N-Nitrosodimethylamine formation in metformin hydrochloride sustained-release tablets: effects of metformin and hypromellose used in drug product formulation

In recent years, nitrosamines have been discovered in some types of drug products that becomes a current regulatory hotspot, and have attracted a lot attention from both regulatory authorities and industry. This manuscript provided an industry perspective on the nitrosamines research. A liquid chromatography coupled with tandem mass spectrometry（LC-MS/MS）method was developed and applied for the quantification of N-nitrosodimethylamine (NDMA) in metformin hydrochloride sustained-release tablets (MET).

Highlights

N-nitrosodimethylamine was detected by a liquid chromatography coupled with tandem mass spectrometry in metformin hydrochloride sustained-release tablets.

API with different particle size would lead to different N-nitrosodimethylamine levels, forced degradation study indicated that dimethylamine and N-nitrosodimethylamine were formed under alkaline and oxidative conditions.

The use of excipients (e.g. hypromellose) that may contain peroxides or nitrite, nitrate should be avoided in the metformin hydrochloride sustained-release tablets formulation.

Addition of antioxidant and Na₂CO₃ can inhibit N-nitrosodimethylamine formation.

The key factors resulting in the NDMA formation in MET were identified through forced degradation and drug-excipient studies, which included high temperature, dimethylamine, strong alkali and oxidation conditions, peroxide and alkaline components contained in the formulation as well as the nitrite and nitrate impurities that might be presented in certain excipients. Further, API particle size and water content of the drug product would also affect the growth rate of NDMA. Therefore, the following mitigation strategies to reduce the risk of nitrosamines in the finished drug product are proposed in this manuscript: 1) avoid the use of excipients containing nitrite, nitrate and peroxide impurities; 2) avoid high temperature and strong alkaline environment in the production and storage condition; 3) maintain an appropriate water content level in the formulation. Based on the above principles, it was recommended to add antioxidant or incorporate excipient such as Na₂CO₃ to modify the formulation pH to weak basic environment in the formulation of MET, which can could effectively prevent formation of NDMA in the stability process.

Gugu Hao, Rong Hu, Xiaoqin Wang, Pan Gao, Lin Wang, Manhua Jiang, Libo Xin, Guoying Tan, Yanping Zhao, Fuzhou Sun, Dexin Chu, Jinqian Lv, Jinsong You, Fangfang Huang, Xuezhi Song, N-Nitrosodimethylamine formation in metformin hydrochloride sustained-release tablets: effects of metformin and hypromellose used in drug product formulation, Journal of Pharmaceutical and Biomedical Analysis, 2022, 115066, ISSN 0731-7085,
https://doi.org/10.1016/j.jpba.2022.115066.

excipients formulation