The mitigation of nitrosamine formation in drug products has been studied and approaches such as using formulations with pH modifiers and antioxidants have been shown to decrease the formation of nitrosamines. However, more studies are needed to explore the effectivness of mitigation strategies with different drug models and formulations. The primary objective of this work was to assess the role of different antioxidants and pH modifiers in tablet formulations to mitigate the formation of NDMA, prepared in-house, using metformin hydrochloride as a model drug. A study design for manufacturing metformin hydrochloride formulations was created to evaluate potential mitigation stratigies. The formulations were prepared by wet granulation that included a sodium nitrite spike and various antioxidants such as ascorbic acid, caffeic acid and ferulic acid at various concentrations that may inhibit nitrosamine formation. The study design also included pH modifiers such as hydrochloric acid and sodium carbonate. The metformin hydrochloride formulations were placed under stability conditions that included humidity, temperature and time over a six month period. NDMA inhibition was found to be most effective in formulations with basic pH, followed by the addition of tested antioxidants with 0.1% concentrations in the formulations. All tested antioxidants showed complete mitigation in formulations with 0.5% and 1% concentrations. In summary, basic pH and the inclusion of antioxidants exhibited the potential to mitigate the formation of NDMA in metformin hydrochloride tablets.
Keywords: Antioxidants; Metformin hydrochloride; Mitigation; N-Nitrosation; NDMA; Nitrosamines; Stability.
Published by Elsevier B.V.