Computational mechanistic study on N-nitrosation reaction of secondary amines

The presence of potentially carcinogenic nitrosamines in drugs has been a worldwide concern, driving strategies to control or mitigate their formation to protect patient health. Understanding the critical factors for N-nitrosation, such as mechanisms and energy barriers, enhances the risk assessment process to understand potential nitrosamine formation. Evaluation of the structural impact of amines on the N-nitrosation rate in the presence of nitrites and acidic media is of great interest to pharmaceutical companies assessing the risk of nitrosamine drug substance–related impurities. A range of secondary amines was explored using DFT calculations to assess the impact of electronic and steric effects on activation energy. Asym-N₂O₃ was selected as the nitrosating agent since its reaction was shown to be favorable following screening of pathways employing nitrosyl chloride, nitrous acid, asym-N₂O₃, sym-N₂O₃, and trans-cis-N₂O₃. The relatively low activation energies obtained for all amines indicate the reaction is very likely to occur if the reactive components encounter, even for amines with sterically hindered and electron-withdrawing groups. Understanding the interaction between the amine and nitrosating agent is therefore the defining factor in the risk of formation of more complex nitrosamines within drugs.