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

N-亚硝基二甲胺 (NDMA) 是一种可能的人类致癌物。本研究调查了盐酸雷尼替丁中存在 NDMA 的根本原因。对列在欧洲和美国药典中的盐酸雷尼替丁及其固有杂质（Imps. A , B , C , D , E , F , G , H , I , J和K）进行强制热降解研究表明，除了雷尼替丁，Imps。A、C、D、E、H和我以不同的速度以固态或油状液态生产 NDMA。无定形Imps形成 NDMA 的速率。在 110 °C 下强制降解 1 小时，A、C和E比结晶盐酸雷尼替丁高 100 倍。令人惊讶的是，结晶Imp。H，既不带有N，N-二烷基-2-硝基乙烯-1,1-二胺部分也不带有二甲氨基，也在固态下生成 NDMA，而Imp。I，作为油状液体，在中等温度下有利地产生 NDMA（例如, 50 °C)。因此，在生产和储存过程中严格控制盐酸雷尼替丁中的上述特定杂质，可以适当控制雷尼替丁及其药品中的NDMA。了解与稳定性相关的 NDMA 形成的途径可以改进对药物的控制，以减轻这种风险。