Impurity Profiling, Structural Reactivity and Stability Challenges of Fosfomycin: A Critical Review With Emphasis on Epoxide Integrity as a Quality Determinant

Fosfomycin is a structurally unique phosphonic acid antibiotic widely used for the treatment of urinary tract infections (UTIs), particularly those caused by multidrug-resistant (MDR) pathogens. Unlike conventional β-lactam or glycopeptide antibiotics, fosfomycin exerts bactericidal action through irreversible inhibition of MurA enzyme ((UDP-N-acetylglucosamine enolpyruvyl transferase) via its strained epoxide ring. While its small molecular size and high aqueous solubility offer formulation advantages, the molecule’s inherent chemical reactivity presents significant stability and impurity-related challenges. The integrity of the epoxide moiety is directly linked to therapeutic activity, making impurity profiling a critical quality attribute (CQA).