Development and validation of a green RP-HPLC method for simultaneous estimation of paracetamol and caffeine in tablets using quality by design approach and ICH guidelines

Abstract This study describes the development and validation of a green, robust reverse-phase high-performance liquid chromatography (RP-HPLC) method for the simultaneous estimation of Paracetamol and Caffeine in combined tablet dosage form. Method development was carried out using a Quality by Design (QbD) approach, incorporating risk assessment and statistical optimization through a Box–Behnken Design (BBD) to identify critical method parameters. Chromatographic separation was achieved on a C18 column using a mobile phase composed of water (pH 6.5), acetonitrile, and methanol in the ratio of 80:15:5 (v/v/v), with detection at 267 nm using a PDA detector. The optimized method was validated in accordance with ICH Q2(R2) guidelines for specificity, linearity, accuracy, precision, robustness, and system suitability. Retention time of 5.2 min for Paracetamol and 6.8 min for Caffeine indicated good resolution and peak symmetry. Recovery values ranged between 98 and 102%, and %RSD values for system suitability and precision studies were below 2%, confirming method reliability and reproducibility. The proposed method is simple, rapid, cost-effective, and suitable for routine quality control analysis of bulk drugs and marketed pharmaceutical formulations.