has anyone experience with NMPA in his drug substance or drug product? The precursor will likely be N-methylaniline, in special cases N-dimethylanilin, but could you please inform about the source of the precursor and probably the conditions needed for the nitrosation?
For example N-dimethylanilin is a known and specified impurity in dextromethorphan, but could wet granulation and acidic conditions at temperatures above 60°C be risk factors for the formation of NMPA in the finished dosage form (e.g. tablets)?
You are correct, a potential source of NMPA is N-methylaniline (NMA), which is a known impurity of Dimethylaniline (DMA). We had performed a NAP test on DMA and found it to be highly susceptible to dealkylation, leading to the formation of NMPA via NMA. DMA can undergo oxidative or nitrosative dealkylation to form secondary amines (NMA). This reaction is often catalyzed by nitrosating agents in acidic media, effectively converting a stable tertiary amine into a highly reactive secondary amine in situ. Your process conditions are highly favorable for NMPA formation if your excipients contain nitrites.
This is theoretical possibility based on your explanation.
During wet granulation at ~60 °C, N,N‑dimethylaniline can undergo partial demethylation to N‑methylaniline under moist, oxidative, and mildly acidic conditions; the resulting secondary amine may then be nitrosated by trace nitrosating species from water or excipients, forming N‑nitrosomethylaniline.