CN107941936A - The method and application of separation determination razaxaban and its impurity - Google Patents
The method and application of separation determination razaxaban and its impurity Download PDFInfo
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- CN107941936A CN107941936A CN201711143900.1A CN201711143900A CN107941936A CN 107941936 A CN107941936 A CN 107941936A CN 201711143900 A CN201711143900 A CN 201711143900A CN 107941936 A CN107941936 A CN 107941936A
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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
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Abstract
The invention belongs to analytical chemistry field, and in particular to a kind of method and the application of separation determination razaxaban and its impurity.Reagent composition for separation determination razaxaban and its impurity is：Diluent：The aqueous solution of acedic acid；Mobile phase A：Buffer salt solution containing methanol and acetonitrile；Mobile phase B：The mixed liquor of buffer salt solution and acetonitrile.Use the method for mentioned reagent composition separation determination razaxaban and its impurity for：Take razaxaban to be dissolved in diluent and obtain sample solution；Prepare mobile phase；The sample solution is injected in separation detecting system, elution is carried out to the sample solution with the mobile phase and separates to obtain eluent；The eluent is measured into detector.The present invention can be by razaxaban and its separated from impurities, and baseline is good, and high sensitivity, analysis time is short, favorable reproducibility, can efficiently separate and measure each related content of material in razaxaban bulk pharmaceutical chemicals and preparation.
Description
Technical field
The invention belongs to analytical chemistry field, and in particular to the method for a kind of separation determination razaxaban and its impurity and
Using.
Background technology
Razaxaban is the oral anticoagulation of the direct inhibiting factor Xa of a high selectivity, its molecular formula is
C19H18ClN3O5S, chemistry are entitled：The chloro- N- of 5- ({ (5S) -2- oxos -3- [4- (3- oxo -4- morpholinyls)-phenyl] -1,3-
Oxazolidine -5- bases }-methyl) -2- thiophene-formamide, its structural formula is：
In the technique of synthesis razaxaban, the intermediate and unknown impuritie of some known structures because remove not exclusively and
Residual, influences the purity and quality of razaxaban, the intermediate of these known structures and the impurity of unknown structure and cuts down husky class
Catabolite be referred to as related material (i.e. impurity) usually said in Control of drug quality.These impurity are intended to be controlled
System, to ensure razaxaban quality.
The import standard for the razaxaban piece that State Food and Drug Administration issues, standard No. JX20080077.
The import standard cannot separate the impurity C after impurity I, impurity J and main peak and impurity F, impurity L, impurity E；It is miscellaneous
The solvent effect of matter H is obvious, and strong influence peak shape, influences to integrate, and then influences the extraction recovery of impurity H；In addition import
The acid concentration of the diluent of standard is larger, influences the stability of main ingredient, and then is reduced to impurity I, impurity J and unknown impuritie etc..
Patent CN 105004802B disclose one kind liquid chromatography for separating and determining razaxaban and its related impurities
Method, its mobile phase A adds ion pair, long the time required to balance, and ion-pairing agent is unstable, baseline have it is many not
The small peak known, produces related substance-measuring greatly interference, and cannot add the removal of ghost peak pillar.
Patent CN 105738489A disclose a kind of method with liquid chromatography for measuring razaxaban and its impurity.Its
The impurity that can be analyzed is less, only 5 kinds.Diluent produces solvent effect with impurity H, the extraction of impurity H is influenced, so as to influence
The accuracy of impurity extracting method.
Therefore up to the present, it can also stablize without disclosed method report, measure comprehensively exactly while separate profit and cut down
Husky class and its preparation impurity.Therefore develop it is a kind of can comprehensively, it is quick, stablize separation analysis razaxaban and its preparation impurity
Method, the quality control for medicine are very significant work.
The content of the invention
In view of this, it is an object of the invention to provide a kind of method of separation determination razaxaban and its impurity, it is adopted
With suitable diluent and mobile phase A, B, can quickly, stablize, accurately and comprehensively separation analysis razaxaban and its preparation
Impurity.
