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High sensitivity analysis method of genotoxic impurities in nintedanib ethanesulfonate

A technology for nintedanib ethanesulfonate and genotoxicity, which is applied in the field of analysis of genotoxic impurities in nintedanib ethanesulfonate, can solve unseen and other problems, and achieves simple operation, low cost, efficient separation and detection Effect

Active Publication Date: 2017-06-13
常州佳德医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the quality standards of nintedanib ethanesulfonate are not included in domestic and foreign pharmacopoeias, and there are no reports on the determination of this impurity at home and abroad. According to the relevant provisions of the Principles, according to the threshold of toxicological concern (TTC) as the threshold for evaluating most genotoxic impurities, the maximum intake limit of genotoxic impurities is 1.5 μg / g

Method used

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  • High sensitivity analysis method of genotoxic impurities in nintedanib ethanesulfonate
  • High sensitivity analysis method of genotoxic impurities in nintedanib ethanesulfonate
  • High sensitivity analysis method of genotoxic impurities in nintedanib ethanesulfonate

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Example 1: Analysis of nintedanib ethanesulfonate and genotoxic impurity JD0101 by high performance liquid chromatography-mass spectrometry tandem method.

[0036] 1. Preparation of standard stock solution

[0037] Accurately weigh about 10mg of impurity JD0101, put it in a 100mL measuring bottle, dissolve it with methanol and dilute to the mark to make a solution containing about 0.1mg of JD0101 per 1mL as JD0101 standard stock solution Ⅰ. Precisely pipette 0.1mL of JD0101 standard stock solution Ⅰ, put it in a 100mL volumetric flask, dilute to the mark with methanol, and make standard stock solution Ⅱ containing 0.1μg of JD0101 per 1mL. Then dissolve and gradually dilute to the desired concentration with methanol-water (70:30V / V).

[0038] Two, the test solution

[0039] Accurately weigh about 20 mg of the test product, put it in a 50 mL measuring bottle, dissolve and dilute it with methanol-water (70:30 V / V) to make a solution containing about 0.4 mg per 1 mL as th...

Embodiment 2

[0069] Example 2: High-performance liquid chromatography analysis of nintedanib ethanesulfonate and genotoxic impurity JD0101

[0070] 1. Preparation of standard stock solution

[0071] Accurately weigh about 10mg of impurity JD0101, put it in a 100mL measuring bottle, dissolve it with methanol and dilute to the mark to make a solution containing about 0.1mg of JD0101 per 1mL as JD0101 standard stock solution Ⅰ. Precisely pipette 1mL of JD0101 stock solution Ⅰ, put it in a 100mL measuring bottle, dilute to the mark with methanol, and make standard stock solution Ⅱ containing 1μg of JD0101 per 1mL. Afterwards, gradually dilute to the desired concentration with methanol-water (70:30V / V).

[0072] 2. Instrument and liquid chromatography conditions

[0073] Waters Empower3 chromatographic workstation, automatic sampler, column thermostat. The chromatographic column is ShimadzuInertSustain C18 (4.6*150mm, 5μm), the flow rate is 0.4mL / min, the detection wavelength is 242nm, the c...

Embodiment 3

[0084] 1, the preparation of standard stock solution is identical with embodiment 1;

[0085] 2, need testing solution is identical with embodiment 1;

[0086] 3. Instrument and chromatographic conditions: the temperature of the sample chamber is 5°C, and the rest are the same as in Example 1;

[0087] 4. The methodological verification is the same as in Example 1, and the results show that the average recovery rate of impurity JD0101 (according to the Pharmacopoeia regulation 80-115%) is 99.9%, and the RSD is 3.6%, showing that the accuracy of the method for detecting impurity JD0101 is very good.

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Abstract

The invention discloses a high sensitivity analysis method of genotoxic impurities in nintedanib ethanesulfonate. The method is used for analysis of genotoxic impurity N-(4-aminophenyl)-N, N'-dimethyl-1-piperazine acetylamine (JD0101) in nintedanib ethanesulfonate through a high performance liquid chromatography-mass spectrometry combined analysis method. According to the method, a sample is dissolved in a mixed phase of an organic solvent and water, and the solution is subjected to gradient elution in an octadecyl-bonded silica gel chromatographic column utilizing a methanol and ammonium formate aqueous solution as a mobile phase. The method effectively solves the problem that the UV detector has poor impurity JD0101 detection sensitivity, can efficiently isolate and detect the impurity JD0101 and has the advantages of simpleness, fastness, high specificity and high sensitivity.

Description

technical field [0001] The present invention relates to a method for analyzing genotoxic impurities in nintedanib ethanesulfonate, in particular to a method for analyzing genotoxic impurities N-(4- Aminophenyl)-N,N'-dimethyl-1-piperazineacetamide (code JD0101) for separation and quantitative determination. Background technique [0002] Nintedanib (Nintedanib) is an oral triple angiokinase inhibitor developed by Boehringer Ingelheim, approved by the FDA in October 2014 (nintedanib) for the treatment of idiopathic pulmonary fibrosis (IPF), becoming the first tyrosine kinase inhibitor (TKI) approved for the treatment of IPF. Nintedanib acts on growth factor receptors that have been proven to have potential effects in the pathological mechanism of pulmonary fibrosis, among which the most important growth factor receptors are platelet-derived growth factor receptor (PDGFR), adult Fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR); ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/88
CPCG01N30/88G01N2030/884
Inventor 朱小华
Owner 常州佳德医药科技有限公司
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