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Method for separating and determining rivaroxaban and impurities thereof, and application thereof

A technology for rivaroxaban and impurities, which is applied in the field of analytical chemistry, can solve the problem of not being able to separate and detect rivaroxaban and related impurities at the same time, and achieves a simple and feasible method, strong specificity, and ensured quality controllable. Effect

Active Publication Date: 2015-10-28
CHONGQING HUAPONT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The patent application number CN103558326A discloses a method for determining the content of rivaroxaban in rivaroxaban tablets. In this method, only the content of rivaroxaban in the product can be detected, and simultaneous separation and detection of rivaroxaban cannot be achieved. The purpose of rivaroxaban and its related impurities; the patent application number WO2012035057 discloses a method for the separation and determination of rivaroxaban and its related impurities by liquid chromatography, and the detected impurities are two related impurities (see patent WO2012035057 for the structural formula) , where the disclosed impurity A has the same structure as the impurity B in the impurity list of the present invention, and the rest are different, and in this patent, it takes 56 minutes to completely separate the related impurities of rivaroxaban by high performance liquid chromatography
Therefore, so far, there is no published method report that can rapidly determine and simultaneously separate rivaroxaban and its 10 preparation impurities.

Method used

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  • Method for separating and determining rivaroxaban and impurities thereof, and application thereof
  • Method for separating and determining rivaroxaban and impurities thereof, and application thereof
  • Method for separating and determining rivaroxaban and impurities thereof, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1 The method for separation and determination of rivaroxaban and its impurities

[0050] (1) Take an appropriate amount of rivaroxaban and an impurity reference substance, and dissolve the sample with 30% acetonitrile aqueous solution to obtain a sample solution;

[0051](2) Preparation of mobile phase A: Weigh 2.0 g of sodium pentane sulfonate, pipette 2.0 ml of phosphoric acid in a 1000 ml volumetric flask, add water to dissolve and dilute to the mark, and adjust the pH value to 4.0±0.1; mobile phase B is acetonitrile;

[0052] (3) Take 10 μl of the sample solution of step (1) and inject it into a chromatograph whose model is Shimadzu LC-20AT. The chromatographic column model is Purospher Star RP-18. The temperature of the column oven is 30°C;

[0053] Table 1 The volume of mobile phase A and mobile phase B for linear gradient elution

[0054] time (min)

[0055] Linear gradient elution was performed according to the data shown in Table 1, and ...

Embodiment 2

[0056] Embodiment 2 Chromatographic detection of rivaroxaban and its impurities

[0057] The diluent was used as a blank control sample, and the sample solution described in step 1) in Example 1 was used as a test sample. Take the diluent and the sample solution respectively and inject samples according to the chromatographic conditions of the method in Example 1, record the chromatogram, and the measurement results are shown in Table 2. High performance liquid chromatography see figure 1 , figure 2 .

[0058] Table 2 test results

[0059]

[0060] The test results show that the diluent does not interfere with the detection of the test product; the number of theoretical plates of each main impurity peak is greater than 10,000; the degree of separation between each chromatographic peak is greater than 1.5; it can be seen that the method has high column efficiency and good separation effect. Strong specificity.

Embodiment 3

[0061] Embodiment 3 does not add acidic ion pair reagent comparative example

[0062] A phosphate buffer solution without acidic ion-pairing reagent was used as the mobile phase A, acetonitrile was used as the mobile phase B, the detection wavelength was 250nm, and the flow rate was 1.0ml / min, and the gradient program in the following table was used for elution:

[0063] time (min)

0

13.0

13.1

18.0

Mobile phase A(%)

92

49

92

92

Mobile phase B(%)

8

51

8

8

[0064] Get the sample solution described in step 1) in embodiment 1, record the chromatogram, the results are shown in image 3 .

[0065] The test results show that under the chromatographic conditions in the comparative example, impurity H is a split peak, and impurity E and impurity F cannot be effectively separated, which affects the accurate quantitative detection of impurities. The results of comparative examples show that the present inven...

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Abstract

The invention relates to a method for separating and determining rivaroxaban and impurities thereof, and application thereof, belonging to the technical field of analytical chemistry. A reagent composition used for separating and determining rivaroxaban and impurities thereof comprises a reagent A and a reagent B, where the reagent A is an inorganic salt buffer system with an acidic ion-pairing agent which has a concentration of 0.2 to 4.0 g / L, and the reagent B is an organic solvent. The method for separating and determining rivaroxaban and impurities by using the reagent composition comprises the following steps: dissolving rivaroxaban in an aqueous acetonitrile solution so as to obtain a sample solution; preparing a mobile phase; injecting the sample solution into a separation and detection system and carrying out separation and detection on the sample solution by using the mobile phase so as to obtain eluate; and allowing the eluate to enter a detector for determination. The method provided by the invention can completely separate rivaroxaban from the impurities thereof at the same time and has the advantages of simplicity, high sensitivity, short analysis time, strong specificity, good reproducibility and capacity of simultaneously and effectively separating and determining contents of relevant substances in the bulk drug and preparations of rivaroxaban.

Description

technical field [0001] The invention belongs to the field of analytical chemistry, and in particular relates to a method and application for simultaneously separating and measuring rivaroxaban and its impurities. Background technique [0002] Rivaroxaban (trade name: Xarelto) is a new oral anticoagulant drug developed by Bayer Pharmaceuticals in Germany. It is mainly used for adult patients undergoing elective hip or knee replacement surgery to prevent venous thrombosis. This product is highly selective and competitive, with low bleeding risk and good safety. Rivaroxaban chemical name: 5-chloro-nitrogen-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine -5-yl}methyl)-2-thiophene-carboxamide, the molecular formula is C 19 h 18 ClN 3 o 5 S. The structural formula of rivaroxaban is: [0003] [0004] Generally speaking, the total content of a drug impurity should be less than 1.0%, and the content of a single impurity should be less than 0.1%. For the impu...

Claims

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Application Information

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IPC IPC(8): G01N30/02
Inventor 张荣张波
Owner CHONGQING HUAPONT PHARMA
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