CN108061767B - Method for separating and measuring rivaroxaban intermediate and related impurities thereof by HP L C method - Google Patents
Method for separating and measuring rivaroxaban intermediate and related impurities thereof by HP L C method Download PDFInfo
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Abstract
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and determining rivaroxaban intermediates and related impurities thereof by an HP L C method.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and determining rivaroxaban intermediates and related impurities thereof by using an HP L C method.
Background
Rivaroxaban (Rivaroxaban), trade name: xarelto, a new oral anticoagulant drug developed in bayer pharmacy in germany, is mainly used for adult patients who undergo elective hip or knee replacement surgery to prevent venous thrombosis. The product has high selectivity and competitiveness, low risk of hemorrhage, and good safety. Rivaroxaban has the molecular formula of C19H18ClN3O5S, chemistryName: 5-chloro-nitrogen- ({ (5S) -2-oxo-3- [ -4- (3-oxo-4-morpholinyl) phenyl]-1, 3-oxazolidin-5-yl } methyl) -2-thiophene-carboxamide, of the formula:
generally, the total content of one drug impurity should be less than 1.0%, and the content of a single impurity should be less than 0.1%, and strict control is required for impurities generated in the preparation process of rivaroxaban or related substances introduced in the preparation process of rivaroxaban, whether in bulk drugs or preparations. The patent with the application number of CN103558326A discloses a method for determining the content of rivaroxaban in rivaroxaban tablets, wherein only the content of rivaroxaban in a product can be detected in the method, and the aim of simultaneously separating and detecting rivaroxaban and related impurities can not be fulfilled; patent with application number WO2012035057 discloses a method for separating and determining rivaroxaban and related impurities thereof by using liquid chromatography, the detected impurities are two related impurities (see patent WO2012035057 for structural formula), wherein the disclosed impurity a has the same structure as the impurity B in the impurity list of the invention, and the rest is different, and in the patent, 56 minutes are needed for completely separating the related impurities of rivaroxaban by using high performance liquid chromatography.
5-chlorothiophene-2-carboxylic acid, which is a key intermediate for synthesizing rivaroxaban and has a chemical formula of C5H3ClO2S, the structural formula is as follows:
so far, no document reports a detection method of the intermediate independently, and no published method reports a method for simultaneously separating and determining rivaroxaban intermediate and related impurities, but the analysis and research of the intermediate plays a crucial role in controlling the reaction process and improving the quality and also directly influences the quality of the rivaroxaban finished product. Therefore, it is necessary to establish a simple and effective method for quality control of the intermediate.
Disclosure of Invention
The method can effectively separate the rivaroxaban intermediate and the related impurities thereof, and has the advantages of high sensitivity and separation degree, good repeatability and durability, simple operation and stable and reliable result.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for separating and determining rivaroxaban intermediate and related impurities thereof by using an HP L C method comprises the steps of using octadecylsilane chemically bonded silica as a filler, performing gradient elution by using a mobile phase A and a mobile phase B, and detecting the mixture by using a detector, wherein the related impurities comprise one or more of impurities a, B, C, d, e, f and g, and the specific structural formula is as follows:
the mobile phase A is trifluoroacetic acid aqueous solution, and the mobile phase B is organic solvent.
The rivaroxaban intermediate is 5-chlorothiophene-2-carboxylic acid, is a key intermediate for synthesizing rivaroxaban, and has a chemical formula of C5H3ClO2S, the structural formula is as follows:
the analysis and research of the intermediate plays a crucial role in controlling the reaction process and improving the quality, and directly influences the quality of the rivaroxaban finished product. The detection and analysis method can effectively separate rivaroxaban intermediates and related impurities, and has the advantages of high sensitivity and separation degree, good repeatability and durability, simple operation, and stable and reliable result.
Further, the mass percent of the trifluoroacetic acid in the trifluoroacetic acid aqueous solution is 0.03-0.08%.
Preferably, the mass percentage of the trifluoroacetic acid in the trifluoroacetic acid aqueous solution is 0.04-0.07%.
Preferably, the mass percentage of trifluoroacetic acid in the aqueous trifluoroacetic acid solution is 0.05%.
Further, the organic solvent is one or more of acetonitrile, ethanol and methanol.
Further, the organic solvent is methanol.
Further, the gradient elution was set as follows:
the flow rate of the mobile phase for elution is 0.7-1.3 ml/min.
