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

Abstract

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.