Pathways for N-Nitroso Compound Formation: Secondary Amines and Beyond

Abstract

Recent drug recalls (e.g., valsartan and ranitidine) linked to the discovery of nitrosamine impurities have led to increased regulatory scrutiny in the manufacturing process of marketed medicines, notably for determining any sources of risk for nitrosamine (or related N-nitroso compound) formation within the manufacturing process. This review seeks to aid the risk assessment process through identifying known conditions and reactants through which N-nitroso compounds can be formed.

The Use of Potassium/Sodium Nitrite as a Nitrosating Agent in the Electrooxidative N‐Nitrosation of Secondary Amines

“…Apart from the wide biological importance of N‐nitrosamines, they have also found broad use in both organic synthesis and in the field of material science [3] . N‐nitrosamines are traditionally prepared by the polar addition of secondary amines and an in situ generated electrophilic NO+ cation under strongly acidic conditions [4] . The reaction of secondary amines and nitrous acid which are in situ generated from nitrite (e. g. NaNO 2 , KNO 2 ) and a concentrated mineral acid (e. g. HCl, H 2 SO 4 ) are currently the fundamental process for the production of N‐nitrosamines on both laboratory and industrial scales (Scheme 1a) [5] .…”

“…[3] N-nitrosamines are traditionally prepared by the polar addition of secondary amines and an in situ generated electrophilic NO + cation under strongly acidic conditions. [4] The reaction of secondary amines and nitrous acid which are in situ generated from nitrite (e. g. NaNO 2 , KNO 2 ) and a concentrated mineral acid (e. g. HCl, H 2 SO 4 ) are currently the fundamental process for the production of N-nitrosamines on both laboratory and industrial scales (Scheme 1a). [5] This is because sodium/potassium nitrite are the most readily available nitrosating reagents.…”

Nitrate Is Nitrate: The Status Quo of Using Nitrate through Vegetable Extracts in Meat Products

“…Secondary amine N -nitrosation is one of the most studied. These compounds react with most nitrosating agents at different rates, depending on structural or physicochemical factors, namely their pKa and the steric medium near the nitrogen atom [ 64 ].…”

Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates**

“…Notably, a great deal of waste and safety concerns commonly originate from the use of solvents, typically responsible for 80–90 % of total mass consumption in a given industrial process [3] . Besides environmental and safety issues, solvents can also generate dangerous contaminants in the produced APIs, such as cancerogenic nitrosamines derived from trace secondary amine impurities in N , N ‐dimethylformamide [4,5] . In this regard, mechanochemistry [6–8] as an essentially solvent‐free technique can beneficially contribute to the ongoing green renovation of the pharma industry [9–11] .…”