As a preference, the gradient elution is set as follows:
the flow rate at which the mobile phase elutes was 1.0 ml/min.
Further, the particle size of the octadecylsilane chemically bonded silica chromatographic column filler is 3-6 μm; the temperature of the chromatographic column is 25-35 ℃.
Preferably, the particle diameter of the octadecylsilane chemically bonded silica chromatographic column filler is 5 μm; the column temperature of the chromatographic column was 30 ℃.
Further, the detection wavelength of the detector is 262nm +/-2 nm and 237nm +/-2 nm.
Preferably, the detection wavelengths of the detectors are 262nm and 237 nm.
Further, a method for separating and determining rivaroxaban intermediate and related impurities thereof by using an HP L C method, wherein the related impurities are impurity a, impurity b, impurity C, impurity d, impurity e, impurity f and impurity g, and the method specifically comprises the following steps:
1) preparing a test solution: dissolving a test sample in a diluent to obtain a test sample solution;
2) preparing a reference solution: dissolving and diluting a rivaroxaban intermediate, an impurity a, an impurity b, an impurity c, an impurity d, an impurity e, an impurity f and an impurity g reference substance by using a diluent to prepare a reference substance solution;
3) respectively sampling the test solution in the step 1) and the reference solution in the step 2), performing high performance liquid chromatography analysis, recording a chromatogram, determining the retention time of the rivaroxaban intermediate and related impurities, and calculating the content of the rivaroxaban intermediate and related impurities in the test solution by peak area according to an external standard method.
The linear relationship of the rivaroxaban intermediate and each of impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g is shown in the following table:
| name (R) | Concentration Range (μ g/ml) | Regression equation | Coefficient of correlation (r) |
| Rivaroxaban intermediates | 0.1548～2.5805 | Y＝1.1627X+0.0015 | 0.9997 |
| Impurity a | 0.1861～3.1014 | Y＝0.9475X-0.0315 | 0.9990 |
| Impurity b | 0.1530～2.5500 | Y＝1.0173X-0.0181 | 0.9996 |
| Impurity c | 0.1536～2.5608 | Y＝0.7328X+0.0059 | 0.9996 |
| Impurity d | 0.1554～2.5896 | Y＝1.2458X-0.0226 | 0.9997 |
| Impurity e | 0.1608～2.6802 | Y＝0.7467X-0.0224 | 0.9992 |
| Impurity f | 0.1577～2.6280 | Y＝1.9106X-0.0571 | 0.9997 |
| Impurity g | 0.1607～2.6780 | Y＝0.9236X-0.0182 | 0.9996 |
Further, the diluent is a methanol water solution with the mass fraction of 65%.
The invention also aims to provide a reagent composition for determining rivaroxaban intermediates and related impurities thereof by solid-liquid separation, which consists of the following reagents:
reagent A: trifluoroacetic acid aqueous solution;
and (3) reagent B: an organic solvent;
the related impurities comprise one or more of impurities a, b, c, d, e, f and g;
the mass percent of the trifluoroacetic acid in the trifluoroacetic acid aqueous solution is 0.03-0.08%; the organic solvent is one or more of acetonitrile, ethanol and methanol.
Preferably, the mass percent of the trifluoroacetic acid in the trifluoroacetic acid aqueous solution is 0.05%; the organic solvent is methanol.
The reagent composition for determining the rivaroxaban intermediate and the related impurities thereof through solid-liquid separation can effectively separate the rivaroxaban intermediate and the related impurities thereof, and has extremely important significance for realizing the quality control of the rivaroxaban intermediate and the rivaroxaban.
The invention has the beneficial effects that:
1) the invention provides a method for separating and determining rivaroxaban intermediates and related impurities thereof by using an HP L C method, the method can effectively separate the rivaroxaban intermediates and the related impurities thereof, and the method has the advantages of high sensitivity and separation degree, good repeatability and durability, simplicity in operation, and stable and reliable results.
2) The analysis and research of the rivaroxaban intermediate plays a crucial role in controlling the reaction process and improving the quality, and also directly influences the quality of the rivaroxaban finished product, so the method has a very important significance in realizing the quality control of the rivaroxaban intermediate and the rivaroxaban.
Drawings
FIG. 1 is a mixed solution chromatogram; note: 1-impurity f, 2-impurity d, 3-impurity b, 4-intermediate, 5-impurity a, 6-impurity g, 7-impurity c, 8-impurity e.
