<p>The present research work is an application of Quality-based Design (QbD) approach for the development of sensitive and selective stability indicating chromatographic methods for the simultaneous estimation of AXS-05 in its synthetic mixture. The combination is in the clinical trial, so the complete work was performed in the synthetic mixture. Fractional factorial design was used to optimize the chromatographic conditions for HPLC method for the synthetic mixture. The optimized method for the combination produced sharp peaks with good resolution (&gt; 2). Method development for the combination is validated by RP-HPLC (QbD approach). Accuracy, precision, linearity, LOD, LOQ, repeatability, reproducibility and percentage recovery are complied with ICH guidelines. Forced degradation study for the synthetic mixture of the combination is performed. Synthetic mixture was treated for acid hydrolysis, base hydrolysis, oxidative stress and thermal stress. Percentage degradation obtained was within the limit, and all the results were complied with ICH guideline. The proposed method is found to be simple, sensitive, economical, precise and robust and can be applicable to the routine analysis of the selected combination.</p>