ArticleAAPS PharmSciTech2025
LC-ESI-HRMS-Based Evaluation of Antioxidants as Additives to Inhibit Genotoxic Nitrosamine Formation in Metformin Hydrochloride Tablets.
Article in AAPS PharmSciTech, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nitrosamines, particularly N-nitrosodimethylamine (NDMA), have raised significant regulatory and safety concerns due to it's genotoxic and carcinogenic properties. Although NDMA formation in metformin hydrochloride (MET) tablets under nitrosating conditions is well-established, the potential of antioxidants to inhibit this impurity remains underexplored. This study evaluated the effectiveness of antioxidant additives, trolox (TRX), ascorbic acid (ASA), and alpha-tocopherol (Alpha- T), in minimizing NDMA formation during storage. MET tablets were formulated into three groups: (a) spiked with sodium nitrite (NaNO₂), (b) spiked with NaNO₂ and antioxidants, and (c) containing antioxidants without NaNO₂. A total of 23 batches were manufactured and subjected to both accelerated and long-term stability conditions for three months. NDMA levels, quantified by validated LC-HRMS method, showed significant increase under stress conditions, which were attenuated by antioxidant inclusion. TRX (5%) demonstrated the highest inhibition of NDMA formation (62.16%) under accelerated storage (Day 90), followed by ASA (31.80%) and Alpha-T (32.28%). Similar trends were observed in long term conditions. In vitro Caco-2 permeability assay revealed a 2.17-fold increase in MET transport with 10% TRX. Genotoxicity studies using the in vitro comet assay in HepG2 cells confirmed TRX as the most effective antioxidant in reducing NDMA-induced DNA damage. These results demonstrate that antioxidant incorporation can effectively control NDMA formation and improve bioavailability in MET tablets, offering a formulation-based approach to mitigate nitrosamine risk.
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Registered trials
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