Comprehensive review on impurity profiling, control strategies and analytical methods of Baloxavir Marboxil and Baloxavir acid

Baloxavir Marboxil (BXM) is a novel antiviral drug primarily used for the treatment of influenza A and B. This comprehensive review provides a detailed exploration of the regulatory status of BXM and its active form, Baloxavir Acid (BXA), along with impurity profiling studies and current regulatory control strategies for the related organic impurities. Efforts have been made to review the literature findings and analytical advancements over the past two decades. This write-up discusses metabolites, degradation products, stereoisomers, process-related impurities, and stable isotopes of BXM and BXA. A total of five metabolites, twelve degradation products, fourteen chiral compounds (including diastereomers and enantiomers), forty process-related impurities (including starting materials, intermediates, and by-products), and five stable isotopes were identified from the literature. Additionally, this review work reveals the metabolic pathways of five active metabolites reported under USFDA guidance and investigates their degradation mechanisms under stress-testing conditions, including hydrolysis, oxidation, photolysis, heat, and humidity. A wide range of analytical methods reported in literature for the assay and organic related impurities testing are evaluated, including spectroscopic methods, liquid chromatography, and hyphenated techniques such as liquid chromatography–mass spectrometry. Furthermore, regulatory guidelines related to the control of organic impurities and assay specification limits are discussed. This comprehensive review serves as an essential reference for emerging researchers engaged in the development of stability-indicating analytical methods, the identification of newly formed degradation products and impurities, and the quantitative estimation the organic impurities of BXM and BXA, thereby supporting drug product development and enhancing the quality, safety, and efficacy of pharmaceutical medications.