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44 Pharmaceutical Technology ® Trends in Formulation 2022 eBook PharmTech.com Qualit y Ranitidine. Since then, there have been several recalls based on detection of nitrosamines other than NDMA in marketed drug products, including Rifampin and Rifapentine, Varenicline, Quinapril, and Hydrochlo- rothiazide (4,5,6,7, 8, 9). Regulatory agencies all over the world have pub- lished guidance documents and recommendations to address the nitrosamines in drug products. FDA published a finalized guidance, Control of Nitrosamine Impurities in Human Drugs, in September 2020 and updated it in February 2021 (10). The European Medi- cines Agency (EMA) published Questions and Answers for Marketing Authorisation Holders/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products (11), which it regularly updates. Health Canada has published, Nitrosamine Impurities in Medications: Guidance (12). Anvisa and other agen- cies have published similar documents regarding risk assessment of nitrosamines. The guidance documents have asked the sponsors of prescription and over-the- counter drugs to perform an initial risk assessment for presence of nitrosamines, of the approved, pending, and in some cases, discontinued products and eventu- ally perform confirmatory testing and modification of dossiers, if needed. While all the agencies have men- tioned the risk related to "nitrosamines" in their rec- ommendations, in many cases, the boundary between the "nitrosamines" and "nitrosamides" have been smeared and sponsors have treated nitrosamides and nitrosamines the same way in their risk evaluation. Discussion Activation of nitrosamides and not nitrosamines. The N-nitroso compounds can be broadly divided into two categories (1), the nitrosamines and nitrosamides (Figure 1). N-nitrosamines are derived by the reaction of secondary and tertiary amines with nitrous acid or other nitrosating agents. These can be formally con- sidered as "amides" of nitrous acid and are known to be stable, one of the reasons that they are ubiquitous. N-nitrosamines need to be metabolized in the body to elicit their mutagenic or, in many cases, carcinogenic behavior. It is believed that most of these compounds are activated by alpha hydroxylation in presence of Cy tochrome P450 and NADPH (nicotinamide ade- nine dinucleotide phosphate) (Figure 2), which leads to the formation of an electrophilic carbocation and can alkylate the DNA. Whereas, N-nitrosamides are compounds where there is a carbonyl group (C=O or C=N) attached to the nitrogen bearing the "NO" group (Figure 1). Members of this class include N-nitroso- amides, N-nitrosocarbamates, N-nitrosoureas, and N-nitrosoguanidines. These classes of compounds are very different from N-nitrosamines in their mode of activation in vivo and in vitro, as they do not need to be metabolized to produce the electrophile carbocation. The instability of compounds of the N-nitrosoamide category is due to conjoining of two electropositive functional groups, NNO and C=O (or C=N). Also, in this class, the N-nitrosamides of primary amines behave differently from N-nitrosourea, N-nitrosocarbamates, and N-nitrosoguanidines. Literature indicates that N-nitrosamides of primary amines rearrange (possi- bly by a 1,3-sigmatropic shift) to eventually produce a diazonium cation (3) as shown in Figure 2. These compounds are also known to undergo base catalyzed decomposition to produce diazoalkanes. While the degradation pathways of N-nitrosamides of primary amines have limited information in the public do- main, the solvolytic decomposition of N-nitrosoureas and N-nitrosoguanidines and N-nitrosoureas are well ! ! ! "#$%&'!()!*+,,#-.'!,/&%0/%&',!+1!!!23#/&+,+!0+45+%36,7! ! ! ! ! ! ! "#$%&'!8)!90/#:;/#+3!+1!3#/&+,;4#6',!:'&,%,!3#/&+,;4#3',!<(=7!! ! ! ! "#$%&'!()!*+,,#-.'!,/&%0/%&',!+1!!!23#/&+,+!0+45+%36,7! ! ! ! ! ! ! "#$%&'!8)!90/#:;/#+3!+1!3#/&+,;4#6',!:'&,%,!3#/&+,;4#3',!<(=7!! FIGURE 1. Possible structures of N-nitroso compounds. FIGURES COURTESY OF THE AUTHOR.