Nitrosamine mitigation: NDMA impurity formation and its inhibition in metformin hydrochloride tablets.
Diaa Shakleya, Alaadin Alayoubi, Dustin Brown, Alaa Mokbel, Nicolas Abrigo, Adil Mohammad, Jiang Wang, David Li, Maha Shaklah, Fahd M Alsharif, Saaniya Desai, Martha Essandoh, Patrick J Faustino, Muhammad Ashraf, Thomas O' Connor, Matthew Vera, Andre Raw, Vilayat A Sayeed, David Keire
Author Information
Diaa Shakleya: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. Electronic address: diaa.shakleya@fda.hhs.gov.
Alaadin Alayoubi: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Dustin Brown: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Alaa Mokbel: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Nicolas Abrigo: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Adil Mohammad: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Jiang Wang: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
David Li: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Maha Shaklah: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Fahd M Alsharif: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Saaniya Desai: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Martha Essandoh: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Patrick J Faustino: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Muhammad Ashraf: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Thomas O' Connor: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Matthew Vera: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Assessment, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Andre Raw: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Assessment, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Vilayat A Sayeed: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Assessment, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
David Keire: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Office of Pharmaceutical Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
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.