To achieve the above object, the technical scheme is that：
The method of above-mentioned separation determination razaxaban and its impurity comprises the steps of：
1) take razaxaban to be dissolved in diluent and obtain sample solution；
2) mobile phase is prepared：
A reagent preparations A obtains mobile phase A；
B reagent preparations B obtains Mobile phase B；
3) the step 1) sample solution is injected in separation detecting system, with mobile phase step 2) described to step 1)
The sample solution carries out elution and separates to obtain eluent；
4) the step 3) eluent is measured into detector.
Step 3) the separation detecting system is high performance liquid chromatograph, its chromatographic column filler is octadecylsilane key
Close silica gel；
The impurity of the razaxaban includes process contaminants and degradation impurity, be impurity A, impurity B, impurity C, impurity D,
Impurity E, impurity F, impurity G, impurity H, impurity I, the one or more of impurity J and impurity L, its structure are：
Impurity L
As preferable scheme, chromatographic column post case temperature is 20-50 DEG C.
Diluent：The aqueous solution of acetonitrile-acid, wherein the concentration of acid is 0.01-5mmol/L.
Being found by our experiment, diluent acidity exceedes 40mmol/L, in relation to material, impurity and master in sample
Peak is unstable；Not acid adding then the auxiliary material cross-linked carboxymethyl sodium in sample can and our impurity H react, influence carrying for impurity H
Take, so as to influence the accuracy of impurity extracting method in sample.Therefore diluent adds the acid of suitable concentration, is extracted, both
It can prevent extraction of the interference of auxiliary material to impurity H, also can guarantee that the stability of sample solution.
Reagent A：The volume accounting of buffer salt solution containing methanol and acetonitrile, wherein methanol and acetonitrile is 0-10%, and
It is 0-30% that acetonitrile, which accounts for methanol and the volume ratio of acetonitrile,；
Reagent B：Buffer salt solution-acetonitrile.
Above-mentioned mobile phase A, B can guarantee that the constant of buffer salt, so can guarantee that the pure of the baseline in relation to substance-measuring
It is net and stable, and buffer salt solution is added, it can guarantee that the pH stable of mobile phase, prevent the shifting of impurity G, impurity I, impurity L
It is dynamic.
Total accounting of the initial proportion of mobile phase, methanol and acetonitrile must not exceed 10%, and acetonitrile accounts for methanol and acetonitrile
Ratio is not greater than 30%, and otherwise the solvent effect of impurity H can be shown on the instrument having, it is possible to different instruments
Performance state is different, and some performance theory pedal numbers reduce, and some hangovers, what is had is bimodal.
As preferable scheme, reagent A, the buffer salt solution of B are selected from following buffer salt：Phosphate, formates, acetic acid
Salt, citrate, perchlorate, its concentration are 0.005-0.02mol/L.
Further, the buffer salt solution preferably phosphate buffer solution.
Further, the pH value of the buffer system is 3-5.Solution ph is adjusted with phosphoric acid solution, in this pH value section
Razaxaban and its impurity can be separated well.
As preferable scheme, acid solution is phosphoric acid solution in diluent, and the volume content of acetonitrile is in diluent
20%-50%.
As preferable scheme, the wavelength of the step 4) detector is 210-280nm.
As preferable scheme, the step 3) flow rate of mobile phase is 0.8-2ml/min.
Sample introduction speed can also influence chromatographic column separating effect and analysis result.The influence of sample introduction speed：Sample introduction speed is slowly then
Chromatographic peak profile can be widened, influence separating effect.Flow velocity 1.5 ensures that analysis time is shorter, and peak shape is preferable, and theoretical pedal number is high.
Therefore, further, flow velocity is preferably 1.5ml/min.
The above method can quickly realize the separation and detection of above-mentioned impurity at the same time, and stability is strong and precision and sensitivity
Height, razaxaban and its 11 kinds of impurity A-J and L can be kept completely separate and be detected, there is provided razaxaban and its correlation are miscellaneous
The method of the separation determination of matter, ensures that the quality controllable of razaxaban bulk pharmaceutical chemicals and its preparation, and finally determines product
It is safe and effective.
