Solid State Kinetics of Nitrosation Using Native Sources of Nitrite.

While many reactive species are known to cause N-nitrosation, trace nitrite (NO), 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 NO can influence the favored nitrosation conditions and final amount of nitrosamine being formed. Using native levels of NO, most likely present as ammonium nitrite (NHNO), 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 NHNO into N and HO 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 NO as spiking reagents, such as NaNO, may lead to unrealistic worst-case situations when the main form of NO in the drug product (DP) under evaluation may be NHNO. As well, measuring NO in freshly manufactured excipients containing NO potentially as NHNO may lead to biased high NO content, which is not representative of the actual amounts present at the time of DP manufacture.