CN108061767A - The method of HPLC method separation determination Rivaroxaban intermediates and its related impurities - Google Patents
The method of HPLC method separation determination Rivaroxaban intermediates and its related impurities Download PDFInfo
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- CN108061767A CN108061767A CN201711276181.0A CN201711276181A CN108061767A CN 108061767 A CN108061767 A CN 108061767A CN 201711276181 A CN201711276181 A CN 201711276181A CN 108061767 A CN108061767 A CN 108061767A
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- trifluoroacetic acid
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/047—Standards external
Abstract
The invention belongs to analytical chemistry fields, more particularly to a kind of HPLC methods separation determination Rivaroxaban intermediate and its method of related impurities, the chromatographic column that the method uses is using octadecylsilane chemically bonded silica as filler, gradient elution is carried out using mobile phase A and Mobile phase B, is detected into detector；The related impurities includes the one or more of impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g, and the mobile phase A is trifluoroacetic acid aqueous solution, and the Mobile phase B is organic solvent.The method of the present invention can effectively separate Rivaroxaban intermediate and its related impurities, and this method has very high sensitivity and separating degree, repeatability and durability are good, it is easy to operate, as a result it is reliable and stable, for realizing that Rivaroxaban intermediate and razaxaban quality control are extremely important.
Description
Technical field
The invention belongs to analytical chemistry fields, and in particular to a kind of HPLC methods separation determination Rivaroxaban intermediate and its phase
The method for closing impurity.
Background technology
Razaxaban (Rivaroxaban), trade name：Xarelto is that a kind of new of Bayer Bitterfeld GmbH pharmacy exploitation takes orally
Anticoagulant, the adult patients of be mainly used for selecting a time hip joint or replacement knee in arthroplasty, to prevent venous thronbosis.This product
Selectivity and competitiveness with height, bleeding risk is low, and security is good.Razaxaban molecular formula is C19H18ClN3O5S, chemistry
Title：The chloro- nitrogen of 5--({ (5S) -2- oxygen -3- [- 4- (3- oxygen -4- morpholinyls) phenyl] -1,3- oxazolidine -5- bases } methyl) -2- thiophenes
Fen-carboxylic acid amides, chemical structural formula are as follows：
Usually, a kind of impurity of the drug total content should be less than 1.0%, and single impurity content should be less than 0.1%, for system
The impurity or the related substance of introducing generated during standby razaxaban, is whether required to carry out in bulk pharmaceutical chemicals or preparation
Stringent control.The patent of Application No. CN103558326A discloses a kind of side for measuring razaxaban content in razaxaban piece
Method can only detect the content of razaxaban in product in the method, it is impossible to reach and meanwhile separate and detect razaxaban and its
The purpose of related impurities；The patent of Application No. WO2012035057 discloses a kind of cuts down sand with liquid chromatography for separating and determining profit
Class and its method of related impurities, the impurity of detection is two related impuritieses (structural formula is referring to patent WO2012035057),
Disclosed in impurity A it is identical with the impurity B structure in impurity list of the present invention, remaining is different, and in this patent, utilizes
The related impurities that high performance liquid chromatography is kept completely separate razaxaban needs 56 minutes.
5- chlorothiophene -2- carboxylic acids, be synthesize razaxaban key intermediate, chemical formula C5H3ClO2S, structural formula
It is as follows：
So far, the detection method of the intermediate is individually reported there has been no document, is more reported without disclosed method
It can separation determination Rivaroxaban intermediate and its method of related impurities, but the analysis and research of the intermediate were to reacting simultaneously
The control of journey and the raising of quality play a crucial role, and also directly affect the quality of razaxaban finished product.Therefore, have
Necessity establishes a kind of simple effective method and carries out quality control to the intermediate.
The content of the invention
In view of this, it is an object of the invention to provide a kind of HPLC methods separation determination Rivaroxaban intermediate and its correlations
The method of impurity；The method of the present invention can effectively separate Rivaroxaban intermediate and its related impurities, and this method has
There are very high sensitivity and separating degree, repeatability and durability are good, easy to operate, as a result reliable and stable.
To achieve the above object, the technical scheme is that：
The method of HPLC method separation determination Rivaroxaban intermediates and its related impurities, the chromatographic column that the method uses are
Using octadecylsilane chemically bonded silica as filler, gradient elution is carried out using mobile phase A and Mobile phase B, is carried out into detector
Detection；The related impurities includes the one or more of impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g,
Concrete structure 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 acids, is the key intermediate for synthesizing razaxaban, chemical
Formula is C5H3ClO2S, structural formula are as follows：
The analysis and research of the intermediate play a crucial role the control of reaction process and the raising of quality,
Directly affect the quality of razaxaban finished product.The determination method of the present invention can effectively by Rivaroxaban intermediate and its
Related impurities separates, and this method has very high sensitivity and separating degree, and repeatability and durability are good, easy to operate, as a result
It is reliable and stable.
