液质联用法同时测定雷尼替丁中NDMA和其他杂质

田珩; 吴纯敏; 贝琦华; 严全鸿

doi:10.13748/j.cnki.issn1007-7693.20250107

液质联用法同时测定雷尼替丁中NDMA和其他杂质

Simultaneous Determination of NDMA and Other Impurities in Ranitidine by Liquid Chromatography-mass Spectrometry

摘要

摘要:
目的建立一种可同时测定雷尼替丁中N-亚硝基二甲胺(N-nitrosodimethylamine，NDMA)和其他杂质的方法。
方法采用液相色谱-高分辨质谱或液相色谱-三重四极杆质谱，以Titank C₁₈色谱柱(150 mm×4.6 mm，3 μm)为固定相，以含5 mmol·L⁻¹乙酸铵的0.1%氨水水溶液-含0.1%氨水的乙腈溶液为流动相，梯度洗脱，流速0.5 mL·min⁻¹，采用加热电喷雾离子(HESI)源或大气压化学电离(APCI)源，分别对应平行反应监测结合全扫描/二级扫描2种模式交替及多反应监测模式采集质谱数据，紫外或DAD检测器采集紫外吸收图谱和数据，同时对雷尼替丁中NDMA和其他杂质进行定性和定量分析。
结果 NDMA和雷尼替丁各有关物质峰与雷尼替丁峰分离良好，NDMA在2~1000 ng·mL⁻¹线性关系良好，相关系数(r²)>0.99；定量下限为1.01 ng·mL⁻¹(HESI)或2.08 ng·mL⁻¹(APCI)，检出限为0.50 ng·mL⁻¹(HESI)或1.04 ng·mL⁻¹(APCI)；3个不同加标水平下，2台仪器的平均回收率分别在93.6%~101.3%和97.5%~99.9%，相对标准偏差(RSD，n=6)分别在1.6%~2.7%和3.5%~4.8%。8批样品中NDMA含量在0.06~66.55 mg·kg⁻¹，最大单杂在0.05%~0.18%，总杂质在0.15%~0.97%；共识别出14种杂质，除1批胶囊样品中最大单杂为EP杂质I外，其他7批样品中的最大单杂均为EP杂质A。
结论本方法专属性强，灵敏度高，可同时测定雷尼替丁中NDMA和其他有关物质，适用于不同原理和离子源的质谱检测器，有助于相关产品的质量研究。

Abstract:
OBJECTIVE To establish a method for simultaneous determination of N-nitrosodimethylamine(NDMA) and other impurities in ranitidine.
METHODS Liquid chromatography-high resolution mass spectrometry or liquid chromatography-triple quadrupole mass spectrometry was used with Titank C₁₈ column(150 mm×4.6 mm, 3 μm) as the stationary phase, 0.1% ammonia water solution containing 5 mmol·L⁻¹ ammonium acetate-acetonitrile containing 0.1% ammonia water as mobile phase for gradient elution. The flow rate was 0.5 mL·min⁻¹. The mass spectrometry data were acquired using the heated electrospray ionization(HESI) source or atmospheric pressure chemical ionization(APCI) source, with the parallel reaction monitoring combined with alternating of Full MS/dd-MS² mode and multiple reaction monitoring respectively. The UV absorption spectrum and data were collected by UV or DAD detector. The qualitative and quantitative analysis of NDMA and other impurities in ranitidine were conducted simultaneously.
RESULTS NDMA and related substances of ranitidine were well separated from the ranitidine, and NDMA showed a good linear relationship within the concentration range of 2–1000 ng·mL⁻¹, with the correlation coefficient(r²) >0.99; the lower limit of quantification was 1.01 ng·mL⁻¹(HESI) or 2.08 ng·mL⁻¹(APCI), and the detection limit was 0.50 ng·mL⁻¹(HESI) or 1.04 ng·mL⁻¹(APCI); at 3 different spiking levels, the average recoveries of the 2 instruments ranged from 93.6% to 101.3% and 97.5% to 99.9%, respectively, with relative standard deviations(RSD, n=6) ranged from 1.6% to 2.7% and 3.5% to 4.8%, respectively. The NDMA content in 8 batches of samples ranged from 0.06 mg·kg⁻¹ to 66.55 mg·kg⁻¹, with the maximum single impurity ranged from 0.05% to 0.18% and the total impurity ranged from 0.15% to 0.97%. A total of 14 impurities were identified. Except for 1 batch of capsule sample in which the largest single impurity identified as EP impurity I, the largest single impurity in the other 7 batches of samples was EP impurity A.
CONCLUSION The proposed method is specific and sensitive for the simultaneous detecting of NDMA and other related substances in ranitidine, which is suitable for mass spectrometry detectors with different principles and ion sources, and can be used for quality studies of related products.

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