N-nitrosamines (nitrosamines) are highly potent carcinogens that have been an industry wide problem since 2018 when N-nitrosodimethylamine (NDMA) was discovered at above acceptable levels in the block-buster blood pressure regulator drug Valsartan. This finding led to the recall of a number of structurally similar drug products from the market. The regulatory bodies demanded that costly and time consuming batch testing of all Active Pharmaceutical Ingredients (API), intermediates, and materials of drug products must be carried out to rule out N-nitrosamine contamination. Estimations about the associated risk of contamination in the API can, however, be made in-silico, and these estimations are largely based on the physicochemical properties of the nitrosamine impurity and how these properties influence its removal or "purge" during the API synthesis. Reactivity data on N-nitrosamines will greatly improve knowledge about their purge during a drug manufacturing process. Current reviews of N-nitrosamine reactivity focus on dialkyl and aryl nitrosamines, due to their prevelance in early discoveries of N-nitrosamine contamination in drug products. Although, recent research has discovered that many more structural classes of N-nitrosamine may be of concern to human health, with the API’s themselves being potential N-nitrosamine precursors. This renders the current knowledge base of N-nitrosamine reactivity insufficient, and calls for a more comprehensive investigation. Furthermore, the current reported reaction conditions to destroy N-nitrosamines are often harsh or with limited substrate scope. This prompts the discovery of milder reaction conditions which are applicable to a diverse range of structural classes of N-nitrosamine which can be applied during high-value chemical manufacture.
The following work details a data-driven review of N-nitrosamine reactivity, incorporating cheminformatics processes to condense data to retrieve reactions on N-nitrosamines. The curated dataset includes reactivity examples for multiple structural classes of N-nitrosamines. The findings indicate that the reactivity of N-nitrosamines is highly dependent on the surrounding structural environment, particularly the alpha and beta positions relative to the N-N=O substructure shared by all N-nitrosamines, as structural modifications at these positions can open the door to otherwise unaccessible reactivity. The summarised reactivity table generated is significant in the advancement of purge assessment tools, as it can be applied to a broad range of structural classes of N-nitrosamine to estimate their reactivity, and possibly negate the requirement for costly and time consuming empirical analysis.
Following this, a reactivity screen is performed on eight relevant N-nitrosamines, whose reactivity is expected to be representative of all structural classes of N-nitrosamine. Four broad spectrum methods of destroying N-nitrosamines are found, that are milder reaction conditions than previously reported. Namely, these reaction conditions are as follows: 1. Ethanolic hydrogenchloride (HCl) at 50C for 16 hours at 20 molar equivalents of HCl, 2. Diisobutylaluminium hydride (DiBAL-H) (5 molar equivalents) in tetrahydrofuran (THF) at room temperature for 1 hour, 3. Sodium dithionite (20 molar equivalents) in 20\% w/v sodium hydroxide (NaOH) at 50C for 16 hours, 4. Sodium dithionite (20 molar equivalents) in 1 M NaOH at 50C for 16 hours. These findings, particularly reaction condition 4, have a significant purpose in the late stage removal of N-nitrosamines during API manufacture, as the nitrosamines can be removed with confidence without modifications to the API itself.
