Excipient nitrite levels are not static material attributes: Nitrite generation from environmental NOx and implications for drug product manufacturing

Résumé fourni par la source

Nitrites in pharmaceutical excipients are a known critical factor for the formation of nitrosamine impurities. The origin and variability of nitrite levels are, however, not yet fully understood. In this study, we investigated the formation and uptake of nitrite in a broad panel of common excipients under controlled exposure to nitrogen oxides (NO x ). Our data show that most tested excipients are susceptible to NO x -driven nitrite accumulation, an effect mediated via hydrolysis and disproportionation mechanism. Substantial differences in nitrite accumulation were observed among excipients, governed by their physicochemical properties including pH and specific surface area. Carbonate excipients exhibit the highest absolute nitrite accumulation due to efficient chemical trapping but they also create a less favorable microenvironment for nitrosamine formation due to their basic pH value. In contrast, starch and microcrystalline cellulose (MCC) show only moderate formation of nitrite but potential higher risk for nitrosamine formation due to their high percentage in typical drug formulations and their rather neutral pH. Ambient air exposure studies confirmed that nitrite levels can increase significantly even under laboratory conditions, making environmental NO x a potential contributor to variability in measured nitrite levels. These findings demonstrate that nitrite levels in excipients are no static material atributes but rather dynamic properties potentially influenced by environmental exposure and process conditions. Consequently, control of air quality and material handling can be a tool to mitigate nitrosamine formation risk in pharmaceutical products. Further studies should assess the extent of nitrite uptake of typical formulations under manufacturing conditions involving high air throughput, such as fluid-bed granulation or film coating, to better understand the practical relevance of these findings.

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