吉非替尼片有关物质和质量控制研究

Study on the Related Substances and Quality Control of Gefitinib Tablets

关键词:  高效液相色谱法  吉非替尼片  有关物质  聚类分析  质量控制

Key words:  HPLC  Gefitinib tablets  related substances  cluster analysis  quality control

摘要:

目的 建立吉非替尼片中有关物质的HPLC 测定方法，为该产品的质量控制和评价提供数据支持。方法 采用岛津GL Inertsustain C18色谱柱(3.0 mm×100 mm, 3 μm)，流动相A为0.05 mol?L-1乙酸铵溶液-甲醇(83:17)，流动相B为乙腈，梯度洗脱，流速0.5 mL?min-1，柱温55 ℃，检测波长247 nm，进样量5 μL。结果 吉非替尼与各杂质色谱峰均能有效分离，吉非替尼和14个杂质分别在各自浓度范围内与峰面积呈良好线性关系（r＞0.9994，n=5），检测限在0.02~0.12 μg?mL-1，定量限在0.06~0.35μg?mL-1，杂质1~14的校正因子在0.47~3.65，平均回收率为98.0%~102.0%（n=9）。9家企业146批次吉非替尼片中单个杂质均小于0.1%，杂质总量均小于0.2%，产品的总体质量情况较好。聚类分析结果表明杂质4可作为吉非替尼片制剂生产和贮存的关键质控杂质，杂质8、9、11、12、13和14可作为吉非替尼原料药的关键质控杂质，生产企业可通过监控上述杂质优化生产工艺、筛选优质原料药以提升产品质量。结论 该法专属性强，快速准确，可用于吉非替尼片中有关物质的测定，通过聚类分析确认的关键质控杂质可为吉非替尼片的质量控制及评价提供数据参考。

Abstract:

OBJECTIVE An HPLC method for the determination of related substances in Gefitinib tablets was established, so as to provide data support for the quality control and evaluation of the product. METHODS The separation was performed on a Shimadazu GL Inertsustain C18 column(3.0 mm×100 mm,3 μm), mobile phase A was 0.05 mol?L-1 ammonium acetate solution-methanol(83:17), mobile phase B was acetonitrile. The flow rate was 0.5 mL?min-1 with gradient elution. The detection wavelength was 247 nm, the column temperature was 55 ℃, and the injection volume was 5 μL. RESULTS Gefitinib and the impurities were separated well. The linear relationship between peak area and the concentration range of Gefitinib and 14 known impurities ( r＞0.9994, n=5) were good enough. The limits of quantitation were 0.06~0.35μg?mL-1 and the limits of detection were 0.02~0.12 μg?mL-1. The average recoveries of impurities 1～14 were 98.0%~102.0% ( n=9) and the correction factors were 0.47～3.65, respectively. The results of 146 batches Gefitinib tablets from 9 different companies showed that the content of single impurity was less than 0.1%, and the total content of impurities was less than 0.2%. The overall quality of this product is good. The result of cluster analysis showed that impurity 4 can be considered as a key quality control impurity for the production and storage of Gefitinib tablets, and impurities 8, 9, 11, 12, 13 and 14 can be considered as key quality control impurities of Gefitinib raw material. Production enterprises could optimize the production process and screen high-quality APIs by monitoring the above impurities to improve product quality. CONCLUSION This method was specific, simple and accurate, which can be used for the quality control of related substances in Gefitinib tablets. The key quality control impurities established by cluster analysis could provide data support for controlling and evaluating the quality of Gefitinib tablets.