摘要:
研制他唑巴坦杂质A国家标准物质，为提高国内他唑巴坦的质量控制标准提供依据。对他唑巴坦杂质A进行合成，利用红外、质谱、核磁共振波谱技术进行结构确认，并对杂质A进行含量均匀性检查和短期稳定性考察，再测定其水分和炽灼残渣含量，并以10 mmol/L醋酸铵溶液-乙腈（98∶2）为流动相的高相液相色谱法测定杂质A的纯度，应用质量平衡法确定首批他唑巴坦杂质A国家标准物质的含量，同时采用核磁共振波谱定量法测定其含量，与质量平衡法结果相互验证。结果发现，本研究所研制的他唑巴坦杂质A标准物质与《中华人民共和国药典：二部》（2015年版）他唑巴坦系统适用性溶液中最大降解杂质和USP41中收载的他唑巴坦有关物质A标准物质结构一致；在95%置信范围内，分装后杂质A的瓶间和瓶内方差之比为0.61（小于F0.05（11，12）），均匀性良好；杂质A中有机杂质含量为0.90%，水分含量为1.24%，无机杂质含量为0.25%，以质量平衡法确定杂质A含量为97.6%，与核磁共振波谱定量法结果97.1%基本一致；在25 ℃条件下，杂质A面积归一化纯度在0、3、5和10 d的均值均为99.1%，证明样品在室温下10 d内稳定。本研究首次制备了他唑巴坦杂质A国家标准物质。
Abstract:
To improve the standard of quality control of tazobactam and its preparations in China, national reference standard of tazobactam impurity A was developed. After tazobactam impurity A was synthesized, its structure was validated by infrared (IR), mass spectrometry (MS) and nuclear magnetic resonance (NMR), and its content uniformity and short-term stability were measured and investigated. Then, water content and residue on ignition of impurity A were determined, and its purity was determined using high performance liquid chromatography (HPLC) with 10 mmol/L ammonium acetate solution-acetonitrile (98∶2) as the mobile phase. Mass balance method was used to determine the content of the first batch of tazobactam impurity A national standard substance. Meanwhile, nuclear magnetic quantitative method was used to calculate the content, which was mutually verified with the mass balance method. The developed reference material of tazobactam impurity A is consistent with the maximum degradation impurity in tazobactam system applicability solution and the reference material of tazobactam related substance A contained in USP41. Within the 95% confidence range, the ratio of inter- and intra-bottle variance of impurity A after separation was 0.61 (< F0.05(11,12)), proving that the uniformity was satisfying. The contents of organic impurity, water content and inorganic impurity in impurity A were 0.90%, 1.24% and 0.25%, respectively. The content of impurity A was determined to be 97.6% by mass balance method, which was basically consistent with the result of nuclear magnetic quantitative method (97.1%). Under the condition of 25 °C, the area normalized purity of impurity A was 99.1% at 0, 3, 5 and 10 days, proving that the sample was stable at room temperature for 10 days. Finally the first batch of national standard substance of tazobactam impurity A was established successfully.
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