Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite

Since late 2019, concerns regarding trace levels of the probable human carcinogen N-dimethylnitrosamine (NDMA) in Metformin-containing pharmaceuticals have been an issue if they exceeded the maximum allowable intake of 96 ng/day for a medicine with long-term intake. Here, we report results from an extensive analysis of NDMA content along the active pharmaceutical ingredient (API) manufacturing process as well as two different drug product manufacturing processes. Our findings confirm that Metformin API is not a significant source of NDMA found in Metformin pharmaceuticals and that NDMA is created at those steps of the drug product manufacturing that introduce heat and nitrite.

We demonstrate that reduction of nitrite from excipients is an effective means to reduce NDMA in the drug product. Limiting residual dimethylamine in the API has proven to be another important factor for NDMA control as dimethylamine leads to formation of NDMA in the drug products. Furthermore, analysis of historical batches of drug products has shown that NDMA may increase during storage, but the levels reached were not shelf-life limiting for the products under study.

Following excipients are mentioned in the study besides other: Povidone K30, Magnesium stearate, Carmellose sodium, HPMC 100 K, HPMC E5, Microcrystalline cellulose

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Joerg Schlingemann, Celine Boucley, Sebastian Hickert, Laura Bourasseau, Matt Walker, Caroline Celdran, Thibaut Chemarin, Celine Pegues, Matthias Fritzsche, Judith Keitel, Anja Goettsche, Maic Seegel, Stefan Leicht, Brunhilde Guessregen, Philipp Reifenberg, Stephanie Wetzel, Tim Müller, Fanny Schooren, Tobias Schuster, Mike Liebhold, Annette Kirsch, Phillip Krueger, Christoph Saal, Bruno Mouton, Sandra Masanes, Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite, International Journal of Pharmaceutics,
Volume 620, 2022, 121740, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2022.121740.

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