CN106226421A - A kind of Sorafenib Tosylate has the detection method of related substance - Google Patents
A kind of Sorafenib Tosylate has the detection method of related substance Download PDFInfo
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- G—PHYSICS
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- 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 present invention relates to analytical chemistry field, specifically disclosing a kind of Sorafenib Tosylate has the detection method of related substance.Detection method of the present invention takes Sorafenib Tosylate product to be tested preparation need testing solution, need testing solution is diluted 100 times as contrast solution, then pH3.0 phosphate buffer (takes 1.36g potassium dihydrogen phosphate, it is dissolved in water and is diluted to 1000ml, with phosphorus acid for adjusting pH value to 3.0) as mobile phase A, with acetonitrile ethanol (60:40) as Mobile phase B, according to the form below carries out gradient elution；Detection wavelength is 250nm, and column temperature is 35 DEG C.Carry out HPLC detection respectively, record the content of related substance according to the main constituent Self-control method of the correction up factor.The present invention uses acetonitrile ethanol phosphate buffer gradient elution system, the chromatographic peak making Sorafenib Tosylate can have related substance peak separating degree higher with other, and peak type symmetry is higher, it is beneficial to the detection of related substance, there is higher system suitability, in specificity, quantitative limit, detection limit, the range of linearity and repeatability, all show unrivaled advantage simultaneously, there is higher precision.
Description
Technical field
The present invention relates to analytical chemistry field, a kind of toluenesulfonic acid rope draws the detection of related substance
Method.
Background technology
Sorafenib Tosylate, English entitled Sorafenib Tosylate, indication is for being applicable to treat not expert
The advanced renal cell carcinoma of art；Treatment cannot be performed the operation or the primary hepatocarcinoma of metastasis.According to our early stage research and development experience, first
What benzenesulfonic acid Sorafenib was currently known mainly have related substance is impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, miscellaneous
Matter G and impurity H, come from synthesis material, intermediate and catabolite, and structural formula is as follows:
In view of the strict demand of current Sorafenib Tosylate product, need after synthesis Sorafenib Tosylate
Carry out the detection about content of material, to reaching standard-required.
Referring in addition to pertinent literature, employing pH2.4 phosphate buffer salt-acetonitrile-ethanol gradient elution, but p-methyl benzenesulfonic acid peak
And between impurity A peak, before main peak and its peak, between other impurities F peak, separating degree is poor, affects the inspection of impurity.Existing detection
Method, not good enough owing to there is chromatographic condition and method so that it is in system suitability, repeatability, the range of linearity, quantitative limit, inspection
Survey the aspects such as limit poor.
Summary of the invention
It is an object of the invention to provide a kind of Sorafenib Tosylate and have the detection method of related substance so that it is in system
The aspects such as the suitability, specificity, repeatability, the range of linearity, quantitative limit, detection limit comply fully with standard and have higher precision
Degree.For achieving the above object, the present invention provides following technical scheme: a kind of Sorafenib Tosylate has the detection side of related substance
Method, including: take Sorafenib Tosylate product to be tested preparation need testing solution, need testing solution is diluted 1000 times as comparison
Solution, then with potassium dihydrogen phosphate as mobile phase A, be that Mobile phase B is carried out respectively with ethanol-acetonitrile (6:4) mixed solution
HPLC detects, according to the main constituent Self-control method computing formula of the correction up factor: there is the content=F × (A confession/A of related substance
Right) × 0.1%, calculate and obtain the content having related substance；Optimize not for existing detection method chromatographic condition, cause and affect first
Benzenesulfonic acid Sorafenib is about material impurities A and the detection of impurity F, and the present invention adjusts chromatographic condition, to be not added with correction factor
Based on main constituent Self-control method, it is provided that a kind of in system suitability, repeatability, the range of linearity, quantitative limit, detection limit etc.
Aspect complies fully with the new detection method of standard.
