Strategies for stabilizing formulation and QbD assisted development of robust stability indicating method of azilsartan medoxomil/chlorthalidone

•AZM/CLT hydrolytic degradation pathways related to product instability issue were studied.•Triggers of instability during formulation and analysis were identified and avoided.•With central composite design four chromatographic factors were optimized.•Multi-criterion responses were handled by desirability function.•Robust stability Indicating method was developed and validated. Reasons for formulation instability were investigated either encountered during production or analytical processes of azilsartan medoxomil (AZM)/chlorthalidone hydrochloride (CLT) tablets. Through the identification of the most feasible degradation pathways, several strategies were proposed to enhance the stability of AZM/CLT formulation. Furthermore, a robust HPLC-UV method was developed and validated for the determination of AZM, CLT in the presence of their possible degradation products. For chromatographic method development, typical quality by design (QbD) approach was implemented. In order to optimize fourteen chromatographic responses, we have used a central composite design with four factors (pH, temperature, flow rate, and acetonitrile %). However, the developed method provides a design space, but optimum parameters were Inertsil C8 column (150 x 4.6 mm, 5 μm), mobile phase composed of 0.025 M phosphate buffer pH 2.7 and acetonitrile (52.5: 47.5%), with flow rate of 1.5 mL.min−1 and detection wavelength 225 nm at 33 °C. The method was then validated according to ICH guidelines and applied to quantitate AZM and CLT in the pharmaceutical formulation. To the best of our knowledge, this manuscript is the first attempt to discuss such instability issues, to propose strategies that enhance the stability of AZM/CLT tablet formulation, to develop robust stability-indicating method taking into consideration the realistic degradation products in addition to minor ones.