Implementation of DoE and Risk-Based Enhanced Analytical Quality by Design Approach to Stability-Indicating RP-HPLC Method for Stability Study of Bosutinib

Background: Bosutinib is a small-molecule BCR-ABL and Src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia. According to published literature, no stability-indicating reversed-phase (RP)-HPLC method has been reported for the estimation of bosutinib. Objective: A stability-indicating RP-HPLC method has been developed for the stability study of bosutinib, using a risk- and design of experiments (DoE)-based enhanced analytical quality by design (AQbD) approach. Method: The risk-based AQbD approach was applied by risk parameter identification and risk assessment by risk priority number (RPN) ranking and filtering, as per International Conference on Harmonization (ICH) Q9 guidelines. The DoE-based AQbD approach was implemented by response surface analysis using a central composite design. The risks of critical method risk parameters were mitigated by navigation of design space and framing of control strategy. Results: Chromatographic separation was performed using a C18 column and acetonitrile-1.0% triethylamine (v/v) in water (pH 7.0, adjusted by ortho-phosphoric acid). The developed method was validated according to ICH Q2 (R1). The developed and validated method was applied for the assay of bosutinib in pharmaceutical dosage forms. The developed method was extended for an oxidative degradation kinetic study of bosutinib at different pH conditions. Conclusions: The developed RP-HPLC method can be used as an analytical tool for quality control and stability studies of pharmaceutical dosage forms of bosutinib in the pharmaceutical industry. Highlights: The development and validation of a stability-indicating RP-HPLC method for the estimation of bosutinib by implementation of a DoE- and risk-based enhanced AQbD approach. The method was applied to assay pharmaceutical dosage forms and in an oxidative degradation kinetic study.