Module 3 - Strategic case studies in practice

introduced into a synthetic process. Since azides can be depleted by nitrites as outlined below in the sartan case, the relevance of this observation remains to be clarified.

2.2.2.1.2. Theoretically possible root-causes for N- nitrosamines in pharmaceutical products linked with solvents, reagents, catalysts In the case of sartans, solvents such as dimethylformamide (DMF), N- methylpyrrolidone (NMP) and triethylamine (TEA) represent sources of amines such as dimethylamine (DMA), methybutylamine (MBA) and diethylamine (DEA), susceptible to N- nitrosamine formation. In addition, the solvent/reagent TEA is able to form NDEA by nitrosative dealkylation. Based on evaluation of available literature information, the (potential) presence of secondary/tertiary amines and NOX in solvents listed in the ICH Q3C (R7) Guideline was assessed. The main outcome is summarized as follows: Similar to DMF, dimethylacetamide is produced on industrial scale by reaction of dimethylamine with acetic acid, acetic anhydride, or acetate esters indicating dimethylamine to be an expected impurity [Le Berre et al. (2013)]. Due to high structural and functional similarity, both carboxylic acid derivatives possess comparable chemical properties, e.g. liberation of dimethylamine upon hydrolysis. It is concluded that the ICH Q3C (R7) solvent dimethylacetamide represents –in addition to DMF and NMP- an additional source of secondary amines susceptible to NDMA formation in combination with nitrosating agents. The ICH Q3C (R7) solvent TEA is frequently used as reagent or solvent in organic synthesis and API manufacture. According to Spiegelhalder et al. (1978), commercially available lots of secondary/ tertiary amines were found to be contaminated with the corresponding N- nitrosamines, showing levels to range between 0.03 - 53.0 ppm. For example, NDMA was quantified to contaminate DMA solution significantly, ranging from 0.65 – 17.3 ppm. The highest N- nitrosamine concentration was detected in pyrrolidine (i.e. 53.0 ppm), while 0.03 ppm NDEA were found in TEA. Comparable results were reported one year later by Bontoyan et al. (1979). The relevance of these results, discovered 40 years ago in secondary and tertiary amines of unknown quality, is currently considered unknown. The phase transfer catalysts TEA HCl and tetrabutylammonium bromide (TBAB) were identified as precursors of N- nitrosamines such as NDEA and N- nitrosodibutylamine (NDBA). Basically, the susceptibility of ammonium salts to form N- nitrosamines was discovered without clarifying reaction mechanism as shown above [Fiddler et al. (1972)]. Considering that quaternary alkyl ammonium salts are derived from the corresponding secondary and tertiary amines, these precursors represent potential impurities [Roose et al. (2015)], having also the potential to react with nitrosating reagents. Based on information from literature, nitroalkanes such as 2-nitropropane and nitromethane were used to act as a source of nitrous acid in combination with certain oxidants/catalyst and to form N- nitrosamine in combination with secondary and tertiary amines [Franck et al. (1970); Potturi et al. (2012) ; Zhang et al. (2013)]. According to S. B. Markovsky [Ullmann's Encyclopedia of Industrial Chemistry (2012)], the ICH Q3C (R7) solvent nitromethane is usually produced on industrial scale by high temperature vapour-vapour-phase nitration of propane with nitric acid, followed by aqueous working-up and drying procedures before being separated by fractional column distillation. Consequently, low-level contamination with nitric acid, nitrous acid and nitrogen oxides etc. seems to be unlikely, but cannot be ruled out per se . During ranitidine synthesis, the precursor 1,1- bis(methylthio)-2-nitroethene is produced by reaction of dimethyl- N- methylcarbonimidodithionate with nitromethane, before being incorporated into ranitidine drug substance [Kleemann, Engel 2019].

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