The second object of the present invention is in providing a kind of above method in separation determination razaxaban bulk pharmaceutical chemicals and preparation
Each application in relation to content of material.The above method can be stablized, quickly measure exactly while separate razaxaban and its bulk pharmaceutical chemicals
With preparation impurity, the quality control to medicine is very significant work.
The beneficial effects of the present invention are：
1) diluent provided by the invention adds the acid of suitable concentration, can prevent the interference of auxiliary material from being carried to impurity H
Take, also can guarantee that the stability of sample solution and chromatographic peak, compared with 105738489 A of prior art patent CN, diluent is not
The solvent effect of impurity H can be produced, separation is high, and the rate of recovery is high；
2) mobile phase provided by the invention, by the accounting for adjusting methanol and acetonitrile, there is provided the ratio model of two kinds of components
Enclose, avoid the solvent effect of the outer impurity H of this scope；
3) high efficiency liquid chromatography for separating and determining razaxaban and its impurity provided by the invention, this method can at the same time by
Razaxaban and its separated from impurities are simultaneously detected, can separated dopant species be 11 kinds；
4) method provided by the invention is simple and feasible, high sensitivity, and accuracy is high, favorable reproducibility, can efficiently separate and
Each related content of material in razaxaban preparation is measured, ensures that the quality controllable of razaxaban bulk pharmaceutical chemicals and its preparation,
And finally determine the safe and effective of product.
Brief description of the drawings
Fig. 1 is the high-efficient liquid phase chromatogram of embodiment diluent 1.
Fig. 2 is the high-efficient liquid phase chromatogram of embodiment diluent.
Fig. 3 is the high-efficient liquid phase chromatogram of embodiment razaxaban system suitability experimental solutions.
Fig. 4 is the high-efficient liquid phase chromatogram of embodiment razaxaban reference substance solution.
Fig. 5 is the high-efficient liquid phase chromatogram of embodiment razaxaban test solution.
Fig. 6 is the high-efficient liquid phase chromatogram of comparative example blank solvent.
Fig. 7 is the high-efficient liquid phase chromatogram of comparative example razaxaban sample solution.
Embodiment
Hereinafter reference will be made to the drawings is described in detail the preferred embodiment of the present invention.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
The method of separation determination razaxaban and its impurity
1. instrument and condition
Instrument：High performance liquid chromatograph；
Chromatographic column：It is filler with octadecylsilane chemically bonded silica, Agilent Eclipe XDB-C18,250mm ×
4.6mm, 5 μm or the suitable chromatographic column of performance；
Detector Detection wavelength：250nm；
Flow rate of mobile phase：1.5ml/min；
Mobile phase A：1.0mol/L sodium dihydrogen phosphates (with phosphoric acid tune pH value to 3.0) 10ml is taken, adds water to 900ml,
After shaking up, 50ml methanol and 50ml acetonitriles are added；
Mobile phase B：1.0mol/L sodium dihydrogen phosphates (with phosphoric acid tune pH value to 3.0) 10ml is taken, adds water to 300ml,
After shaking up, 700ml acetonitriles are added；
Diluent 1：Acetonitrile -0.2mol/L phosphoric acid solutions-water (300: 10: 690)；
Diluent 2：Acetonitrile -0.2mol/L phosphoric acid solutions-water (600: 10: 390)；
Diluent：2mmol/L phosphoric acid solutions；
Chromatographic column post case temperature is 40 DEG C；
Sample size：5μl.
2. experimental procedure
(1) system suitability solution：It is (impure A, impurity G, impurity B, miscellaneous to weigh razaxaban impurity K reference substances
Matter I, impurity J, razaxaban, impurity C, impurity E, impurity L and impurity F) 10mg, put in 25ml measuring bottles, add diluent 2 appropriate,
Ultrasound makes dissolving, lets cool, and is diluted to scale with diluent, shakes up, as system suitability solution.
