mol kg^-1) concentrations. The volumetric pairwise interaction coefficient, <i>S</i>_v, is negative (-330 to -760) corresponding to stronger solute-solvent interactions. Structure-making occurs at low (290-305 K) and high (305-330 K) temperatures but structure-breaking occurs at intermediate (<i>ca.</i> 305 K) temperatures. The hydrodynamic diameter (<i>D</i>_h) of the aggregates ranges from 200 to <i>ca.</i> 500 nm at 0.4456 × 10^-4 mol kg^-1 of E.L-PGA. A breaking-making-breaking nature of the water structure is observed with increasing concentrations of D-(+)-glucose in E.L-PGA-D-(+)-glucose-water systems. The <i>S</i>_v varies from 30 to 40 due to stronger solute-solute interactions. A small amount of D-(+)-glucose (up to 10.0 × 10^-3 mol kg^-1) causes water structure breaking and further addition helps to add water molecules around E.L-PGA. In a ternary system of 0.8993 × 10^-4 mol kg^-1 of E.L-PGA, 5.6533 × 10^-3 mol kg^-1 of D-(+)-glucose, and water, the <i>D</i>_h of the clusters is in the range of 400-1000 nm. For both binary and ternary systems, Δ<i>G</i>, Δ<i>H</i>, and Δ<i>S</i> vary from 8.4 to 9.2 kJ mol^-1, 12 to 17 kJ mol^-1, and 12 to 26 J mol^-1, respectively. These results offer valuable insights into the molecular-level interactions of E.L-PGA with D-(+)-glucose under different perturbations and help understand pharmacological action and potential contraindications to open new avenues for the development of efficacious antidiabetic drugs.