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

Abstract

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 (ca. 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, S_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 (ca. 305 K) temperatures. The hydrodynamic diameter (D_h) of the aggregates ranges from 200 to ca. 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 S_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 D_h of the clusters is in the range of 400–1000 nm. For both binary and ternary systems, ΔG, ΔH, and ΔS 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.