Test solution：This product 5 (specification 20mg) or 10 (specification 10mg) are taken, is put in 250ml measuring bottles, adds dilution
The about 125ml of agent 2, is ultrasonically treated about 15 minutes (shaking at any time), makes disintegration of tablet complete, let cool, quarter is diluted to diluent
Degree, shakes up, and filters, takes subsequent filtrate as test solution；
Reference substance solution：It is appropriate that precision weighs razaxaban reference substance, adds diluent 1 to dissolve and dilutes and is made in every 1ml
Containing about the solution of 400 μ g, shake up, precision measures 1.0ml, puts in 100ml measuring bottles, is diluted to scale with diluent 1, shakes up, essence
Close measurement solution 2.0ml, puts in 10ml measuring bottles, is diluted to scale with diluent 1, shakes up, as reference substance solution.
(3) take each 5 μ l injections of above-mentioned diluent, system suitability solution, test solution, reference substance solution high
Effect liquid phase chromatogram instrument, is measured by above-mentioned chromatographic condition, and the data as shown in table 1 carry out linear gradient elution, records chromatography
Figure, the result is shown in Figure 1-5.
1 gradient elution program of table
3. experimental result
(1) check
If any impurity peaks in test solution chromatogram, in addition to solvent peak and gradient elution peak, calculated by following equation each
The content of impurity, each impurity must not cross limit in following table and provide that total impurities must not cross 0.5%.Table 2 below is classified as each impurity
Typical retention time, relative retention time, correction factor and the limit regulation at peak..Calculation formula：
In formula：Ax--- impurity peaks peak area in test solution；
As--- main peak peak area in reference substance solution；
Cx--- the concentration of razaxaban in test solution, μ g/ml；
Cs--- reference substance solution concentration, μ g/ml；
F --- impurity correction factor.
Retention time, correction factor and the limit regulation of 2 each impurity of table
(2) system suitability is tested
Take 5 μ l of system suitability solution to inject liquid chromatograph, record chromatogram, the separation of impurity L and impurity F
Degree should be not less than 1.0.
(3) determination method
System suitability solution is taken to cross column, measurement result is shown in Table 3.
3 measuring result of table
Result of the test shows that method baseline provided by the invention is good, and diluent does not disturb the detection of test sample；Each chromatography
Separating degree between peak is all higher than 1.5；It can be seen from the above that this method column effect height, good separating effect, specificity are strong.
Comparative example
1. instrument and condition
High performance liquid chromatograph：Shimadzu LC-20AT
Chromatographic column：Purospher Star RP-18 (55 × 4mm, 3 μm)
Detector Detection wavelength：250nm
Sample size：10μl
Diluent：30% acetonitrile
2. the method for separation determination razaxaban and its impurity
(1) take razaxaban and reference substance each appropriate, sample solution is obtained with 30% acetonitrile solution sample dissolution；
(2) preparation of mobile phase A：Weigh sodium pentanesulfonate 0.8g, pipette phosphoric acid 0.67ml in 1000ml volumetric flasks,
It is dissolved in water and is diluted to scale, pH value is adjusted to 3.8 ± 0.1 with the sodium hydroxide solution of 1mol/L；Mobile phase B is acetonitrile；
(3) diluent and 10 μ l of the sample solution of step (1) is taken to inject the chromatograph of model Shimadzu LC-20AT, chromatography
Column type number is Purospher Star RP-18, and setting flow rate of mobile phase is 1.0ml/min, Detection wavelength 250nm, chromatography
Column post case temperature is 30 DEG C；
4 gradient elution program of table
Data as shown in table 4 carry out linear gradient elution, complete separation and measure of the razaxaban in relation to material.Note
Chromatogram is recorded, reference substance solution measurement result is shown in Table 5, and high-efficient liquid phase chromatogram is shown in Fig. 6, Fig. 7.
5 measuring result of table
With reference to Fig. 6 and Fig. 7, the baseline of comparative example 2 has many unknown small peaks, and pole is produced to related substance-measuring
Big interference, and the removal of ghost peak pillar cannot be added.Therefore the surveyed accuracy in relation to content of material can be influenced.
