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Method for detecting methanesulfonate genotoxic impurities in lenvatinib mesylate by gas chromatography

A technology of gas chromatography and methyl methanesulfonate, applied in the field of pharmaceutical analysis, can solve the problems of low accuracy, inability to accurately control mesylate substances, low recovery rate, etc.

Pending Publication Date: 2021-04-20
南京佰麦生物技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is the peak area external standard method, when the test product is lenvatinib mesylate, the interference of the test product itself in the derivatization process is very large, the recovery rate is lower than 80%, the accuracy of the method is low, and it cannot be obtained. Accurate control of mesylate substances

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  • Method for detecting methanesulfonate genotoxic impurities in lenvatinib mesylate by gas chromatography
  • Method for detecting methanesulfonate genotoxic impurities in lenvatinib mesylate by gas chromatography
  • Method for detecting methanesulfonate genotoxic impurities in lenvatinib mesylate by gas chromatography

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] 1) Test solution preparation:

[0063] (1) Solvent: Acetonitrile and water are mixed in a volume ratio of 60:40;

[0064] (2) Derivatization solution: Weigh 20 g of sodium iodide and 20 mg of vitamin C, weigh them accurately, add water to dissolve and dilute to 20 mL, and obtain a derivatization solution containing about 1 g of sodium iodide and 1 mg of vitamin C per 1 ml.

[0065] (3) Blank solution: Weigh 10g of sodium iodide and 10mg of vitamin C, weigh them accurately, add water to dissolve and dilute to 10ml, and obtain a blank solution containing 1g of sodium iodide and 1mg of vitamin C per 1ml of solution.

[0066] (4) Reference substance stock solution: Weigh 25 mg of methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate respectively, weigh them accurately, add 100 mL of solvent to quantitatively dilute to make about 1 ml of methanesulfonic acid A solution of 250 μg each of methyl ester, ethyl methanesulfonate and isopropyl methanesulfo...

Embodiment 2

[0093] Embodiment 2 external standard method comparative verification

[0094] Under the preparation of the solution, solvent, 100% reference substance solution, 50% limit solution of the test product, 100% limit solution of the test product, and 150% limit solution of the test product are chromatographed according to specificity Conditional headspace injection was performed, and the recovery rate was determined by the peak area external standard method.

[0095] Table 2 External standard method recovery rate result

[0096]

[0097] In conclusion, under the chromatographic conditions, the components of methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate were derivatized to generate methyl iodide, ethyl iodide and isopropane iodide respectively, and the recoveries of each component were average. If it is not within the range of 80% to 120%, the accuracy of the method does not meet the requirements. It is necessary to improve the optimization met...

Embodiment 3

[0098] Embodiment 3 standard addition method verification

[0099] Need testing solution, need testing solution spiked 50% limit solution, need testing substance spike 100% limit solution, need testing sample spike 150% limit solution headspace sample record chromatogram respectively, as Figure 4 to Figure 7 , according to each chromatogram, calculate the content of mesylate impurities by the standard addition method. In the chromatogram of the test product spiked solution, methyl iodide (methyl methanesulfonate), ethyl iodide (ethyl methanesulfonate), and isopropane iodide (isopropyl methanesulfonate) go out successively. The degree of separation is greater than 1.5. Taking the added content (μg / ml) of each mesylate reference substance as the X-axis, and taking the peak area as the Y-axis, draw a standard curve. Calculate the content of each mesylate in the test product by the following formula.

[0100] Methyl methanesulfonate or ethyl methanesulfonate or isopropyl metha...

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Abstract

The invention discloses a method for detecting methanesulfonate genotoxic impurities in lenvatinib mesylate by gas chromatography, the methanesulfonate genotoxic impurities may be contained in an antitumor drug lenvatinib mesylate, and at present, the methanesulfonate genotoxic impurities are generally detected by liquid chromatography or gas chromatography-mass spectrometry; according to the method, a sample is derivatized through a derivatization solution of sodium iodide and vitamin C, methanesulfonate substances in lenvatinib mesylate are detected by adopting a gas chromatograph, methanesulfonate impurities are calculated by adopting a standard addition method, the interference of a test sample can be effectively reduced, the method is superior to a common external standard method and a common internal standard method in accuracy, methodology verification proves that the method has good sensitivity, precision and accuracy, and the method is low in detection cost, high in operability and superior to a conventional liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry method.

Description

technical field [0001] The invention relates to the field of drug analysis, in particular to a gas chromatography method for detecting mesylate genotoxic impurities that may be contained in antitumor drugs. Background technique [0002] Lenvatinib mesylate is a tyrosine kinase (RTK) receptor inhibitor that inhibits the kinase activity of the vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4) In addition, it can also inhibit other RTKs related to pro-angiogenic and tumorigenesis pathways, including fibroblast growth factor (FGF), receptors FGFR1, 2, 3 and 4, platelet-derived growth factor (PDGF) receptors PDGFRα, KIT and RET. [0003] The structural formula of lenvatinib mesylate is: [0004] [0005] Mesylate substances are impurities that may be produced during the production process of lenvatinib mesylate. This type of impurity has a genotoxicity warning structure. According to the ICH M7 guidelines, mesylate substances n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/06G01N30/68
Inventor 于学珍蒋玉伟鲍晓芳
Owner 南京佰麦生物技术有限公司
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