As preferably, detection method of the present invention includes: take Sorafenib Tosylate product to be tested preparation test sample molten
Liquid, using need testing solution dilute 1000 times as reference substance solution, then with potassium dihydrogen phosphate solution as mobile phase A, with
Ethanol-acetonitrile (6:4) mixed solution is that Mobile phase B carries out HPLC detection respectively, right according to the main constituent self of the correction up factor
According to method computing formula: have the content=F of related substance × (A confession/A to) × 1%, calculate and obtain the content having related substance；Wherein, F
For there being the relative correction factor of related substance, A for there being the peak area of related substance for need testing solution, and A is to for contrast solution main peak peak
Area, described relative correction factor is the slope slope with the equation of linear regression having related substance of main constituent equation of linear regression
Ratio.Described relative correction factor is relative value, will not become in theory, but because of the existence of experimental error, has minor variations,
On final result without impact.Preferably, described impurity A, impurity B, impurity C, impurity D, impurity E and the relative correction of impurity F
The factor is respectively 1.05,0.88,0.80,0.67,0.69 and 0.71.
As preferably, gradient elution program such as following table:
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 65 | 35 |
| 10 | 50 | 50 |
| 26 | 50 | 50 |
| 27 | 65 | 35 |
| 45 | 65 | 35 |
As preferably, in described potassium dihydrogen phosphate, the amount of the material of potassium dihydrogen phosphate is 0.02mol/L；As excellent
Choosing, in described acetonitrile alcohol mixed solution, the percent by volume of acetonitrile ethanol is 60:40；
As preferably, the specification of the Waters Symmetry C18 chromatographic column of described HPLC detection is 100 × 4.6mm, 5 μ
M, its less particle diameter of employing and length are the chromatographs of Sorafenib Tosylate sheet chromatographic column used in the prior art 2 times
Post, makes the associated material of Sorafenib Tosylate and the separating degree that is respectively arranged with between related substance higher.
As preferably, described preparation need testing solution is configured to for using mixed solution (eluting phase A: eluting phase B=1:3)
Concentration is the need testing solution of 0.2mg/mL.It is highly preferred that described preparation need testing solution is: take Sorafenib Tosylate about
27.4mg, puts in 100ml measuring bottle, adds mixed solution appropriate, and ultrasonic is that it dissolves, and lets cool, is diluted to scale with mixed solution, shakes
Even, as need testing solution；
As preferably, the detection wavelength of described HPLC detection is 250nm；
As preferably, the flow velocity of described HPLC detection is 1.0mL/min；
As preferably, the sample size of described HPLC detection is 20 μ l；
As preferably, the column temperature of described HPLC detection is 35 DEG C；
As preferably, detection method of the present invention carries out system suitability detection step before being additionally included in HPLC detection
Rapid: according to the chromatographic condition of formal detection, sample introduction blank solution, system suitability solution respectively, record chromatogram, by adjusting
Chromatographic column and chromatograph make noiseless peak in blank solution chromatogram, in system suitability solution chromatogram Sorafenib with to first
Benzenesulfonic acid, impurity A, impurity B, impurity C, impurity D, separating degree between impurity E and impurity F cannot be less than 1.5；Described blank
Solution is eluting phase A: eluting phase B volume ratio is the mixed solution of 1:3, described system suitability solution prepared by following methods and
Become: separately take impurity A, impurity B, impurity C, impurity D, impurity E, each about 10mg of impurity F reference substance, accurately weighed, put 100ml measuring bottle
In, solubilizer is appropriate, ultrasonic makes dissolving, lets cool, with solvent dilution to scale, shakes up, and precision measures 10ml, puts 50ml measuring bottle
In, with solvent dilution to scale, shake up, as reference substance stock solution；Take Sorafenib Tosylate reference substance more appropriate (about
Be equivalent to Sorafenib 20mg), accurately weighed, to put in 100ml measuring bottle, solubilizer is appropriate, ultrasonic makes dissolving, lets cool, more accurate
Add above-mentioned reference substance stock solution 1ml, with solvent dilution to scale, shake up, as system suitability solution.
In the test of system suitability, and Sorafenib is immediate related substance F, itself and the separating degree of Sorafenib
It is about 1.8, more than the 1.5 of standard-required, and the immediate relevant substance A of p-methyl benzenesulfonic acid, it divides with p-methyl benzenesulfonic acid
Being about 1.9 from degree, more than the 1.5 of standard-required, isolating of showing that detection method of the present invention can be intact is each relevant
Material peak and Sorafenib main constituent peak, noiseless between each peak, it is beneficial to detection.
