Solid State Kinetics of Nitrosation Using Native Sources of Nitrite

Abstract

While many reactive species are known to cause N-nitrosation, trace nitrite (NO₂^-), which may be present in several excipients, is a source of nitrosating agents in pharmaceutical formulations. In this study we have found that the salt form of NO₂^- can influence the favored nitrosation conditions and final amount of nitrosamine being formed. Using native levels of NO₂^-, most likely present as ammonium nitrite (NH₄NO₂), in microcrystalline cellulose, we have determined the kinetics of nitrosamine formation in solid state with dimethylamine substrate present in metformin, used as model compound. It was found that the competing degradation of NH₄NO₂ into N₂ and H₂O limited the amount of nitrosamine formation to a great extent. Empirically modelling the kinetic data predicted reaching at maximum 1.6% conversion over a hypothetical 3-year shelf-life. These results also showed that using other sources of NO₂^- as spiking reagents, such as NaNO₂, may lead to unrealistic worst-case situations when the main form of NO₂^- in the drug product (DP) under evaluation may be NH₄NO₂. As well, measuring NO₂^- in freshly manufactured excipients containing NO₂^- potentially as NH₄NO₂ may lead to biased high NO₂^- content, which is not representative of the actual amounts present at the time of DP manufacture.

Keywords: Dimethylamine (DMA); Empirical modelling; In-silico; Microcrystalline cellulose (MCC); N-nitrosodimethylamine (NDMA); Nitrite; Nitrosamine; Nitrosation.