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Method for testing genotoxic impurity in sacubitril valsartan sodium starting material

A technology of sacubitrilvaler and sartan sodium, which is applied in the field of analytical chemistry and can solve the problems of inability to complete method verification, sample detection, and low response

Active Publication Date: 2021-04-06
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] According to the relevant provisions of the "Guidelines on the Limits of Genotoxic Impurities" in EMEA, the TTC value of most drugs is evaluated by toxicological concern thresholds. The intake of genotoxic impurities is 1.5 μg / day. Limit = 1.5μg / 0.4g = 3.75ppm. Under conventional HPLC chromatographic conditions, impurity B has a low response at this limit concentration, and method verification and sample detection cannot be completed. There is no literature report on this potential genotoxic impurity detection method

Method used

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  • Method for testing genotoxic impurity in sacubitril valsartan sodium starting material
  • Method for testing genotoxic impurity in sacubitril valsartan sodium starting material
  • Method for testing genotoxic impurity in sacubitril valsartan sodium starting material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1 Impurity B detection method

[0038] Take about 0.3g of the test product, weigh it accurately, put it in a 5ml measuring bottle, add 2ml of methanol to dissolve it, add 2ml of 0.1% ammonia water, let it stand for 5 minutes, dilute to the mark with methanol, shake well, filter, and take the subsequent filtrate as the test sample. Test solution: Accurately weigh an appropriate amount of impurity Ⅱa-7 reference substance, add solvent [methanol-0.1% ammonia solution (60:40)] and quantitatively dilute to make a solution containing 210ng of Ⅱa-7 in every 1ml, as the reference substance solution . Measured according to liquid chromatography (Chinese Pharmacopoeia 2015 edition Sibu general rule 0512) and mass spectrometry (Chinese pharmacopoeia 2015 edition Sibu general rule 0431), using octadecylsilane bonded silica gel as filler (InfinityLabPoroshell 120EC-C18, 4.6mm×50mm , 2.7 μm); the mobile phase A is 0.1% ammonia solution, and the mobile phase B is methanol,...

Embodiment 2

[0040] Example 2 Specificity

[0041] Blank (solvent): methanol:0.1% ammonia solution (60:40).

[0042] Reference substance stock solution: Accurately weigh an appropriate amount of impurity B reference substance, add solvent and quantitatively dilute it to make about 2.1 μg of impurity B per 1 ml, as the reference substance solution.

[0043] Reference substance solution: Accurately measure an appropriate amount of the reference substance stock solution, add solvent and quantitatively dilute to make a solution containing about 210ng of impurity B per 1ml, as the reference substance solution.

[0044] The test solution: take about 0.3g of the test sample, weigh it accurately, put it in a 5ml measuring bottle, add 2ml of methanol to dissolve it, add 2ml of 0.1% ammonia water, let it stand for 5 minutes, dilute to the mark with methanol, shake well, filter, Take the continued filtrate as the test solution.

[0045] Mixed solution: Take about 0.3g of the test product, weigh it ...

Embodiment 3

[0050] Embodiment 3 detection limit and quantitative limit

[0051] Quantitation limit solution: Accurately measure the reference substance solution in Example 2, quantitatively dilute step by step with a solvent, accurately measure 3 μl, inject liquid mass spectrometer, record mass spectrogram, and calculate according to the signal-to-noise ratio not lower than 10:1 The limits of quantitation are shown in Table 3.

[0052] Detection limit solution: Accurately measure the reference substance solution in Example 2, quantitatively dilute step by step with a solvent, accurately measure 3 μl, inject the liquid mass spectrometer, record the mass spectrogram, and calculate according to the signal-to-noise ratio not lower than 3:1 The detection limit is shown in Table 2.

[0053] Table 2 Impurity B detection limit and quantitative limit test results

[0054]

[0055] Precisely measure 3 μl of the limit of quantification solution, inject it into the liquid chromatography-mass spe...

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Abstract

The method for detecting the genotoxic impurity B in the sacubitril valsartan sodium starting material is established by adopting a liquid chromatography-mass spectrometry (LC-MS) technology. The detection method has the advantages of high sensitivity, good specificity, good sample introduction precision and good method accuracy, and realizes effective control of impurities in sacubitril valsartan sodium, so the quality of sacubitril valsartan sodium and the medication safety of patients are guaranteed to a certain degree.

Description

technical field [0001] The invention belongs to the technical field of analytical chemistry, and in particular relates to a genotoxic impurity testing method of sacubitril-valsartan sodium starting material. Background technique [0002] Sacubitril Valsartan Sodium (Sacubitril Valsartan Sodium) is an anti-heart failure drug researched and developed by Novartis PharmaStein AG. It is listed in the United States and the European Union. For adult patients with chronic heart failure (NYHA II-IV, LVEF≤40%) with reduced ejection fraction, to reduce the risk of cardiovascular death and hospitalization for heart failure. [0003] In the synthesis process of the starting material for the synthesis of sacubitril and valsartan sodium, compound B is used. The structure of compound B contains an aldehyde group, which is a genotoxicity warning structure and a potential genotoxic impurity. According to the "Guidelines for Genotoxic Impurities In principle, adequate quality research should...

Claims

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Application Information

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IPC IPC(8): G01N30/02G01N30/06G01N30/30G01N30/32G01N30/34G01N30/72
CPCG01N30/02G01N30/06G01N30/30G01N30/32G01N30/34G01N30/72G01N2030/324
Inventor 朱兵梁颖邵顺陶艳敏张颖杰
Owner NANJING HUAWE MEDICINE TECH DEV
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