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Examples
1, chromatographic conditions:
the chromatographic column is SB-C18250 mm × 4.6.6 mm, 5 μm, the mobile phase A is 0.05% trifluoroacetic acid water solution, the mobile phase B is methanol, and gradient elution is carried out, wherein the gradient elution is set as follows:
flow rate: 1.0ml/min, column temperature: 30 ℃, detection wavelength: 262nm and 237nm, injection volume: 20 μ l.
2 methods and results
2.1 preparation of the solution
Taking a proper amount of rivaroxaban intermediate, respectively adding 65% methanol to dissolve the rivaroxaban intermediate to prepare a solution containing about 0.2mg per 1ml, precisely transferring 0.2ml, placing the solution into a 100ml measuring flask, adding a diluent to dilute the solution to a scale, and shaking up to obtain a reference solution.
2.2 specificity
Weighing a proper amount of rivaroxaban intermediate, and 7 impurity reference substances including impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g in total. Diluting with diluent to obtain impurity positioning solution and mixed solution, precisely measuring 20 μ l, respectively injecting into liquid chromatograph, and recording chromatogram, wherein the result of mixed solution is shown in FIG. 1. In the mixed solution, the rivaroxaban intermediate peak was completely separated from each impurity peak, the separation degree was 10.82, and the retention time was 21.192 (fig. 1).
2.3 System applicability
Taking a proper amount of rivaroxaban intermediate, adding a diluent to dissolve the rivaroxaban intermediate to prepare a solution containing about 0.2mg per 1ml, precisely transferring 0.2ml, placing the solution into a 100ml measuring flask, adding the diluent to dilute the solution to the scale, and shaking up (0.2%). Precisely measuring 20 mu l of the sample, injecting the sample into a liquid chromatograph, continuously sampling for 6 times, recording a chromatogram, and separating and calculating the peak area of the rivaroxaban intermediate and the Relative Standard Deviation (RSD) of the retention time, wherein the result is shown in a table 1. The theoretical plate number of the rivaroxaban intermediate is 36922 and is more than 5000; the RSD of the peak area was 1.20%, less than 2.0% (Table 1).
TABLE 1 System suitability solution assay results
| Number of times | Retention time (min) | Peak area | Number of theoretical plate |
| 1 | 21.856 | 1.0605 | 37062 |
| 2 | 21.824 | 1.0842 | 36771 |
| 3 | 21.824 | 1.0895 | 36527 |
| 4 | 21.824 | 1.0629 | 36744 |
| 5 | 21.803 | 1.0607 | 36832 |
| 6 | 21.813 | 1.0659 | 37596 |
| Mean value of | 21.824 | 1.0706 | 36922 |
| RSD％ | 0.08％ | 1.20％ | ― |
2.4 precision
Taking about 25mg of rivaroxaban intermediate, precisely weighing, and totally 6 parts. Respectively placing the mixture into 50ml measuring flasks, adding a diluent to dissolve the mixture and diluting the mixture to a scale to obtain a test solution; and respectively and precisely taking 1ml of the test solution to be tested, placing the test solution in a 50ml measuring flask, adding a diluent to dilute the test solution to be graduated, shaking up, precisely taking 1ml of the test solution to be placed in a 10ml measuring flask, adding the diluent to dilute the test solution to be graduated, and shaking up to obtain the self-control solution. Precisely measuring the above solutions at 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram. The total impurity content and RSD in 6 portions of sample solution are calculated according to the main component self-contrast method added with correction factors. The total impurities of 6 parts of test sample are respectively 0.100%, 0.102%, 0.103%, 0.102% and 0.101%, and the RSD is 8.4% and less than 10%, which meets the requirement of high performance liquid chromatography for checking related substances.
2.5 Linear sum Range
Taking a proper amount of rivaroxaban intermediate and each impurity reference substance, adding a diluent to dissolve the rivaroxaban intermediate and each impurity reference substance, diluting the rivaroxaban intermediate and each impurity reference substance into linear stock solution with the concentration of about 5 mu g in 1ml, respectively transferring 0.3ml, 0.5 ml, 0.8 ml, 1.0ml, 2.0 ml and 5.0ml into a 10ml measuring flask, diluting to the scale, and measuring. And recording the peak area A, and establishing a standard curve by taking the concentration C as an abscissa and the A as an ordinate. To obtain a linear equation (table 2), rivaroxaban intermediate and each impurity have a good linear relationship in the linear range.
