国产阿莫西林克拉维酸钾片质量评价

Quality evaluation of domestic amoxicillin and clavulanate potassium tablets

目的:考察现行质量标准的科学性,评价国产阿莫西林克拉维酸钾片的质量现状及存在的问题。方法:采用现行标准对抽验样品进行法定检验;建立并完善了用于探索性研究的多个方法:(1)采用中国药典2010年版中梯度条件代替原标准中的方法对抽验样品进行有关物质检查;(2)采用LC-MS法[Agilent 1100 LC/MSD Trap液质联用仪,Shim-pack CLC-ODSC18(4.6 mm×150 mm,5μm,日本岛津公司)]研究本品的杂质谱,根据该研究结果,建立了分区域计算有关物质的方法;(3)采用交叉验证法验证和完善了现有的NIR定性定量模型并新建了NIR水分定量模型;(4)采用自动取样溶出仪(SOTAXAT7 Smart)进行溶出试验、采用新建立UPLC法(Agilent Technologies 1920 Infinity型超高压液相色谱仪)测定溶出量,研究国内外口服制剂溶出行为的差异。结果:法定检验显示,本次抽验样品绝大多数批次符合标准规定;杂质谱研究结果显示,口服制剂中有19个潜在杂质,不同来源的杂质具有明显分区,与阿莫西林有关的杂质主要集中在克拉维酸主峰后,而与克拉维酸有关的杂质则集中在克拉维酸主峰前,采用杂质归属分区域法检测杂质含量,得到的杂质含量更合理;本品溶液状态稳定性较差(温度>25℃时,3h降解2.0%～3.1%,尤其是克拉维酸组分);验证并完善了现有的NIR定性、定量模型并新建了NIR水分测定模型;新建的UPLC快速检测方法使两组分在1分钟内出峰完毕,满足了快速测定的要求;不同生产厂家片剂之间溶出行为差异显著,与进口片剂溶出曲线也明显不同。结论:目前绝大部分国产阿莫西林克拉维酸钾片的产品质量能符合现行标准要求;现行标准存在缺陷,如有关物质检查的计算方法不尽合理;新建计算方法能有效弥补现行标准的缺陷,测定结果能更真实地反映药品质量,有助于发现目前产品中的质量问题,进而促进产品质量的提高。

Objective：To evaluate the suitability of statutory standard and the quality condition of amoxicillin and clavulanate potassium tablets.Methods：Using statutory methods to test the samples.Establish or improve some methods for the exploratory research：（1）Using the gradient elution method in ChP 2010 to determine the related substances for amoxicillin and clavulanate potassium tablets.（2）LC-MS method（Agilent 1100 LC /MSD Trap）was carried on a shim-pack CLC-ODS C18 column（4.6 mm×150 mm,5 μm Shimazu）to study the impurities profile of amoxicillin and clavulanate potassium tablets.According to the result of this research,we established the new impurities calculation method（calculate in different division）.（3）The stability of amoxicillin and clavulanate potassium in solution was detected in different time and temperature.（4）Use the crossed-validation method of NIR to validate and improve the qualitative and quantitative models using in the mobile Lab vehicle,and established the quantitative model of water-detection.（5）The automated sampling dissolution analyzer（SOTAX AT7 Smart）and the new established UPLC method（Agilent Technologies 1920 Infinity UPLC）were used to research the difference of dissolution behavior of amoxicillin and clavulanate potassium tablets between domestic and foreign tablets.Rseults： The quality of domestic amoxicillin and clavulanate potassium tablets met the requirement of current statutory standards.19 impurities were detected from the tablet.The result showed the impurities from different sources had obvious division,and the impurities of amoxicillin were eluted mainly after the peak of clavulanate in the chromatogram,whereas the impurities of clavulanate mainly before this peak.The off-standard rate of samples by using the new calculation method instead of the previous was increased significantly.The stability of the solution is not very good,especially clavulanate.Validate and improve the qualitative and quantitative models using in the mobile Lab vehicle,and established the quantitative model of water-detection.The new-established UPLC method can satisfy the requirement of fast-testing by shorting the time for an analysis program within 1 minute.The dissolution behavior of amoxicillin and clavulanate potassium tablets were different between different manufacturers.Conclusions：The quality of domestic amoxicillin and clavulanate potassium tablets met the requirement of current statutory standards.There are still some defects in current standards,for example,the calculation method of the impurities is not very reasonable.The new-established method can be used to improve the quality specification,and is suitable for controlling the quality of this drug.