Implication of Ionic Liquids in Empagliflozin-Isonicotinic acid Eutectic System: Mechanochemical Synthesis, Characterisation and Performance Attributes

Abstract

Pharmaceutical eutectic mixtures offer promising effects in enhancing the physicochemical properties of drug molecules. Development of eutectic mixtures by mechanochemical synthesis is a sustainable and eco-friendly approach. Recently, ionic liquid-assisted grinding (ILAG) has gained popularity due to its sustainable alternative to conventional organic solvents, aligning with the principles of green chemistry. Empagliflozin (EPG) is a sodium-glucose co-transporter-2 inhibitor, used in the treatment of type 2 diabetes mellitus. However, low solubility and poor permeability resulted in compromised biopharmaceutical attributes. In the present work, a eutectic mixture of EPG with isonicotinic acid (INA) has been developed in 1:1 stoichiometry mechanochemically by employing two approaches, viz., liquid-assisted grinding (LAG) & ILAG. Developed eutectic mixtures (EINA & ENA-IL) have been confirmed by PXRD and DSC, while quantitative phase analysis (QPA) was employed to confirm the weight fractions of binary components in eutectic mixtures. However, there was a greater depression in the melting point observed in EINA-IL, which is ascribed to the greater miscibility among the binary components in the presence of ionic liquid (1-Ethyl-3-methylimidazolium Tetrafluoroborate) and was supported by FESEM and FTIR investigation. EINA-IL showed notable enhancement in solubility (7 – 11 folds) and intrinsic drug release (4.9-fold) over EINA and EPG. This improvement of EINA-IL was rationalised with greater miscibility of binary components in the presence of IL and differential surface anisotropy, thereby facilitating improved dissolution rate. However, there was relatively lesser membrane permeability improvement in EINA-IL over EINA, which is ascribed to the stronger molecular interactions in the solution phase, as confirmed by 1H NMR spectroscopy, thereby diminishing the passive diffusion. Therefore, the study highlights the role of ILs in tuning the performance attributes (solubility, release profile, and membrane diffusion) of a eutectic mixture between EPG & INA, and can be explored in the solid form screening workflow of other pharmaceuticals.