二甲双胍亚硝胺杂质研究及亲水凝胶骨架材料的筛选

目的 探讨不同亲水凝胶骨架材料与盐酸二甲双胍(metformin hydrochloride,MET)降解生成N-二甲基亚硝胺(N-dimethylnitrosamine,NDMA)之间的相关性,筛选合适的骨架材料用于制备MET缓释片。方法 以高效液相色谱-三重四极杆串联质谱为NDMA监测手段,通过原辅料相容性考察确定产生NDMA风险较低的骨架材料,而后考察溶胀性能,确定溶胀作用与参比制剂相似的骨架材料,将筛选出的骨架材料制备缓释片后考察其体外溶出和剂量倾泻的行为。结果 原辅料相容性考察发现羟丙甲纤维素(hypromellose,HPMC)是引起MET降解产生NDMA的主要原因,并筛选出溶胀作用与HPMC相似的卡波姆,以其为骨架材料制备缓释片可获得与参比制剂相似的溶出曲线,且剂量倾泻风险较低,产品稳定性良好。结论 卡波姆可作为HPMC的替代材料,用于制备MET缓释片。

Research on Metformin Hydrochloride Nitrosamine Impurities and Screen of Hydrophilic Gel Matrix Materials

OBJECTIVE To investigate the correlation between different hydrophilic gel matrix materials and the presence of N-dimethylnitrosamine(NDMA) in metformin hydrochloride(MET) in order to screen the appropriate matrix materials for the preparation of MET sustained-release tablets. METHODS High performance liquid chromatography-triple quadrupole tandem mass spectrometry was used to monitor NDMA. The matrix materials with lower risk of NDMA and similar swelling effect to reference listed drug were firstly determined by compatibility study between raw materials and excipients followed by swelling performance test, then MET sustained-release tablets were prepared with the selected material to investigate its in vitro dissolution behaviors and the risk of alcohol-induced dose dumping. RESULTS It was found that hypromellose(HPMC) was the main cause of the presence of NDMA in MET, and carbopol had similar swelling performance to HPMC. MET sustained-release tablets prepared with carbopol as the matrix material had similar dissolution profiles with reference listed drug, lower risk of dose dumping and better product stability. CONCLUSION Carbopol can be used as an alternative material for HPMC to prepare MET sustained-release tablets.