Compared with comparative example, method baseline provided by the invention is good, and diluent does not disturb the detection of test sample, point
From height, the rate of recovery is high and accuracy is high, therefore can efficiently separate and measure each related content of material in razaxaban preparation,
Ensure that the quality controllable of razaxaban bulk pharmaceutical chemicals and its preparation, and finally determine the safe and effective of product.
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, can be to the skill of the present invention
Art scheme technical scheme is modified or replaced equivalently, without departing from the objective and scope of technical solution of the present invention, it should all cover at this
Among the right of invention.
Claims (8)
1. a kind of method of separation determination razaxaban and its impurity, it is characterised in that comprise the steps of：
1) take razaxaban to be dissolved in diluent and obtain sample solution；
2) mobile phase is prepared：
A reagent preparations A obtains mobile phase A；
B reagent preparations B obtains Mobile phase B；
3) the step 1) sample solution is injected into high performance liquid chromatograph, with mobile phase step 2) described to sample step 1) described
Product solution carries out elution and separates to obtain eluent；
4) the step 3) eluent is measured into detector；
Diluent：The aqueous solution of acetonitrile-acid, wherein the concentration of acid is 0.01-5mmol/L；
Reagent A：The volume accounting of buffer salt solution containing methanol and acetonitrile, wherein methanol and acetonitrile is 0-10%, and acetonitrile
The volume ratio for accounting for methanol and acetonitrile is 0-30%；
Reagent B：Buffer salt solution-acetonitrile；
Step 3) the high performance liquid chromatograph, its chromatographic column filler are octadecylsilane chemically bonded silica.
The impurity of the razaxaban includes process contaminants and degradation impurity, be impurity A, impurity B, impurity C, impurity D, impurity E,
Impurity F, impurity G, impurity H, impurity I, the one or more of impurity J and impurity L, its structure are：
2. method of separating and assaying according to claim 1, it is characterised in that buffer salt solution described in reagent A, B be selected from
Lower buffer salt：Phosphate, formates, acetate, citrate, perchlorate, its concentration are 0.005-0.02mol/L.
3. method of separating and assaying according to claim 2, it is characterised in that the buffer salt solution preferably phosphate delays
Fliud flushing.
4. method of separating and assaying according to claim 1, it is characterised in that acid solution described in diluent is phosphoric acid solution,
Acetonitrile volume content is 20-50% in diluent.
5. method of separating and assaying according to claim 1, it is characterised in that acetonitrile volume content described in reagent B is 50%-
80%.
6. method of separating and assaying according to claim 1, it is characterised in that the step 3) flow rate of mobile phase is 0.8-
2ml/min。
7. method of separating and assaying according to claim 1, it is characterised in that the high performance liquid chromatograph, its chromatographic column
Post case temperature is 20-50 DEG C.
8. the method described in claim 1 in separation determination razaxaban bulk pharmaceutical chemicals and preparation each related content of material should
With.
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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 |
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| CN110118836A (en) * | 2019-05-29 | 2019-08-13 | 北京悦康科创医药科技股份有限公司 | The method of genetoxic impurity in high effective liquid chromatography for measuring razaxaban |
| CN110849994A (en) * | 2019-11-25 | 2020-02-28 | 湖南九典制药股份有限公司 | Method for separating related substances in rivaroxaban |
| CN110849994B (en) * | 2019-11-25 | 2022-07-01 | 湖南九典制药股份有限公司 | Method for separating related substances in rivaroxaban |
| CN112557543A (en) * | 2020-12-09 | 2021-03-26 | 江苏嘉逸医药有限公司 | Method for measuring rivaroxaban and related substances thereof |
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| CN115469038B (en) * | 2022-10-26 | 2024-04-30 | 苏州中化药品工业有限公司 | Extraction and detection method of insoluble drugs in jam and insoluble drug mixture |
| CN116500173A (en) * | 2023-07-03 | 2023-07-28 | 则正(上海)生物科技有限公司 | Method for determining impurity content in rivaroxaban drug |
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