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A method for detecting trace genotoxic impurities in voriconazole

A technology for voriconazole and genotoxicity is applied in the field of detection of genotoxic impurities, which can solve the problems of no obvious improvement in ultraviolet absorption intensity and inability to solve the quantitative detection of low content, and achieves the effect of ensuring drug safety, easy operation and good separation.

Active Publication Date: 2022-03-08
WUHAN ZY PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the research and development process of the present invention, it has been tried to use thiophenol and other common derivatization reagents to enhance ultraviolet absorption for derivatization treatment, but the final ultraviolet absorption intensity has not been significantly improved, and the problem of low-content quantitative detection cannot be solved.

Method used

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  • A method for detecting trace genotoxic impurities in voriconazole
  • A method for detecting trace genotoxic impurities in voriconazole
  • A method for detecting trace genotoxic impurities in voriconazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1: Detection of genotoxic impurity IN-001 in voriconazole bulk drug

[0075] (1) Instruments and chromatographic conditions used:

[0076] Instrument: high performance liquid chromatography, Shimadzu, LC20AT

[0077] Column: Agilent C 18 , particle size 5μm, inner diameter 4.6*250mm

[0078] Detection wavelength: 267nm

[0079] Injection volume: 20μL

[0080] Column temperature: 40°C

[0081] Mobile phase A: 0.1% formic acid solution; Mobile phase B: acetonitrile

[0082] Flow rate: 1mL / min

[0083] The elution gradient is shown in Table 1:

[0084] Table 1

[0085] time (min) Mobile phase A(%) Mobile phase B(%) 0 80 20 10～25 20 80 25～33 10 90 33～35 10 90 35～40 80 20 40 80 20

[0086] (2) Solution preparation

[0087] Formic acid solution: Take 1mL of formic acid into 1000mL of water and mix well.

[0088] Preparation of biphenyl-4-thiophenol solution: Accurately weigh 10mg of biphenyl-4-thiophenol i...

Embodiment 2- Embodiment 9

[0122] Detection of genotoxic impurity IN-001 in voriconazole API under different detection conditions

[0123] In Example 2-Example 9, except for the following conditions, other parameters and operations are the same as in Example 1, and the specific test conditions and test results are shown in Table 4.

[0124] Table 4

[0125]

[0126] Comparing the above experimental results with the results of Example 1, it can be seen that the detection method of the present invention has good stability and high detection accuracy, and can be used for quality control of voriconazole bulk drug.

Embodiment 10～ Embodiment 14

[0128] Detection of genotoxic impurity IN-001 in voriconazole API with different additions of derivatization reagents

[0129] The applicant also conducted research on impurity detection methods under the conditions of different additions of derivatization reagents. With reference to the operation method of Example 1, the amount of biphenyl-4-thiophenol solution taken in the blank solution, contrast solution, need testing solution and spiked need testing solution is respectively 150 μ L, 200 μ L, 300 μ L, 500 μ L and 1 mL, and other Parameters and operation steps are all the same as in Example 1, and are tested.

[0130] Comparing the experimental results with the results of Example 1, it is found that when the amount of derivatization reagent added is large, such as 500 μL and 1 mL, the adjacent peaks interfere with the derivatization product peak, although the derivatization product peak can be detected, but its quantitative Accuracy decreased; when the amount of derivatiza...

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Abstract

The invention discloses a method for detecting genotoxic impurities in voriconazole. It includes the following steps: after derivatizing the sample to be tested with biphenyl-4-thiophenol, high performance liquid chromatography is used to detect the genotoxic impurity; the sample to be tested is a voriconazole crude drug; the genotoxic impurity is (R / S)-4-(1-bromoethyl)-5-fluoro-6-chloro-pyrimidine. The method can not only realize the effective separation of voriconazole and related genotoxic impurities, but also realize the quantitative detection of micro-content, so as to effectively control the content of genotoxic impurities in the crude drug and ensure drug safety. The detection method of the invention adopts common reagents, and has the advantages of simple operation, good separation degree and high sensitivity. The detection can be achieved by ordinary high performance liquid chromatography, without the need to purchase and combine other instruments, the operation is convenient, and the detection cost is low.

Description

technical field [0001] The invention relates to the technical field of drug detection, in particular to a method for detecting trace genotoxic impurities in voriconazole, in particular to a method for detecting genotoxic impurities containing bromoalkyl functional groups in voriconazole. Background technique [0002] Voriconazole (Voriconazole), trade name Vfend, is a second-generation triazole antifungal drug, developed by Pfizer Company of the United States, and officially listed by FDA in 2002. It is currently the most successful structurally modified compound based on fluconazole. It has the characteristics of high efficiency and low toxicity, and is used for the treatment of fatal deep fungal infections. Voriconazole has the characteristics of broad antibacterial spectrum and strong antibacterial efficacy. It has bactericidal effect on Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Aspergillus nidulans, and Candida albicans, Candida k...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N30/88G01N30/06
CPCG01N30/88G01N30/06G01N2030/067G01N2030/8872
Inventor 向杰刘学威韦彦斌唐红伟
Owner WUHAN ZY PHARM CO LTD