20.500.12556/RUL-148688 NDMA formation due to active ingredient degradation and nitrite traces in drug product N-nitrosamines are genotoxic compounds which can be found as impurities in drug substances and drug products used in the pharmaceutical industry. To date, several possible nitrosamine sources in drug products have been reported and this study aims to illuminate another one. A case of afatinib drug product was investigated, in which up to 50 ppb N-nitrosodimethylamine (NDMA) traces were detected. Afatinib was found to degrade to the secondary amine dimethylamine (DMA), forming NDMA with traces of nitrite in crospovidone. Two series of film-coated tablets were prepared with crospovidone from two different manufacturers, containing different levels of nitrites. Tablets were subjected to an accelerated stability study (40 °C/75% relative humidity) or stored at room temperature and levels of NDMA, DMA and nitrite in tablets were monitored. NDMA and nitrite were found on ppb levels, whereas DMA was detected on ppm levels. NDMA formation in the drug product was found to be time, temperature and nitrite dependent and it was emphasized that DMA and nitrite should be reduced. The accelerated stability study proved to be a useful tool for predicting nitrosamine formation in the drug product. N-nitrosodimethylamine NDMA afatinib drug product drug substance degradation dimethylamine DMA nitrite excipient crospovidone stability study N-nitrozodimetilamin NDMA zdravilo afatinib razgradnja zdravilne učinkovine dimetilamin DMA nitriti pomožne snovi krospovidon stabilnostne študije farmacevtska industrija true false true Angleški jezik Slovenski jezik Članek v reviji 2023-08-29 11:01:15 2023-08-29 11:01:16 2023-08-30 03:40:30 0000-00-00 00:00:00 2023 0 0 Str. 1277-1286 iss. 5 Vol. 112 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 661.12 0022-3549 10.1016/j.xphs.2023.03.007 146220547 1-s2.0-S0022354923001077-main.pdf 1-s2.0-S0022354923001077-main.pdf 1 D268C6B83026B705F8EA90E0DE7E161E f2c37a8cb1651bb53487bcb888dafae955c7b745193b3b5a155b517775d4ee1b 28515e26-464b-11ee-a605-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=173000 https://www.sciencedirect.com/science/article/pii/S0022354923001077 0 e586c079-464a-11ee-a605-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=172999 Fakulteta za farmacijo 0 0 0