Further, the mass percent of trifluoroacetic acid is 0.03%~0.08% in the trifluoroacetic acid aqueous solution.
As a preferred embodiment, in the trifluoroacetic acid aqueous solution mass percent of trifluoroacetic acid for 0.04%~
0.07%.
As a preferred embodiment, the mass percent of trifluoroacetic acid is 0.05% in the trifluoroacetic acid aqueous solution.
Further, the organic solvent is the one or more of acetonitrile, ethyl alcohol and methanol.
Further, the organic solvent is methanol.
Further, the gradient elution is set as follows：
The flow velocity that the mobile phase is eluted is 0.7-1.3ml/min.
As a preferred embodiment, the gradient elution setting is as follows：
The flow velocity that the mobile phase is eluted is 1.0ml/min.
Further, the grain diameter of the octadecylsilane chemically bonded silica chromatographic column filler is 3-6 μm；The chromatographic column
Column temperature be 25-35 DEG C.
As a preferred embodiment, the grain diameter of the octadecylsilane chemically bonded silica chromatographic column filler is 5 μm；The color
The column temperature for composing column is 30 DEG C.
Further, the Detection wavelength of the detector is 262nm ± 2nm and 237nm ± 2nm.
As a preferred embodiment, the Detection wavelength of the detector is 262nm and 237nm.
Further, HPLC methods separation determination Rivaroxaban intermediate and its method of related impurities, the related impurities are
Impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g, specifically include following steps：
1) test solution is prepared：Test sample is taken to be dissolved in diluent, obtains test solution；
2) reference substance solution is prepared：Take Rivaroxaban intermediate and impurity a, impurity b, impurity c, impurity d, impurity e, impurity
F and impurity g reference substances, reference substance solution is made with diluent dissolved dilution；
3) the step 1) test solution and step 2) the reference substance solution sample introduction are taken respectively, carry out high-efficient liquid phase color
Spectrum analysis records chromatogram, Rivaroxaban intermediate and its retention time of related impurities is determined, by external standard method in terms of peak area
Calculate Rivaroxaban intermediate and its content of related impurities in test solution.
Rivaroxaban intermediate and each impurity a, impurity b, impurity c, impurity d, impurity e, the linear line of impurity f and impurity g
Sexual intercourse is as shown in the table：
| Title | Concentration range (μ g/ml) | Regression equation | Related coefficient (r) |
| Rivaroxaban intermediate | 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 the methanol aqueous solution that mass fraction is 65%.
The second object of the present invention is to provide a kind of in separation of solid and liquid measure Rivaroxaban intermediate and its related impurities
Reagent composition, be made of following reagent：
Reagent A：Trifluoroacetic acid aqueous solution；
Reagent B：Organic solvent；
The related impurities includes one kind or more of impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g
Kind；
The mass percent of trifluoroacetic acid is 0.03%~0.08% in the trifluoroacetic acid aqueous solution；The organic solvent
For the one or more of acetonitrile, ethyl alcohol and methanol.
As a preferred embodiment, the mass percent of trifluoroacetic acid is 0.05% in the trifluoroacetic acid aqueous solution；It is described to have
Solvent is methanol.
The reagent composition energy of Rivaroxaban intermediate and its related impurities is measured provided by the present invention for separation of solid and liquid
Rivaroxaban intermediate and its related impurities are efficiently separated, for realizing that Rivaroxaban intermediate and razaxaban quality control have
There is extremely important meaning.
The beneficial effects of the present invention are：
1) the present invention provides a kind of HPLC methods separation determination Rivaroxaban intermediate and its method of related impurities, this hairs
Bright method can effectively separate Rivaroxaban intermediate and its related impurities, and this method have very high sensitivity and
Separating degree, repeatability and durability are good, easy to operate, as a result reliable and stable.
2) analysis and research of Rivaroxaban intermediate play the control of reaction process and the raising of quality in the present invention
Vital effect also directly affects the quality of razaxaban finished product, and institute is in this way for realizing Rivaroxaban intermediate
And razaxaban quality control is extremely important.
Description of the drawings
Fig. 1 is mixed solution chromatogram；Note：1- impurity f, 2- impurity d, 3- impurity b, 4- intermediate, 5- impurity a, 6- are miscellaneous
Matter g, 7- impurity c, 8- impurity e.
