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Method for simultaneously detecting genotoxic impurities 5-isoquinoline sulfonic acid methyl ester and 5-isoquinoline sulfonic acid ethyl ester in fasudil hydrochloride

A technology of methyl isoquinoline sulfonate and ethyl isoquinoline sulfonate, applied in the field of detection of genotoxic impurities in Fasudil hydrochloride, achieving good accuracy, good solution stability, and improved sensitivity

Active Publication Date: 2020-09-04
北京阳光诺和药物研究股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Potentially genotoxic impurities are similar to genotoxic impurities in structure, and are warning, but compounds such as aflatoxins, nitrosamine compounds, and methylsulfonate that have not been proved by experiments are common genotoxic impurities

Method used

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  • Method for simultaneously detecting genotoxic impurities 5-isoquinoline sulfonic acid methyl ester and 5-isoquinoline sulfonic acid ethyl ester in fasudil hydrochloride
  • Method for simultaneously detecting genotoxic impurities 5-isoquinoline sulfonic acid methyl ester and 5-isoquinoline sulfonic acid ethyl ester in fasudil hydrochloride
  • Method for simultaneously detecting genotoxic impurities 5-isoquinoline sulfonic acid methyl ester and 5-isoquinoline sulfonic acid ethyl ester in fasudil hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1, determination of HPLC detection method of the present invention

[0048] Ultraviolet spectrum scanning of methyl 5-isoquinolinesulfonate and ethyl 5-isoquinolinesulfonate: Accurately weigh the appropriate amount of methyl 5-isoquinolinesulfonate and ethyl 5-isoquinolinesulfonate , respectively add acetonitrile to dissolve and dilute to prepare a solution containing about 5.0 μg / ml of methyl 5-isoquinolinesulfonate and ethyl 5-isoquinolinesulfonate. Each solution was scanned in the range of 400nm-200nm, and the results are shown in Table 1.

[0049] Table 1 The maximum absorption wavelengths of methyl 5-isoquinolinesulfonate and ethyl 5-isoquinolinesulfonate

[0050] name maximum absorption wavelength Methyl 5-isoquinolinesulfonate A238.00nm Ethyl 5-isoquinolinesulfonate A238.00nm solvent blank /

[0051] It can be seen that methyl 5-isoquinolinesulfonate and ethyl 5-isoquinolinesulfonate all have larger absorption at a...

Embodiment 2

[0072] Embodiment 2, the separation and determination of fasudil hydrochloride and its genotoxic impurities in the test product

[0073] 1. Preparation of related solutions

[0074] (1) 5-isoquinolinesulfonate methyl ester stock solution: take an appropriate amount of 5-isoquinolinesulfonate methyl ester reference substance, accurately weighed, dissolve with methanol and quantitatively dilute to make a solution containing 1 μg per 1ml, as 5 - Methyl isoquinolinesulfonate stock solution.

[0075] (2) 5-isoquinoline sulfonate ethyl ester stock solution: take an appropriate amount of 5-isoquinoline sulfonate ethyl ester reference substance, accurately weighed, dissolve with methanol and quantitatively dilute to make a solution containing 1 μg per 1 ml, as 5 - Ethyl isoquinolinesulfonate stock solution.

[0076] (3) System suitability solution: take about 50 mg of fasudil hydrochloride reference substance (source: China Institute for Food and Drug Control batch number: 100614-20...

Embodiment 3

[0093] Embodiment 3, linear relationship test

[0094] Take an appropriate amount of 5-isoquinolinesulfonate methyl ester and 5-isoquinolinesulfonate ethyl ester reference substance, add mobile phase A to dilute to make a solution containing about 1 μg of each reference substance per 1ml, as a linear stock solution; Take an appropriate amount of linear stock solution and dilute with mobile phase A to make solutions with concentrations of limit of quantification, 0.04 μg / ml, 0.08 μg / ml, 0.12 μg / ml, 0.16 μg / ml, as linear solutions of various concentrations.

[0095] Precisely measure 20 μl of each of the above solutions and inject them into the liquid chromatograph, and record the chromatograms. Make a linear equation with the concentration C (μg / ml) on the peak area (A), and the results are shown in Table 5 and Table 6.

[0096] Table 5 Linear results of methyl 5-isoquinolinesulfonate

[0097]

[0098] Table 6 Linearity results of ethyl 5-isoquinolinesulfonate

[0099] ...

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Abstract

The invention discloses a method for simultaneously detecting genotoxic impurities including methyl 5-isoquinoline sulfonate and ethyl 5-isoquinoline sulfonate in fasudil hydrochloride. The detectionmethod comprises the following steps: carrying out HPLC detection, wherein the HPLC detection conditions are as follows: a stationary phase is octadecylsilane chemically bonded silica, the detection wavelength is 238 nm, the mobile phase A is a triethylamine aqueous solution with the volume fraction of 0.5%, and phosphoric acid is adopted to adjust the pH to 7.0, a mobile phase B is methanol, theelution mode is gradient elution, wherein the procedure of the elution gradient is as follows: in 0-18 minutes, the volume fraction of the mobile phase A is 99%; in 18-35 min, the volume fraction of the mobile phase A is reduced from 99% to 40%; in 35-40 min, the volume fraction of the mobile phase A is kept at 40%in 40-41 min, the volume fraction of the mobile phase A is increased from 40% to 99%, and in 41-50 min, the volume fraction of the mobile phase A is kept at 99%. By using the method, the detection sensitivity can be greatly improved, equipment and instruments are common, the detection cost is low, the operation is extremely simple and convenient, and the detection cost and the detection time are greatly saved.

Description

technical field [0001] The invention relates to a method for detecting genotoxic impurities in fasudil hydrochloride, belonging to the technical field of drug analysis. Background technique [0002] Genotoxic impurities refer to compounds that directly or indirectly damage cellular DNA, cause gene mutations or in vivo mutagenesis, and have the possibility or tendency to cause cancer. Potentially genotoxic impurities are similar to genotoxic impurities in structure, and are warning, but compounds such as aflatoxins, nitrosamine compounds, and methylsulfonate that have not been proved by experiments are common genotoxic impurities . In recent years, regulations and agencies of various countries such as ICH, FDA, EMA, etc. have made clearer requirements on genotoxic impurities, and more and more pharmaceutical companies are focusing on the control and detection of genotoxic impurities in the process of new drug research and development. [0003] The potential genotoxic impuri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/86
CPCG01N30/02G01N30/8679G01N2030/047
Inventor 刘宇晶郑柏松孙丽王金泉万忠民谌宗永
Owner 北京阳光诺和药物研究股份有限公司