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Method for determining rivaroxaban and related substances thereof by using high performance liquid chromatography

A high-performance liquid chromatography and rivaroxaban technology is applied in the field of simultaneous determination of rivaroxaban and related substances by high-performance liquid chromatography, and can solve the problems of low detection sensitivity, poor detection method durability, chromatographic column damage and the like , to achieve the effect of simple data processing, good separation and detection, and good specificity

Active Publication Date: 2020-04-03
GRAND LIFE SCI (LIAONING) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But this method still has obvious defects: at first, this method is more sensitive to mobile phase pH, only has good separation effect between pH3.7-4.2 (as mentioned in embodiment 5 when pH is 3.6, impurity B and G cannot be effectively separated), and the detection method has poor durability
However, ion-pairing reagents will cause irreversible damage to the chromatographic column and affect the active sites on the stationary phase of the chromatographic column, which not only affects the reproducibility and durability of the method, but also greatly shortens the service life of the chromatographic column
[0007] Based on the above reasons, in the prior art, for the separation and detection of rivaroxaban and its related substances, the methods used all have the influence of interference peaks, poor durability, poor reproducibility, low detection sensitivity, and manual calculation is required. Deducting problems such as blank solvents has a great impact on the calculation and judgment of test results

Method used

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  • Method for determining rivaroxaban and related substances thereof by using high performance liquid chromatography
  • Method for determining rivaroxaban and related substances thereof by using high performance liquid chromatography
  • Method for determining rivaroxaban and related substances thereof by using high performance liquid chromatography

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Embodiment 1 Determination of rivaroxaban content and its related substances using the method of the present invention

[0073] 1.1 Instruments and conditions:

[0074] Agilent 1260 liquid chromatography system, column: Yuexu LP-C18 (250mm*4.6mm, 5μm), the detection wavelength is 220nm, 250nm, the column temperature is 35°C, and the flow rate is 1.0mL / min;

[0075] The trapping column is Shimadzu's Ghost Trap DS.

[0076] 1.2 Test steps

[0077] 1) Preparation of mobile phase A: Take 1.42 g of sodium dihydrogen phosphate, dissolve it in 1000 mL of water, adjust the pH to 6.0 with phosphoric acid, and use it as mobile phase A; mobile phase B is acetonitrile;

[0078] 2) Prepare the reference substance solution of rivaroxaban and its related substances:

[0079] ① Preparation of mixed solvent:

[0080] Use mobile phase A and mobile phase B to prepare mixed solvent, wherein the volume ratio of mobile phase A and mobile phase B is 50:50;

[0081] ② Preparation of r...

Embodiment 2

[0095] Example 2 Comparative example of prior art detection of rivaroxaban and its impurities

[0096] Using the chromatographic column and detection method described in Example 1 of patent CN105004802B to detect the content of rivaroxaban and the above-mentioned 8 related substances;

[0097] 1) Preparation of mobile phase A: Weigh 2.0 g of sodium pentanesulfonate, pipette 2.0 mL of phosphoric acid into a 1000 mL volumetric flask, add water to dissolve and dilute to the mark, and adjust the pH to 4.0 with 1 mol / L sodium hydroxide solution; Mobile phase B is acetonitrile;

[0098] 2) Take 25 mg of rivaroxaban, add an appropriate amount of related substance reference substance stock solution prepared in Example 1 of the present invention, and dissolve the sample with 30% acetonitrile aqueous solution to obtain a sample solution;

[0099] 3) Take 10 μl of each sample solution of the blank control and step 2) and inject into the Shimadzu LC-20AT chromatograph. The temperature...

Embodiment 3

[0104] Embodiment 3 The impact of different mobile phase pH values ​​on analysis and detection

[0105] Dissolve sodium dihydrogen phosphate in water with reference to the method in Example 1, adjust the pH to 6.0, 5.5, and 6.5 with phosphoric acid respectively, as mobile phase A; other conditions are the same as in Example 1, and take the sample solution described in Example 1 Inject into a liquid chromatography system for analysis, record the chromatogram, and the test results are shown in Table 6.

[0106] Table 6 Comparison of different mobile phase pH examples

[0107]

[0108]

[0109]The experimental results show that when the pH of mobile phase A is 6.0, 5.5, and 6.5, rivaroxaban and its 8 related substances can be separated well, and the content results of various impurities and rivaroxaban are not affected by pH changes Impact proves that the method of the present invention has better method durability.

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Abstract

The invention provides a method for determining rivaroxaban and related substances thereof by using high performance liquid chromatography, wherein the high performance liquid chromatography comprisesthe following conditions that a stationary phase is octadecylsilane chemically bonded silica,a mobile phase A is selected from a phosphate buffer solution of which the pH value is 5.0-7.0, a citratebuffer solution, an acetate buffer solution or a carbonate buffer solution, a mobile phase B is acetonitrile or methanol, and gradient elution is carried out. The method has the characteristics of good specificity, high sensitivity, good reproducibility, simple post-data processing and the like, especially can solve the problems of interference of a blank solvent, peak pattern difference of individual impurity peaks, low separation degree and the like, and can obtain all contents and related substance analysis results by one-time sample injection.

Description

technical field [0001] The invention belongs to the field of analytical chemistry, and relates to a method and application for simultaneously determining rivaroxaban and related substances thereof by using high-performance liquid chromatography. Background technique [0002] Rivaroxaban (Rivaroxaban, trade name: Xarelto) is an oral anticoagulant drug jointly developed by Bayer and Johnson & Johnson. Many countries have listed on the market one after another, and the market prospect is broad. The chemical name of rivaroxaban is: 5-chloro-nitrogen-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3- Oxazolin-5-yl]methyl]thiophene-2-carboxamide, the molecular formula is C 19 h 18 ClN 3 o 5 S, the structural formula is as follows: [0003] [0004] In the process of synthesizing rivaroxaban, some intermediates or impurities with known structures and impurities with unknown structures remain due to incomplete removal, which will affect the purity and quality of rivaroxaba...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/06
CPCG01N30/02G01N30/06
Inventor 尹秀娥陈阳董乔张良李萍王宏英薛百忠
Owner GRAND LIFE SCI (LIAONING) CO LTD
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