Impact of antioxidant excipients on N-nitrosamine formation and bioequivalence in metformin formulations (review article).

The discovery of N-nitrosamine impurities in pharmaceutical products has raised serious quality concerns, particularly in metformin products, which are widely used in the treatment of type 2 diabetes mellitus. The detection of N-nitrosodimethylamine (NDMA) in metformin products has led to global recalls and increased regulatory investigations. Generic manufacturers face the challenge of balancing stringent bioequivalence requirements for Biopharmaceutical Classification System (BCS) Class III drugs, which require strict control of excipient composition while ensuring N-nitrosamine control and therapeutic equivalence. The use of antioxidants as a strategy to reduce N-nitrosamine formation requires careful consideration to maintain both bioequivalence and product safety. This article evaluates the use of antioxidants for the prevention of N-nitrosamine formation in metformin formulations, addressing the implications of this strategy on bioequivalence and its relationship with the regulatory framework.