5种β受体拮抗剂类药物中的N-亚硝基类杂质的含量研究
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篇名: 5种β受体拮抗剂类药物中的N-亚硝基类杂质的含量研究
TITLE: Content study of N-nitroso impurities in 5 types of β-blockers
摘要: 目的 测定普萘洛尔、美托洛尔、阿替洛尔、艾司洛尔、比索洛尔原料药/制剂中N-亚硝基类杂质含量,明确其含量的关注阈值。方法采用超高效液相色谱-四极杆/静电场轨道阱高分辨质谱技术。以ACEExcel3C18-AR为色谱柱,以含0.01mol/L乙酸铵的0.2%甲酸溶液-甲醇为流动相进行梯度洗脱,流速为0.60mL/min,柱温为40℃,进样量为5μL;以可加热的电喷雾离子源为离子源,以全扫描-选择离子监测模式进行正离子扫描。采用该法对10家企业生产的15批β受体拮抗剂类药物原料药/制剂中N-亚硝基类杂质含量进行测定,并采用DiscoveryStudio软件对待测杂质进行毒性预测和关注阈值估算。结果5种β受体拮抗剂类药物中,N-亚硝基普萘洛尔、N-亚硝基美托洛尔、N-亚硝基阿替洛尔、N-亚硝基艾司洛尔、N-亚硝基比索洛尔检测质量浓度的线性范围分别为1.01~503.38、1.02~508.38、0.97~483.63、1.11~554.27、1.05~523.92ng/mL(r>0.999),定量限分别为1.04、0.25、0.05、0.55、1.05ng/mL,检测限分别为0.52、0.08、0.02、0.17、0.52ng/mL,精密度、重复性、加样回收率、稳定性、耐用性试验的RSD均小于7.5%(n=6或n=5)。15批样品中,除1批样品外,其余批次均检出了N-亚硝基普萘洛尔(1.07~8.91ng/mg)、N-亚硝基美托洛尔(1.43~3.37ng/mg)、N-亚硝基阿替洛尔(1.33ng/mg)、N-亚硝基艾司洛尔(0.19ng/mg)、N-亚硝基比索洛尔(1.27ng/mg)。经预测,上述5种杂质有不同程度的生育毒性、致突变性、致癌性,关注阈值分别为1.0、0.4、4.3、0.2、46.7ng/mg。结论所建方法简单快捷、灵敏度高、专属性强,估算的关注阈值明确,可用于多种β受体拮抗剂类药物中N-亚硝基类杂质的含量控制。
ABSTRACT: OBJECTIVE To determine the contents of N-nitroso impurities in raw materials/formulations of propranolol, metoprolol, atenolol, esmolol and bisoprolol, and clarify the attention threshold. METHODS Ultra-high performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry(UPLC-Q/Orbitrap HRMS)was adopted. An ACE Excel 3 C18-AR column was used for the separation and a mixture of 0.2% formic acid solution with 0.01 mol/L ammonium acetate and methanol was employed as the mobile phase by gradient elution, at a flow rate of 0.60 mL/min. The column temperature was set at 40 ℃ , and the sample size was 5 μL. The heated electrospray ionization source was employed in the positive full mass spectra-selected ion monitoring mode. The contents of N-nitroso impurities in raw materials/formulations of 15 batches of β-blockers from 10 manufacturers were determined by this method. Discovery Studio software was applied to predict the toxicity of the impurities and estimate the attention threshold. RESULTS Among 5 kinds of β-blockers, the linear ranges of N-nitroso propranolol, N-nitroso metoprolol, N-nitroso atenolol, N-nitroso esmolol and N-nitroso bisoprolol were 1.01-503.38, 1.02-508.38, 0.97-483.63, 1.11-554.27 and 1.05-523.92 ng/mL, respectively (r>0.999). The limits of quantitation were 1.04, 0.25, 0.05, 0.55 and 1.05 ng/mL, and the limits of detection were 0.52, 0.08, 0.02, 0.17 and 0.52 ng/mL, respectively. RSDs of precision, reproducibility, recovery, stability and durability tests were all lower than 7.5% (n=6 or n=5). Among the 15 batches of samples, except for 1 batch, N-nitroso propranolol (1.07-8.91 ng/mg), N-nitroso metoprolol (1.43-3.37 ng/mg), N-nitroso atenolol (1.33 ng/mg), N-nitroso esmolol (0.19 ng/mg) and N-nitroso bisoprolol (1.27 ng/mg) were detected in all other batches. According to predictions, the above 5 impurities had varying degrees of reproductive toxicity, mutagenicity and carcinogenicity, with attention thresholds of 1.0, 0.4, 4.3, 0.2 and 46.7 ng/mg, respectively. CONCLUSIONS The established method is simple, rapid, sensitive and specific, the estimated attention thresholds are clear, which can be used for the control of N-nitroso impurities in various β-blockers.
期刊: 2024年第35卷第08期
作者: ⨩ᔀ;杨仪雪;戴聪;刘亚雄;严全鸿
AUTHORS: TIAN Heng,YANG Yixue,DAI Cong,LIU Yaxiong,YAN Quanhong
关键字: β受体拮抗剂类药物;N-亚硝基类杂质;超高效液相色谱-四极杆/静电场轨道阱高分辨质谱技术;基因毒性;关注阈值
KEYWORDS: β-blockers; N-nitroso impurities; UPLC-Q/Orbitrap
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