目的: 对市场抽检的注射用奥扎格雷钠开展有关物质研究。方法: 首先建立注射用奥扎格雷钠有关物质的高效液相色谱评价方法,选用Inertsil ODS C18色谱柱,以0.01 mol·L-1醋酸铵缓冲液-甲醇(80∶20)为流动相A,以甲醇为流动相B,梯度洗脱,流速1.0 mL·min-1,检测波长272 nm,进样体积20 μL。采用所建方法对46批注射用奥扎格雷钠开展有关物质评价。含量＞0.1%的杂质采用Q-TOF高分辨质谱以ESI+模式进行质谱扫描。结果: 所建方法检测限为0.010 μg·mL-1,破坏性试验结果表明该条件下,奥扎格雷与杂质分离良好。研究发现所有样品杂质总量均＜1.0%,有5批样品检出含量为0.16%~0.23%的单个最大杂质(杂质Ⅰ),这5批样品杂质总量达到0.61%~0.69%%。加速试验前后各样品的单个最大杂质无明显变化,杂质总量的差异值均＜0.06%。0.9%氯化钠注射液和5%葡萄糖注射液配伍使用对有关物质水平无影响。经高分辨质谱解析,结合生产工艺文献,推测杂质Ⅰ为奥扎格雷原料合成中间体(E)-4-(1-咪唑甲基)肉桂酸甲酯。结论: 市场上的注射用奥扎格雷钠有关物质均符合我国该品种现行质量标准要求。但研究发现,现行质量标准中,有部分杂质未被有效监控。本文所建方法能够有效监控注射用奥扎格雷钠的杂质,获得全面的杂质信息。该方法还可进一步推广应用于奥扎格雷原料药和其他奥扎格雷制剂的产品质量监控。
Objective: To investigate the related substances in ozagrel sodium for injection sampled in the market. Methods: An HPLC method for the evaluation of related substances in ozagrel sodium for injection was established. The chromatography was performed on Inertsil ODS C18 column with 0.01 mol·L-1 ammonium acetate buffer-methanol (80∶20) as mobile phase A and methanol as mobile phase B. The detection wavelength was set at 272 nm at the flow rate of 1.0 mL·min-1, and the sample volume was 20 μL. Forty-six batches of sodium ozagrel for injection were evaluated using the established method. Impurities with content >0.1% were scanned by Q-TOF high resolution mass spectrometry in ESI+ mode. Results: The detection limit of the proposed method was 0.010 μg·mL-1, and the destructive test results showed that ozagrel was well separated from impurities under this condition. It was found that the total amount of impurities in all samples was less than 1.0%, and the single maximum impurity (impurity I) with the content of 0.16%-0.23% was detected in 5 samples, and the total amount of impurities in these 5 samples reached 0.61%-0.69%. The single maximum impurity of each sample had no obvious change before and after the accelerated test, and the difference value of total impurity was <0.06%. The combined use of 0.9% sodium chloride injection and 5% glucose injection had no effect on the level of related substances. Impurity Ⅰ was inferred to be (E)-4-(1-imidazolmethyl) methyl cinnamate synthesized from ozgrel raw material by high resolution mass spectrometry combined with production process literature. Conclusion: The related substances in sodium ozagrel for injection in the market are in line with the existing quality standards of this variety in China. However, it is found that some impurities in the existing quality standards are not effectively monitored. The method developed in this article can effectively monitor the impurities of sodium ozagrel for injection and obtain comprehensive impurity information. The method can be further applied to product quality control of ozagrel raw materials and other ozagrel preparations.
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