<i>N</i>-Nitrosodimethylamine (NDMA) Formation from Ranitidine Impurities: Possible Root Causes of the Presence of NDMA in Ranitidine Hydrochloride

N-Nitrosodimethylamine (NDMA) is a probable human carcinogen. This study investigated the root cause of presence NDMA in ranitidine hydrochloride. Forced thermal degradation studies hydrochloride and its inherent impurities (Imps. A, B, C, D, E, F, G, H, I, J, K) listed European United States Pharmacopeias revealed that addition to ranitidine, Imps. I produce at different rates solid or an oily liquid state. The rate formation from amorphous E was 100 times higher than crystalline under forced 110 °C for 1 h. Surprisingly, Imp. bearing neither N,N-dialkyl-2-nitroethene-1,1-diamine moiety nor dimethylamino group, also generated state, while as liquid, favorably produced moderate temperatures (e.g., 50 °C). Therefore, strict control aforementioned specific during manufacturing storage allows appropriate pharmaceutical products. Understanding pathways stability related enables improved pharmaceuticals mitigate this risk.