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

Abstract

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.

Highlights

Excipient nitrite levels are not static material attributes.
Ambient NOx can significantly contribute to nitrite formation and variability.
Control of process air quality and material handling may be essential for effective mitigation of nitrosamine formation risk.

Introduction

The presence of Nitrosamine Drug Substance Related Impurities (NDSRIs) has become a major focus for both the pharmaceutical industry and regulatory authorities. 1, 2, 3 One of the principal pathways for the formation of these impurities during drug product manufacturing and storage is the reaction of vulnerable drug substances, particularly those containing secondary amine functionalities, with nitrite. 4 Although the presence of nitrite in pharmaceutical excipients at trace (ppb) levels has been known for many years 5, it was historically not viewed as a significant risk to drug product quality until nitrosamine formation from drug substances emerged as a major regulatory concern.

Recently, several reports have documented nitrite impurities in excipients as a root cause for nitrosamine formation 6,7, and multiple excipient manufacturers have begun listing nitrite content in their IPEC declarations, with some now offering explicitly labeled “low-nitrite” grades. 8, 9, 10, 11, 12, 13, 14, 15 In some cases, these materials may simply reflect naturally low nitrite levels in the raw materials original process, whereas in others they result from deliberate modifications to the manufacturing conditions aimed at minimizing nitrite uptake or removing nitrite retrospectively.

To support a more systematic understanding of this issue, a consortium of pharmaceutical companies contributed analytical data to the Lhasa Nitrite Excipient Database, enabling broader insight into nitrite levels across excipient types and suppliers. 16

A key observation from these data is the substantial batch-to-batch and manufacturer-to-manufacturer variability in excipient nitrite content. Some materials, such as lactose, consistently exhibit very low nitrite levels (typically <100 ppb), whereas others, such as magnesium oxide, may exceed 6,000 ppb. Excipients with higher average nitrite content also tend to show the greatest variability both within and across suppliers. This variability complicates nitrite control strategies and NDSRI risk mitigation, underscoring the need to understand the underlying causes and implement robust excipient control approaches.

This study addresses two central questions: (i) the intrinsic susceptibility of excipients to NOx-driven nitrite formation, and (ii) the role of environmental exposure as a previously underappreciated driver of variability in nitrite content.

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Rok Grahek, Simona Peterlin, Monika Malovrh, Pia Repše, Holger Bauer, Joerg Schlingemann, Malcolm Ross, Excipient nitrite levels are not static material attributes: Nitrite generation from environmental NOx and implications for drug product manufacturing, Journal of Pharmaceutical Sciences, 2026, 104482, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2026.104482.