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

化学 赋形剂 N-亚硝二甲胺 色谱法 亚硝酸盐 有机化学 硝酸盐 致癌物
作者
Gugu Hao,Rong Hu,Xiaoqin Wang,Pan Gao,Lin Wang,Manhua Jiang,Libo Xin,Guoying Tan,Yanping Zhao,Fuzhou Sun,Dexin Chu,Jinqian Lv,Jingsong You,Fangfang Huang,Xue‐Zhi Song
出处
期刊:Journal of Pharmaceutical and Biomedical Analysis [Elsevier BV]
卷期号:222: 115066-115066 被引量:21
标识
DOI:10.1016/j.jpba.2022.115066
摘要

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). 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.
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