TABLE 2 Linear measurement results
2.6 limit of quantitation and detection
Weighing a proper amount of rivaroxaban intermediate and each impurity reference substance, adding a diluent to dissolve the rivaroxaban intermediate and each impurity reference substance, diluting the rivaroxaban intermediate and each impurity reference substance into a mixed solution with the concentration of about 5 mu g contained in 1ml, respectively transferring 0.3ml and 0.1ml into a 10ml measuring flask, adding the diluent to dilute the mixed solution to a scale, obtaining a quantitative limit solution and a detection limit solution, and determining. The results of the quantitation limit and detection limit for rivaroxaban and each impurity are shown in table 3.
TABLE 3 quantitation Limit and detection Limit results
| Name (R) | Limit of quantitation (ug/ml) | Signal-to-noise ratio (S/N) | Detection limit (mu g/ml) | Signal-to-noise ratio (S/N) |
| Rivaroxaban intermediates | 0.1548 | 38.7 | 0.0516 | 15.8 |
| Impurity a | 0.1861 | 34.9 | 0.0620 | 10.8 |
| Impurity b | 0.1530 | 31.4 | 0.0510 | 11.8 |
| Impurity c | 0.1536 | 23.3 | 0.0512 | 8.9 |
| Impurity d | 0.1554 | 51.3 | 0.0518 | 17.8 |
| Impurity e | 0.1608 | 23.7 | 0.0536 | 7.4 |
| Impurity f | 0.1577 | 83.4 | 0.0526 | 28.8 |
| Impurity g | 0.1607 | 24.6 | 0.0512 | 8.9 |
And 3, conclusion:
under the chromatographic condition, rivaroxaban intermediates and impurities thereof can be completely separated, the results are all in accordance with the limit specified by Chinese pharmacopoeia, and the obtained results are reliable.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (6)
- The method for separating and determining the rivaroxaban intermediate and the related impurities thereof by using the HP L C method is characterized in that a chromatographic column adopted in the method takes octadecylsilane chemically bonded silica as a filler, mobile phase A and mobile phase B are adopted for gradient elution, and the chromatographic column enters a detector for detection, wherein the related impurities are one or more of impurity a, impurity B, impurity C, impurity d, impurity e, impurity f and impurity g, and the specific structural formula is as follows:
the rivaroxaban intermediate is 5-chlorothiophene-2-carboxylic acid, and the structural formula is as follows:
the mobile phase A is trifluoroacetic acid aqueous solution, and the mobile phase B is methanol;the gradient elution was set as follows:
the flow rate of the mobile phase for elution is 0.7-1.3 ml/min. - 2. The method according to claim 1, wherein the mass percentage of trifluoroacetic acid in the aqueous trifluoroacetic acid solution is 0.03-0.08%.
- 3. The method according to claim 1, wherein the particle size of the octadecylsilane chemically bonded silica chromatographic column packing is 3-6 μm; the temperature of the chromatographic column is 25-35 ℃.
- 4. The method of claim 1, wherein the detector has detection wavelengths of 262nm + 2nm and 237nm + 2 nm.
- 5. The method according to any one of claims 1 to 4, wherein the relevant impurities are impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g, and the method comprises the following steps:1) preparing a test solution: dissolving a test sample in a diluent to obtain a test sample solution;2) preparing a reference solution: dissolving and diluting a rivaroxaban intermediate, an impurity a, an impurity b, an impurity c, an impurity d, an impurity e, an impurity f and an impurity g reference substance by using a diluent to prepare a reference substance solution;3) respectively sampling the test solution in the step 1) and the reference solution in the step 2), performing high performance liquid chromatography analysis, recording a chromatogram, determining the retention time of the rivaroxaban intermediate and related impurities, and calculating the content of the rivaroxaban intermediate and related impurities in the test solution by peak area according to an external standard method.
- 6. The method according to claim 5, wherein the diluent is a 65% methanol aqueous solution.
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| CN110057942B (en) * | 2019-05-20 | 2022-07-01 | 海南皇隆制药股份有限公司 | Detection method for rivaroxaban and related substances of rivaroxaban preparation |
| CN110187023B (en) * | 2019-05-23 | 2021-09-14 | 北京悦康科创医药科技股份有限公司 | Method for testing rivaroxaban related substances |
| CN111983055B (en) * | 2020-07-28 | 2022-05-31 | 安徽联创生物医药股份有限公司 | Method for separating and measuring rivaroxaban intermediate related substances by using HPLC (high performance liquid chromatography) |
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