N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO2

In 2019, N-nitrosodimethylamine (NDMA) exceeding the maximum allowable intake (96 ng/day) was detected in metformin drug products in Singapore, and since then, many of the drug products have been voluntarily recalled globally for the same reason. In our company, the analysis of the metformin drug products showed that small batches (1.9%) of products contained the excessive level of NDMA, so we investigated the root cause of NDMA formation. As a result, we found that dimethylamine (DMA) in the active pharmaceutical ingredient (API) used in the manufacturing process and nitrogen dioxide (NO2) in the atmosphere had considerable influence on the formation of NDMA in metformin drug products. The results of a model experiment simulating a fluidized bed granulator also supported the hypothesis that atmospheric NO2 introduced into the granulator N-nitrosated DMA in the API to form NDMA.