Leveraging Green Chromatography in Quality-by-Design-Driven Study for the Simultaneous Analysis of Essential Single-Pill Antidiabetic Drug Combinations

Micellar liquid chromatography (MLC) has proven beneficial efficiency and ecological impact for routine quality control activities. In the proposed study, cyrene was investigated for the first time, together with other green additives, as a novel safe organic solvent in reversed-phase MLC. Quality-by-design (QbD) approach screened their effect on the separation performance. Six antidiabetic drugs from different classes, namely, metformin (MTF), empagliflozin (EMP), ertugliflozin (ERT), linagliptin (LNT), sitagliptin (SIT), and gliclazide (GCZ) were utilized to assess some newly approved antidiabetic drugs and combinations. An organic solvent-free mobile phase consisting of (0.01 M Brij-35, 0.09 M sodium dodecyl sulfate, and 0.01 M ammonium acetate, pH 5.0) separated the studied drugs using an RP-C18 core–shell column. The flow rate was set at 1.2 mL/min, and analytes were detected using a photodiode array detector at 245, 270, and 225 nm. System suitability parameters demonstrated MLC capability to eliminate organic solvents without compromising separation efficiency. The method was validated across a concentration range of 2.0–30.0 µg/mL for EMP, ERT, and LNT, 20.0–120.0 µg/mL for GCZ and SIT, and 100.0–600.0 µg/mL for MTF. The method successfully determined analytes in different single and multicomponent tablets. Greenness assessment was performed using MoGAPI and AGREE metrics.