NDMA formation due to active ingredient degradation and nitrite traces in drug product

Golob, Nejc (author), Peterlin, Simona (author), Grahek, Rok (author), Roškar, Robert (author)

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.

• Language: English
• Keywords: N-nitrosodimethylamine, NDMA, afatinib drug product, drug substance degradation, dimethylamine, DMA, nitrite, excipient, crospovidone, stability study
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 1277-1286
• Numbering: Vol. 112, iss. 5
• PID: 20.500.12556/RUL-148688
• UDC: 661.12
• ISSN on article: 0022-3549
• DOI: 10.1016/j.xphs.2023.03.007
• COBISS.SI-ID: 146220547
• Publication date in RUL: 29.08.2023

Record is a part of a journal

• Title: Journal of pharmaceutical sciences
• Shortened title: J. pharm. sci.
• Publisher: Elsevier, American Pharmacists Association
• ISSN: 0022-3549
• COBISS.SI-ID: 25777152

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: N-nitrozodimetilamin, NDMA, zdravilo afatinib, razgradnja zdravilne učinkovine, dimetilamin, DMA, nitriti, pomožne snovi, krospovidon, stabilnostne študije, farmacevtska industrija