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.
YE Xiao-xia, GE Yu-qi, LE Jian, WANG Yan, YANG Yong-jian
. Study on influencing factors of metformin hydrochloride’s degradation to N-nitrosodimethylamine induced by sustained-release excipients*[J]. Chinese Journal of Pharmaceutical Analysis, 2021
, 41(2)
: 293
-299
.
DOI: 10.16155/j.0254-1793.2021.02.12
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