目的：以聚丙烯酸树脂Ⅱ-羟丙甲基纤维素体系为模型,研究缓释制剂辅料导致盐酸二甲双胍降解生成基因毒性杂质 N-亚硝基二甲胺（NDMA）的相关影响因素。方法：以高效液相色谱-三重四极杆串 联质谱为 NDMA 监测手段,通过试剂替代确定具有降解作用的氧化剂,而后考察溶剂、氧化剂加入量、加热时间、加热温度等因素对 NDMA 生成量的影响。结果：缓释制剂辅料中的过硫酸钾和次氯酸钠产生协同氧化作用,可使盐酸二甲双胍降解生成 NDMA。甲醇、乙醇对该降解具有抑制作用,而水则具促进作用。过硫酸钾-次氯酸钠二元体系的氧化能力大大高于过硫酸钾或次氯酸钠单一体系的氧化能力。任一氧化剂加入量的增加均可增强二元体系的氧化能力。温度对该二元氧化体系具有重要影响,NDMA 的生成量随温度升高而增加,高于 70 ℃后体系的氧化能力显著提升。该二元氧化体系下,盐酸二甲双胍氧化降解成 NDMA 的反应为零级反应,NDMA 的生成量与反应时间成正比。结论：缓释辅料中的残留氧化剂在高温下导致盐酸二甲双胍降解生成 NDMA。选择氧化剂含量低的辅料、严格控制加热温度和加热时间可有效降低甚至避免 NDMA 的生成。建议将残留氧化剂作为辅料的安全性指标纳入辅料质量标准,加强药用辅料的质量控制。制剂的研发应重视原辅料的相容性研究,尤其是辅料中微量氧化剂对易降解原料药的影响,确保制剂产品的安全性和质量可控性。
Objective：To study related influence factors that affect metformin hydrochloride’s degradation to N-nitrosodimethylamine（NDMA）,a typical genotoxic impurity,induced by sustained-release excipients,with the model of polyacrylic resin Ⅱ-Hydroxypropyl methyl cellulose excipients system. Methods：High performance liquid chromatography triple quadrupole tandem mass spectrometry was used to monitor NDMA,and the oxidants inducing the degradation were confirmed by reagent substitution experiment. Then the effects of solvent,oxidant amount,heating time,heating temperature on the generation of NDMA were investigated. Results：Residues of potassium persulfate and sodium hypochlorite in sustained-release excipients of polyacrylic acid resin Ⅱ and hydroxypropyl methyl cellulose had synergistic oxidation effect,and accelerated the degradation of metformin hydrochloride to NDMA. The oxidation ability of potassium persulfate-sodium hypochlorite binary system was much higher than that of potassium persulfate or sodium hypochlorite single system. Potassium persulfate played the essential role in this binary system. The degradation was inhibited by methanol and ethanol,while promoted by water. The oxidation ability of the system was enhanced by increasing the amount of either oxidant. Temperature had significant effect on the degradation. The NDMA formation increased obviously when temperature increased, especially when the temperature was higher than 70 ℃. The curves of time vs concentration of NDMA at different temperature show that this degradation is a zero order reaction dynamically,the NDMA yield is proportional to the reaction time at all temperatures in this research. Conclusion：Metformin hydrochloride’s degradation to NDMA is induced by the residual oxidant in sustained-release excipient at high temperature. The formation of NDMA can be effectively reduced or even avoided by selecting the excipient with low oxidant content and strictly controlling the heating temperature and heating time. It’s recommended that the residual oxidant should be included in specification to strength the quality control of excipients. Attention should be paid to the compatibility of API and excipients,especially to the influence of trace oxidant in excipients on the easily degradable substance during development of preparations to ensure the safety and quality of pharmaceutical products.
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