Series 2 - Nitrosamine Sources

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2# What causes nitrosamines presence?

 

Technically, nitrosamines may be present due to contamination or intrinsic formation by the reaction of two existing essential components during the manufacturing process: 1) amines and 2) nitrites, under certain conditions (heat, pH, and water content). All amines, including primary, secondary, tertiary, and quaternary, can possibly form nitrosamines. However, secondary amines are the most reactive ones, as they can react directly with nitrites and produce stable nitrosamines (see Figure 1).

 

Figure 1. The Primary, Secondary, and Tertiary Amine Reaction with Nitrites

Drug products comprise Active Pharmaceutical Ingredients (API) and additive substances called excipients. Amines may exist in the drug product, such as in the API structure formula or from excipients, as well as solvents or reagents used in manufacturing. Several common solvents used are Dimethylformamide (containing Dimethylamine as secondary amines) and N-methyl pyrrolidinone (NMP), which, if it undergoes a hydrolysis process, will produce the N-methyl amino-N-butyric acid (which is a secondary amine). Later, with the contribution of nitrites and supporting condition presence, these secondary amines may generate nitrosamine impurities (see Figure 2). Therefore, secondary amines became the most interesting target analytes to be identified and quantified in drug products as part of the effort to minimise nitrosamine formation. See also Figure 3 for several common secondary amines used as solvents.

 

Figure 2. Reaction of N, N-dimethylamine with Nitrite to Form NDMA

Figure 3. Secondary Amines Contained in Pharmaceutical Solvents

But how can we actually analyse amine compounds?



References:
  1. H. Akkaraju, R. Tatia, S. S. Mane, A. B. Khade and S. J. Dengale, Regulatory Toxicology and Pharmacology, 2023, 139, DOI: 10.1016/j.yrtph.2023.105355.
  2. S. Horne, M. D. Vera, L. R. Nagavelli, V. A. Sayeed, L. Heckman, D. Johnson, D. Berger, Y. Y. Yip, C. L. Krahn, L. O. Sizukusa, N. F. M. Rocha, R. N. Bream, J. Ludwig, D. A. Keire and G. Condran, J Pharm Sci, 2023, 112, 1166–1182.
  3. M. Homšak, M. Trampuž, K. Naveršnik, Z. Kitanovski, M. Žnidarič, M. Kiefer and Z. Časar, Processes, 2022, 10, DOI:10.3390/pr10112428.
  4. C. J. Borths, T. Burr, A. Figuccia, J. G. Ford, B. Guan, M. T. Jones, D. Klingeleers, S. Lochner, A. A. Rodriguez and C. Wetter, Org Process Res Dev, 2023, 27, 1693-1702.



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