A Consideration of the Extent That Tertiary Amines Can Form N‑Nitroso Dialkylamines in Pharmaceutical Products

Most secondary amines have the potential to undergo nitrosation in the presence of nitrite under certain conditions, particularly at low pH, to generate N-nitrosamines. Tertiary amines are generally considered to be less prone to nitrosamine formation as they require an additional dealkylation step. A review of the published literature combined with recently generated experimental data from nitrosation experiments carried out on several trialkyl amines further informs on the extent that tertiary amines can form N-nitrosamines by reaction with trace levels of nitrite, which may be present during drug substance or drug product manufacture. Simple trialkylamines, amines containing no additional heteroatoms, have been demonstrated to react via a nitrosative dealkylation mechanism that slowly generates a dialkylamine, which in turn nitrosates. This sequence of reactions to generate a Nnitrosamine is approximately 1000-fold slower than the simple nitrosation of a secondary amine of comparable pKa. Therefore, the formation of N-nitrosamines from simple trialkylamines in pharmaceutical products is typically not considered to be a risk. Dialkylanilines are able to access alternative reaction mechanisms and may undergo dealkylative nitrosation with greater ease than simple trialkylamines and therefore require a more focused risk assessment. Finally, certain structurally complex tertiary amines may contain functional groups that can facilitate the formation of N-nitrosamines through resonance and/or inductive electronic effects. Therefore, structures containing highly functionalized tertiary amines require a thorough, compound-specific assessment to determine the level of risk of nitrosamine generation. Note that in situations where higher amounts of nitrosating agents are present, such as when nitrosation chemistry is used during the drug substance manufacturing process, simple trialkylamines should be considered for N-nitrosamine generation during the risk assessment.