Specific embodiment
Hereinafter reference will be made to the drawings, and the preferred embodiment of the present invention is described in detail.Tool is not specified in preferred embodiment
The experimental method of concrete conditions in the establishment of a specific crime, usually according to normal condition, illustrated embodiment is to preferably be said to present disclosure
It is bright, but be not that present disclosure is only limitted to illustrated embodiment.So those skilled in the art are according to foregoing invention
Content carries out nonessential modifications and adaptations to embodiment, still falls within protection scope of the present invention.
Embodiment
1 chromatographic condition：
Chromatographic column：SB-C18 250mm × 4.6mm, 5 μm, mobile phase A：0.05% trifluoroacetic acid aqueous solution, Mobile phase B：
Methanol, carries out gradient elution, and gradient elution sets as follows：
Flow velocity：1.0ml/min, column temperature：30 DEG C, Detection wavelength：262nm and 237nm, sampling volume：20μl.
2 methods and result
2.1 solution are prepared
Take Rivaroxaban intermediate appropriate, respectively plus 65% methanol dissolves and solution of every 1ml containing about 0.2mg is made, essence
It is close to pipette 0.2ml, it puts in 100ml measuring bottles, diluent is added to be diluted to scale, shake up to get reference substance solution.
2.2 specificity
It weighs appropriate Rivaroxaban intermediate and impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g is total to
Count 7 impurity reference substances.Add dilution dilution agent that impurity positioning solution and mixed solution is made, precision measures 20 μ l, is injected separately into
In liquid chromatograph, chromatogram, mixed solution the result is shown in Figure 1 are recorded.In mixed solution, Rivaroxaban intermediate peak and each impurity
Peak is kept completely separate, separating degree 10.82, and retention time is 21.192 (Fig. 1).
2.3 system suitability
It takes Rivaroxaban intermediate appropriate, diluent is added to dissolve and solution of every 1ml containing about 0.2mg is made, precision pipettes
0.2ml puts in 100ml measuring bottles, diluent is added to be diluted to scale, shakes up (0.2%).Precision measures 20 μ l, injects liquid chromatogram
In instrument, continuous sample introduction 6 times records chromatogram, and separation calculates Rivaroxaban intermediate peak area and retention time relative standard is inclined
Poor (RSD), the results are shown in Table 1.The theoretical cam curve of Rivaroxaban intermediate is 36922, more than 5000；The RSD of peak area is
1.20%, less than 2.0% (table 1).
1 system suitability solution measurement result of table
| Number | Retention time (min) | Peak area | Theoretical cam curve |
| 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 |
| Average value | 21.824 | 1.0706 | 36922 |
| RSD% | 0.08% | 1.20% | ― |
2.4 precision
Rivaroxaban intermediate about 25mg is taken, it is accurately weighed, totally 6 parts.It puts respectively in 50ml measuring bottles, adds diluent dissolving simultaneously
Scale is diluted to, as test solution；And precision takes test solution 1ml to put in 50ml measuring bottles respectively, adds dilution dilution agent
Scale is put, is shaken up, then precision takes 1ml to put in 10ml measuring bottles, and dilution dilution agent is added to put scale, is shaken up to get own control solution.
Precision measures above-mentioned each 20 μ l of solution, is injected separately into liquid chromatograph, records chromatogram.By the correction up factor principal component from
Body counter point calculates total impurities content and RSD in 6 parts of test solutions.Total miscellaneous difference 0.100% of 6 parts of test samples,
0.102%th, 0.103%, 0.103%, 0.102% and 0.101%, RSD 8.4%, less than 10%, meets high performance liquid chromatography
Requirement of the method to Related substances separation.
2.5 linear and scopes
It takes Rivaroxaban intermediate and each impurity reference substance appropriate, diluent dissolving disease is added to be diluted in 1ml containing about 5 μ g's
Linear stock solution pipettes 0.3,0.5,0.8,1.0,2.0 and 5.0ml and puts in 10ml measuring bottles, is diluted to scale, surveyed respectively
It is fixed.Peak area A is recorded, using concentration C as abscissa, A is ordinate, establishes standard curve.Linear equation (table 2) is obtained, profit cuts down sand
Class's intermediate and each impurity have good linear relationship in linear scope.
2 linear determination result of table
2.6 quantitative limits and detection limit
It weighs Rivaroxaban intermediate and each impurity reference substance is appropriate, diluent dissolving disease is added to be diluted in 1ml containing about 5 μ g
Mixed solution pipettes 0.3ml and 0.1ml and puts in 10ml measuring bottles, diluent is added to be diluted to scale respectively, obtains quantitative limit and detection limits
Solution is measured.The quantitative limit of razaxaban and each impurity and detection limit the results are shown in Table 3.
