I am currently in the process of creating a nitrosamine risk assessment for ASA/paracetamol/caffeine tablets and would like to know your opinion on this.
According to the manufacturer’s statements, the majority of the excipients used contain traces of nitrite.
In my risk assessment, I only see the APIs paracetamol and caffeine as relevant, as ASA does not contain nitrogen.
My question would be regarding the formation of N-nitroso-paracetamol. How do you assess the risk of formation and is there any limit value for this? Unfortunately, I couldn’t find anything in my search and also no toxicity data on comparable substances. With regard to caffeine, the manufacturer’s statement mentions the possible impurities theobromine, paraxanthine, theophylline and caffeidine are mentioned, which are typically < 0.05 %. Do you also see a risk of nitrosamine formation here? The manufacturing process involves granulation of the paracetamol and then direct compression with all other APIs and excipients.
Hallo Kevin,
mit Coffein habe ich mich auch gerade auseinandergesetzt und bin dabei auf eine sehr alte Publikation, von 1998, gestoßen, die dir vielleicht weiterhilft:
Mein einfach formuliertes Fazit daraus:
Durch alkalische Hydrolyse und Ringspaltung kann Coffein zu Coffeidin umgewandelt werden. Daraus könnten durch Nitrosierung Mononitrosocoffeidin (MNC) und Dinitrosocoffeidin (DNC) gebildet werden. Dinitrosocoffeidin ist ein Nitrosamid, das sowohl mit als auch ohne metabolische Aktivierung stark mutagen ist, während MNC, wie mehrere andere aromatische asymmetrische Nitrosamine, keine genotoxischen oder mutagenen Eigenschaften aufweist.
Eine “N-Nitroso Caffeine Impurity 1” (CAS-Nr. N/A) wird von einem Syntheselabor (auf Kundenwunsch) angeboten. Es handelt sich um 1,3-Dimethyl-7-nitroso-3,7-dihydro-1H-purine-2,6-dione (N-Nitroso Desmethyl Caffeine). Aber nach meinem Verständnis ist das kein klassisches Nitrosamin…
Vielleicht hilft dir das ein wenig weiter. Falls ich hier völlig falsche Schlüsse gezogen habe, bin ich über eine Korrektur aus der Community sehr dankbar.
Hi,
Paracetamol has amide group, and not secondary amine group so its Nitroso impurity won’t form in the drug product. Caffeine also won’t form Nitroso impurity in the drug product. 1 and 3 position are amide group, and 5 and 7 position will not form Nitroso impurity due to rearrangement reactions on exposure to nitrite ions.
Thank you very much for your feedback. @sarvesh.goel why exactly can the risk of N-nitroso-paracetamol formation be ruled out? The substance n-nitroso-paracetamol is offered for sale online, so a synthesis and thus the theoretical formation is possible, right?
I also consider the risk of nitrosation of caffeine itself to be rather low. However, there are some related substances (e.g. caffeidine as in @Wolffi publication or theophylline) where nitrosamine formation is theoretically possible. The content of these related substances is usually <0.05% in caffeine.
I would be wary of vendor information unless you have seen and checked the characterization data. I recall a paper being published stating that nitrosation of paracetamol led to a rearrangement of the nitroso group that went into the aromatic ring.
Hi sorry for the late reply. There is amide group, its not a secondary amine group. I think with this logic you will agree. As far as the availability of nitroso paracetamol impurity in market is concerned, please check its NMR spectra and you will find the answer if that impurity is correct.