A study of impurities in the repurposed COVID-19 drug hydroxychloroquine sulfate by UHPLC-Q/TOF-MS and LC-SPE-NMR
Xu et al.,
A study of impurities in the repurposed COVID-19 drug hydroxychloroquine sulfate by UHPLC-Q/TOF-MS and..,
Rapid Communications in Mass Spectrometry, doi:10.1002/rcm.9358 (Dosing)
Analysis of HCQ from two manufacturers showing 9 different impurities, with significantly different concentrations for each manufacturer.
Xu et al., 26 Jul 2022, peer-reviewed, 4 authors.
Contact:
clare_ruan@163.com, sunnan@zjut.edu.cn.
Abstract: Ruan Hao (Orcid ID: 0000-0002-7096-0635)
A study of impurities in the repurposed COVID-19 drug hydroxychloroquine sulfate by
UHPLC-Q/TOF-MS and LC-SPE-NMR
Donghai Xu a, Fangfang Pan b, Hao Ruana, b, *, Nan Sun a, **
a
Zhejiang University of Technology, Hangzhou 310014, China
b
Zhejiang Institute for Food and Drug Control, National Medical Product Administration
Key Laboratory for Core Technology of Generic Drug Evaluation, Hangzhou 310052, China
*
Corresponding author. Zhejiang University of Technology, Hangzhou 310014, China.
**
Corresponding author.
E-mail addresses: clare_ruan@163.com (H. Ruan), sunnan@zjut.edu.cn (N. Sun).
ABSTRACT
Rationale: Hydroxychloroquine sulfate is effective in the treatment of malaria, autoimmune
diseases, and as an antiviral drug. However, unreported impurities are often detected in this
drug, which pose a health risk. In this study, the structures of hydroxychloroquine and six
unknown impurities were analyzed using ultra-high performance liquid chromatographyquadrupole/time-of-flight tandem mass spectrometry (UHPLC-Q/TOF MS), and the
structures were characterized using liquid chromatography-solid-phase extraction-nuclear
magnetic resonance spectroscopy (LC-SPE-NMR).
Methods: The column was an Agilent InfinityLad Poroshell HPH-C18 (100 mm × 4.6 mm,
2.7 µm). For the analysis of hydroxychloroquine and six unknown impurities, the mobile
phase was 20 mM ammonium formate aqueous solution and methanol/acetonitrile (80:20,
v/v), using gradient elution. Full-scan MS and MS2 were performed in order to obtain as
much structural information as possible. Additionally, six unknown impurities were separated
by semi-preparative liquid chromatography and characterized by LC-SPE-NMR.
Results: The MS2 fragmentation patterns of the impurities were investigated, leading to more
structural information and an understanding of the fragmentation pathways of the impurities.
The unknown impurities’ structures were confirmed by NMR. In addition, some possible
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doi: 10.1002/rcm.9358
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pathways of the formation of the impurities in the drugs were outlined, and these impurities
were found to be process impurities.
Conclusions: Based on the identification and characterization of these impurities, this study
also describes the cause of the production of the impurities and provides insights for
companies to improve their production processes and a scientific basis for the improvement
of the related pharmacopoeias.
Graphical Abstract
Keywords:
hydroxychloroquine,
impurities,
UHPLC-Q/TOF-MS,
LC-SPE-NMR,
characterization
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