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Method for determining genotoxic impurities in doxofylline bulk drugs

A determination method and genotoxicity technology are applied in the field of determination of genotoxic impurities in doxofylline raw materials, and achieve the effects of reducing the loss of fixative solution, purifying test background and ensuring accuracy

Active Publication Date: 2020-07-17
陕西省食品药品监督检验研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Aiming at the deficiencies in the prior art, in order to solve the practical problem that the two genotoxic impurities of vinyl acetate and / or 2-bromo-1,1-dioxyethane are lacked in the existing analysis method, the present invention provides a Determination method of related above-mentioned two kinds of genotoxic impurities in a kind of doxofylline crude drug

Method used

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  • Method for determining genotoxic impurities in doxofylline bulk drugs
  • Method for determining genotoxic impurities in doxofylline bulk drugs
  • Method for determining genotoxic impurities in doxofylline bulk drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] 1) Sample preparation:

[0094] Preparation of mixed standard series solutions: Accurately weigh an appropriate amount of each reference substance, and use N,N-dimethylformamide to prepare vinyl acetate concentration of 3.846mg / ml, 2-bromo-1,1-dioxyethane concentration It is 0.3167mg / ml single reference substance stock solution, accurately measure 1ml of single reference substance stock solution into the same 100ml volumetric flask, add N,N-dimethylformamide to dilute and dilute to the mark to make a mixed control Sample stock solution, and then accurately draw and mix appropriate amount of reference stock solution, dilute to vinyl acetate concentration of 0.769μg / ml, 1.23μg / ml, 1.54μg / ml, 1.92μg / ml, 2.31μg / ml, 2- Bromo-1,1-dioxyethane concentrations are 0.0633μg / ml, 0.101μg / ml, 0.127μg / ml, 0.158μg / ml, 0.190μg / ml mixed standard series solutions;

[0095] Preparation of the test sample: Accurately weigh 0.3 g of the crude product of doxofylline (this sample is a simulat...

Embodiment 2-7

[0109] Except that the preparation of the test sample adopts the following method, the same measurement conditions and steps as in Example 1 are adopted.

[0110] Preparation of the test product: Accurately weigh 0.3 g of the crude product and finished product of doxofylline (provided by Shaanxi Bosen Bio-Pharmaceutical Co., Ltd.) into a 10 ml volumetric flask, add appropriate amount of N,N-dimethylformamide, shake and mix well , seal and sonicate for 1min until the sample is completely dissolved, add N,N-dimethylformamide to the mark, shake well, pass through a 0.22μm filter membrane, and the filtrate is used as the test sample.

[0111] The measured gas chromatogram is as image 3 shown. image 3 It is the gas chromatography-mass spectrometry analysis spectrum of the sample.

[0112] The content determination results of the samples are shown in Table 2-7 below.

[0113] Table 2 Sample content determination results

[0114]

[0115] Table 3 Sample content determination...

Embodiment 3

[0127] Embodiment 3 methodological investigation

[0128] The specificity, linearity, precision, repeatability, accuracy, stability, detection limit and quantification limit of the method for the determination of two genotoxic impurities in doxofylline bulk drug were investigated. The specific inspection methods are:

[0129] 1. Linear inspection

[0130] Accurately weigh the appropriate amount of each reference substance, and use N,N-dimethylformamide to prepare vinyl acetate concentrations of 0.769 μg / ml, 1.23 μg / ml, 1.54 μg / ml, 1.92 μg / ml, and 2.31 μg / ml , 2-bromo-1,1-dioxyethane concentrations are respectively 0.0633μg / ml, 0.101μg / ml, 0.127μg / ml, 0.158μg / ml, 0.190μg / ml mixed standard series solutions (according to the increasing concentration The sequence is referred to as std1 solution, std2 solution, std3 solution, std4 solution and std5 solution). Inject the mixed standard series solution into the gas chromatograph-mass spectrometer, measure the corresponding peak area...

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Abstract

The invention relates to the technical field of drug analysis, in particular to a method for determining genotoxic impurities in doxofylline bulk drugs. According to the determination method, a gas chromatography-mass spectrometry method is adopted for determination. The method is high in sensitivity, and two genotoxic impurities can be simply, quickly and accurately measured at the same time.

Description

technical field [0001] The invention belongs to the technical field of drug analysis, in particular to a method for determining genotoxic impurities in doxofylline raw materials. Background technique [0002] Doxofylline, a derivative of methylxanthine, is a bronchodilator that can relax tracheal smooth muscle and inhibit asthma by inhibiting phosphodiesterase in smooth muscle cells. [0003] [0004] Doxofylline uses vinyl acetate and 2-bromo-1,1-dioxyethane in the synthesis process, and this structure has potential genotoxicity. According to the usage and dosage of this drug preparation, the impurity limit of the above-mentioned genotoxic impurities is 20ppm, adopting the separation and analysis method of general liquid chromatography and gas chromatography, the determination sensitivity of these two genotoxic impurities is more difficult to meet the control requirements of drug inspection. [0005] Therefore no matter from drug quality control or quality standard rese...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/06G01N30/72
CPCG01N30/02G01N30/06G01N30/72G01N2030/025G01N2030/062
Inventor 罗晶戴涌柳小秦安学霞黄佳焦文冬刘文龙唐娜魏亚宁吴沛佳
Owner 陕西省食品药品监督检验研究院
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