Analytical method development, validation for the estimation of brivaracetam in bulk drug substance by RP-HPLC and identification of its major degradation product: a quality by design approach

Background The research involved a systematic and proactive approach, integrating quality considerations throughout the product lifecycle, from initial conception to final production. A design space was established by thoroughly examining these relationships, ensuring the product consistently meets desired quality standards. Objective This study employed an approach of Quality by Design (AQbD) strategy for developing and validating stability-indicating method for the estimation of brivaracetam in bulk drug substance via RP-HPLC, including characterizing its major degradation products. Methods The analytical separation was performed using a Waters Alliance HPLC system, equipped with an X-Terra RP18 column (250 × 4.6 mm, 5 µm), and a gradient elution technique with mobile phases A (0.1% w/v perchloric acid in water) and B (water: acetonitrile, 10:90, v/v) at a flow rate of 1.2 mL/min, resulting in a retention time of about 16.8 min. Results The major degradation product was identified as (S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanoic acid, with a retention time of 23.6 min, significantly different from brivaracetam. The percentage of degradation in acid conditions was found to be 10%. The method demonstrated high accuracy, with recovery rates between 99.7% and 100.4%. The %RSD value for the method and intermediate precision was 0.2% and 0.3%, respectively. Conclusions The Approach Quality by Design (AQbD) methodology enabled a comprehensive understanding of the factors influencing chromatographic separation, enhancing assurance in the established HPLC method’s capacity to fulfill its intended objectives.