The ubiquitous presence of mutagenic and potentially carcinogenic N-nitrosamine impurities in medicines has become a major issue in the pharmaceutical industry in recent years. Rigorous mitigation strategies to limit their amount in drug products are, therefore, needed. The removal of nitrite, which is a prerequisite reagent for the N-nitrosation of amines, has been acknowledged as one of the most promising strategies. We have conducted an extensive literature search to identify nineteen structurally diverse nitrite scavengers and screened their activity experimentally under pharmaceutically relevant conditions. In the screening phase, we have identified six compounds that proved to have the best nitrite scavenging properties: ascorbic acid (vitamin C), sodium ascorbate, maltol, propyl gallate, para-aminobenzoic acid (PABA), and l-cysteine. These were selected for investigation as inhibitors of the formation of N-methyl-N-nitrosoaniline (NMA) from N-methylaniline and N-nitroso-N’-phenylpiperazine (NPP) from N-phenylpiperazine in both solution and model tablets. Much faster kinetics of NMA formation compared to NPP was observed, but the former was less stable at high temperatures. Vitamin C, PABA, and l-cysteine were recognized as the most effective inhibitors under most studied conditions. The nitrite scavenging activity does not directly translate into N-nitrosation inhibitory effectiveness, indicating other reaction pathways may take place. The study presents an important contribution to identifying physiologically acceptable chemicals that could be added to drugs to prevent N-nitrosation during manufacture and storage.

N-nitrosamines are widespread cancerogenic compounds in human environment, including water, tobacco products, food, and medicinal products. Their presence in pharmaceuticals has recently led to several recalls of important medicines from the market, and strict controls and tight limits of N-nitrosamines are now required. Analytical determination of N-nitrosamines is expensive, laborious, and time-inefficient making development of simpler and faster techniques for their detection crucial. Several reports published in the previous decade have demonstrated that cobalt porphyrin-based chemosensors selectively bind N-nitrosamines, which produces a red shift of characteristic Soret band in UV–Vis spectra. In this study, a thorough re-evaluation of metalloporphyrin/N-nitrosamine adducts was performed using various characterization methods. Herein, we demonstrate that while N-nitrosamines can interact directly with cobalt-based porphyrin complexes, the red shift in UV–Vis spectra is not selectively assured and might also result from the interaction between impurities in N-nitrosamines and porphyrin skeleton or interaction of other functional groups within the N-nitrosamine structure and the metal ion within the porphyrin. We show that pyridine nitrogen is the interacting atom in tobacco-specific N-nitrosamines (TSNAs), as pyridine itself is an active ligand and not the N-nitrosamine moiety. When using Co(II) porphyrins as chemosensors, acidic and basic impurities in dialkyl N-nitrosamines (e.g., formic acid, dimethylamine) are also UV–Vis spectra red shift-producing species. Treatment of these N-nitrosamines with K2CO3 prevents the observed UV–Vis phenomena. These results imply that cobalt-based metalloporphyrins cannot be considered as selective chemosensors for UV–Vis detection of N-nitrosamine moiety-containing species. Therefore, special caution in interpretation of UV–Vis red shift for chemical sensors is suggested.

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