Analytical quality by design approach versus conventional approach: Development of HPLC-DAD method for simultaneous determination of etizolam and propranolol hydrochloride

Abstract

Considering the importance of robust analytics in the pharmaceutical industry, an analytical quality by design (AQbD) based reversed phase liquid chromatographic method was developed for the quantification of propranolol hydrochloride (PRO) and etizolam (ETZ). The developed method was validated and compared with an analytical method of conventional approach. In AQbD approach, analytical target profile (ATP) and risk assessment were tailored to identify critical method variables (CMVs) as inputs. Accordingly, pH (X1) % aqueous composition (X2), flow rate (X3) and % triethylamine (X4) were identified as CMVs and the respective retention time (Y1 and Y2) and theoretical plate (Y3 and Y4) for PRO and ETZ were set as method responses. The central composite design (CCD) predicted the scientific relationship between CMVs (Xn) and method responses (Yn). Then, the method operable design region (MODR) was arrived from systematic simulation and contour plots. There were six candidate methods selected from MODR and they demonstrated the r 2 value > 0.9, thus the model proved its consistency for prediction. The robust range for the selected CMVs was derived from MODR, thus the ranges were 3–4 for pH, 30–35 for % aqueous composition, 0.9–1.1 mL min−1 for flow rate and 0.1–0.2 for % TEA buffer. Finally, the target AQbD method was optimized with pH; 3.5 (X1), 30% of aqueous composition in mobile phase with acetonitrile (X2), 0.9 mL min−1 of flow rate of (X3) and 0. 15% trimethylamine as buffer (X4) and further validated as per ICH Q2 guidelines. The result was compared with the conventional LC method with respect to specificity, accuracy, precision and robustness. The conventional HPLC method failed for robustness and showed relatively higher % RSD values than AQbD method.