(665d) Solid State Kinetics of Nitrosation to Support Model-Based Risk Assessments in Pharmaceutical Processes

The Threshold of Toxicological Concern (TTC) defines an acceptable patient daily intake for any (unstudied) chemical posing a negligible risk of carcinogenicity. A group of high potency mutagenic impurities are referred to as the cohort of concern (CoC), including N-nitroso compounds. CoC nitrosamines can pose a significant carcinogenic risk at intakes below the TTC.^1-3 Understanding their formation rate and the impact of process parameters is important to design engineering controls to mitigate nitrosamine risk of formation.

In a recent work, we showed that dialkylamine molecular descriptors (e.g., bulkiness, aqueous solubility, and steric effects) plays an important role in the aqueous nitrosation rate of the amines in the liquid phase.⁴ Kinetic data for different types of amines were collected at different temperatures and pH and a process model was developed for both homogeneous and heterogeneous reactions. The results were compared to the most common surrogate, dimethylamine. It was found that bulkier amines undergo nitrosation at much slower rates than dimethylamine.

In this work we are extending our previous work to experimentally and theoretically investigate the solid state nitrosation rates in blends of amines and common excipients. A comprehensive model was developed to describe the solid-state reactions based on well-established nitrosation mechanisms.⁵ Reaction rates in solid state were systematically compared to equivalent liquid-phase reaction kinetics to evaluate the applicability of solution-phase kinetic models.

References:

¹ Nudelman, R. et al. The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny. Org. Process Res. Dev. 27, 1719–1735 (2023).

² Licht, W. R.; Deen, W. M. Theoretical Model for Predicting Rates of Nitrosamine and Nitrosamide Formation in the Human Stomach. Carclnogenesis 1988, 9 (12), 2227–2237. https://doi.org/https://doi.org/10.1093/carcin/9.12.2227

³ U.S. Department of Health and Human Services Food and Drug Administration. Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance for Industry; 2023. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs

⁴ Eren, A., & Luciani, C. (2024, October). Improving Our Understanding of Nitrosamine Formation in Pharmaceutics: Computational and Experimental Approaches. In 2024 AIChE Annual Meeting. AIChE.

⁵ Ashworth, I. W.; Dirat, O.; Teasdale, A.; Whiting, M. Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water. Org Process Res Dev 2020, 24 (9), 1629–1646. https://doi.org/10.1021/acs.oprd.0c00224