Content study of N-nitroso impurities in 5 types of β-blockers
- VernacularTitle: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
- Author:
Heng TIAN
1
;
Yixue YANG
1
;
Cong DAI
1
;
Yaxiong LIU
1
;
Quanhong YAN
1
Author Information
1. Guangdong Institute for Drug Control/ NMPA Key Laboratory for Quality Control and Evaluation of Pharmaceutical Excipients，Guangzhou 510180，China
- Publication Type:Journal Article
- Keywords:
β-blockers;
N-nitroso impurities;
UPLC-Q/Orbitrap
- From:
China Pharmacy
2024;35(8):936-941
- CountryChina
- Language:Chinese
-
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.
