Formation of N-Nitrosamines by Reaction of Secondary Dialkylamines with Trace Levels of Nitrite in Aqueous Solution: An Automated Experimental and Kinetic Modeling Study Using Di-n-butylamine

Healthcare marketing authorization holders are undertaking widespread risk assessment activities following the discovery of dialkyl N-nitrosamines in certain drug substances and products. A contribution to this exercise is the kinetic modeling of the reaction of secondary amines with nitrite ion in aqueous solution and identification of conditions where this would present a risk of N-nitrosamine formation. Herein, we describe automated experimental nitrosation studies on di-n-butylamine that highlight the conservative nature of the modeling approach and support the conclusion that N-nitrosamine formation only becomes a significant risk in solution at pH < 6 and at higher concentrations of nitrite. We report kinetic modeling with an updated treatment of temperature dependence and further experimentation on di-n-butylamine demonstrating our approach to be valid. Our experimentation extends to the consideration of N-nitrosamine formation from tertiary amines, which are considered less prone to nitrosation, as the mechanism includes a dealkylative step. We show a 2 orders of magnitude reduction in the rate of formation of N-nitrosodibutylamine from tributylamine compared with di-n-butylamine for the considered pH, nitrite, and amine concentrations.