3 quantitative limit of table and detection limit result
| Title | Quantitative limit (μ g/ml) | Signal-to-noise ratio (S/N) | Detection limit (μ g/ml) | Signal-to-noise ratio (S/N) |
| Rivaroxaban intermediate | 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 |
3 conclusions：
Under the chromatographic condition, Rivaroxaban intermediate and its impurity can be kept completely separate, and as a result meet Chinese Pharmacopoeia
In defined limit, acquired results are reliable.
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to compared with
The present invention is described in detail in good embodiment, it will be understood by those of ordinary skill in the art that, it can be to the skill of the present invention
Art scheme is modified or replaced equivalently, and without departing from the objective and scope of technical solution of the present invention, should all be covered at this
Among the right of invention.
Claims (10)
- The method of 1.HPLC method separation determination Rivaroxaban intermediates and its related impurities, which is characterized in that the method uses Chromatographic column be using octadecylsilane chemically bonded silica as filler, gradient elution is carried out using mobile phase A and Mobile phase B, is entered Detector is detected；The related impurities includes the one of impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g Kind is a variety of, and concrete structure formula is as follows：The mobile phase A is trifluoroacetic acid aqueous solution, and the Mobile phase B is organic solvent.
- 2. according to the method described in claim 1, it is characterized in that, in the trifluoroacetic acid aqueous solution trifluoroacetic acid quality hundred Fraction is 0.03%~0.08%.
- 3. according to the method described in claim 1, it is characterized in that, the organic solvent is one kind of acetonitrile, ethyl alcohol and methanol It is or a variety of.
- 4. according to the method described in claim 3, it is characterized in that, the organic solvent is methanol.
- 5. according to the method described in claim 1, it is characterized in that, gradient elution setting is as follows：The flow velocity that the mobile phase is eluted is 0.7-1.3ml/min.
- 6. the according to the method described in claim 1, it is characterized in that, octadecylsilane chemically bonded silica chromatographic column filler Grain diameter is 3-6 μm；The column temperature of the chromatographic column is 25-35 DEG C.
- 7. according to the method described in claim 1, it is characterized in that, the Detection wavelength of the detector for 262nm ± 2nm and 237nm±2nm。
- 8. according to claim 1-7 any one of them methods, which is characterized in that the related impurities is impurity a, impurity b, miscellaneous Matter c, impurity d, impurity e, impurity f and impurity g, specifically include following steps：1) test solution is prepared：Test sample is taken to be dissolved in diluent, obtains test solution；2) reference substance solution is prepared：Take Rivaroxaban intermediate and impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and Reference substance solution is made with diluent dissolved dilution in impurity g reference substances；3) the step 1) test solution and step 2) the reference substance solution sample introduction are taken respectively, carry out high performance liquid chromatography point Analysis is recorded chromatogram, determines Rivaroxaban intermediate and its retention time of related impurities, supplied by external standard method with calculated by peak area Rivaroxaban intermediate and its content of related impurities in test sample solution.
- 9. according to the method described in claim 8, it is characterized in that, the methanol that it is 65% that the diluent, which is mass fraction, is water-soluble Liquid.
- 10. the reagent composition of Rivaroxaban intermediate and its related impurities is measured for separation of solid and liquid, which is characterized in that by with Lower reagent composition：Reagent A：Trifluoroacetic acid aqueous solution；Reagent B：Organic solvent；The related impurities includes the one or more of impurity a, impurity b, impurity c, impurity d, impurity e, impurity f and impurity g；The mass percent of trifluoroacetic acid is 0.03%~0.08% in the trifluoroacetic acid aqueous solution；The organic solvent is second The one or more of nitrile, ethyl alcohol and methanol.
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Cited By (3)
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| CN110057942A (en) * | 2019-05-20 | 2019-07-26 | 海南皇隆制药股份有限公司 | A kind of detection method of the related substance of razaxaban and its preparation |
| CN110187023A (en) * | 2019-05-23 | 2019-08-30 | 北京悦康科创医药科技股份有限公司 | A kind of method of inspection of the razaxaban in relation to substance |
| CN111983055A (en) * | 2020-07-28 | 2020-11-24 | 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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| CN110057942A (en) * | 2019-05-20 | 2019-07-26 | 海南皇隆制药股份有限公司 | A kind of detection method of the related substance of razaxaban and its preparation |
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| CN111983055A (en) * | 2020-07-28 | 2020-11-24 | 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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