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

• Published in: Chemical & pharmaceutical bulletin Vol. 69; no. 9; pp. 872 - 876
• Main Authors: Yokoo, Hidetomo, Yamamoto, Eiichi, Masada, Sayaka, Uchiyama, Nahoko, Tsuji, Genichiro, Hakamatsuka, Takashi, Demizu, Yosuke, Izutsu, Ken-ichi, Goda, Yukihiro
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01.09.2021; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Carcinogens; Control stability; Crystal structure; Crystallinity; degradation; Diamines; Impurities; impurity; N-Nitrosodimethylamine; N-nitrosodimethylamine (NDMA); Pharmaceuticals; Ranitidine; Ranitidine hydrochloride; stability; Thermal degradation
• ISSN: 0009-2363; 1347-5223; 1347-5223
• DOI: 10.1248/cpb.c21-00289

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.