A chaotropic agent-assisted, AQbD-guided RP-HPLC method for the simultaneous determination of rosuvastatin, atorvastatin, and ezetimibe: a rapid, robust, and green approach

The simultaneous determination of rosuvastatin, atorvastatin, and ezetimibe in pharmaceutical formulations is challenging due to their distinct physicochemical properties. This study details the development and validation of a rapid, robust, and stability-indicating reversed-phase high-performance liquid chromatography method, guided by Analytical Quality by Design, with a focus on method robustness and environmental sustainability.Critical method parameters —potassium hexafluorophosphate (KPF₆) concentration, column temperature, and acetonitrile fraction—were systematically optimized using a Box-Behnken design and response surface methodology. The optimized conditions comprised a 0.2 mM KPF₆ aqueous buffer, a column temperature of 48 °C, and a 60% acetonitrile mobile phase. Under these conditions, efficient separation of rosuvastatin, atorvastatin, and ezetimibe was achieved, with a retention time of 2.29 min for the most lipophilic analyte, atorvastatin. The method demonstrated excellent linearity (r² ≥ 0.996) over 12.0–50.0 µg/mL, high accuracy (98–102% recovery), and precision (%RSD < 2%). Greenness and sustainability were quantitatively confirmed using AGREE (0.61), MoGAPI (75), AGSA (63.89), CACI (70), CaFRI (72), and BAGI (80.0) metrics. This Analytical Quality by Design -guided RP-HPLC method is rapid, reliable, robust, and environmentally favorable, making it highly suitable for routine quality control of pharmaceutical formulations containing rosuvastatin, atorvastatin, and ezetimibe.