In the test of specificity, in the sample collection of illustrative plates after acid, alkali, oxidation, high temperature, illumination degrading, main peak pure
The degree factor is all higher than threshold value, conformance with standard requirement.
In the test of quantitative limit, be equivalent to the relevant material sample signal to noise ratio of sample concentration 0.02% more than 10, protect
In card sample, the related substance that has of more than 0.02% can be with detection by quantitative；In the test of detection limit, be equivalent to sample concentration
The impurity sample signal to noise ratio of 0.007% is more than 3, it is ensured that in sample, the related substance that has of more than 0.007% can be detected, card
The sensitivity of the bright present invention is the highest.
In the test of the range of linearity, detection method of the present invention for the range of linearity being respectively arranged with related substance all meet to
Few standard in the range of LOQ value～index 150%, and regression coefficient is all between 0.9998-1.000, it was demonstrated that in well
Linear relationship.
In replica test, the impurity peak number that 6 times measure is consistent, and the absolute deviation of impurity sum is 1.26%, does not surpasses
Cross the 50% of quality standard limit, it was demonstrated that detection method of the present invention has good precision.
In recovery test, detection method of the present invention all exists for the average recovery rate result being respectively arranged with related substance
Between 98%-105%, meet proof scheme requirement, it was demonstrated that the method has good precision.
In Intermediate precision is tested, detection method of the present invention analyzes the three of personnel's difference analytical tool for difference
Organize record for 6 times to be respectively arranged with related substance number consistent, the RSD of each impurity content is no more than 2%, and the RSD of impurity sum is
1.38%, meet proof scheme requirement, it was demonstrated that the method has good Intermediate precision.
In serviceability test, when pH value, Mobile phase B ratio or the column temperature of mobile phase A are assessed when condition determination has micro-
During little variation, the impregnable Bearing degree of measurement result.Prove that the method has good ruggedness.
From above technical scheme, the present invention uses acetonitrile-ethanol-potassium dihydrogen phosphate gradient elution system, makes
The chromatographic peak obtaining Sorafenib can have related substance peak separating degree higher with other, and peak type symmetry is higher, the most relevant thing
The detection of matter, has higher system suitability, simultaneously repeatability in specificity, quantitative limit, detection limit, the range of linearity and all
Show unrivaled advantage, there is higher precision.
Accompanying drawing explanation
Fig. 1, Sorafenib Tosylate Related substances separation blank solution liquid chromatogram；
Fig. 2, Sorafenib Tosylate Related substances separation system suitability solution liquid chromatographic figure；
Fig. 3, without degradation treatment Sorafenib Tosylate need testing solution liquid chromatogram；
Fig. 4,0.5M HCl degradation treatment toluenesulfonic acid rope draws need testing solution liquid chromatogram；
Fig. 5,0.5M NaOH degradation treatment Sorafenib Tosylate need testing solution liquid chromatogram；
Fig. 6, oxidative degradation process Sorafenib Tosylate need testing solution liquid chromatogram；
Fig. 7, high light degradation treatment Sorafenib Tosylate need testing solution liquid chromatogram；
Fig. 8, high temperature degradation process Sorafenib Tosylate need testing solution liquid chromatogram.
Detailed description of the invention
The invention discloses a kind of Sorafenib Tosylate and have the detection method of related substance.Those skilled in the art are permissible
Use for reference present disclosure, be suitably modified technological parameter and realize.Special needs to be pointed out is, all similar replacements and change are to ability
Being apparent from for field technique personnel, they are considered as being included in the present invention.Detection method of the present invention has been led to
Crossing preferred embodiment to be described, related personnel substantially can be to this paper institute in without departing from present invention, spirit and scope
The method application stated is modified or suitably changes and combine, and realizes and applies the technology of the present invention.
According to detection method of the present invention, it is mainly for known impurity A, impurity B, impurity C, impurity D, impurity E
With the detection of impurity F, but for unknown impurity, detection method of the present invention also can first assume unknown impuritie and Sorafenib
Response value consistent, i.e. relative correction factor is 1.0, then carries out checking test, by the result counter push away be assumed to be true, thus
Detect the content of unknown impuritie.
The chromatograph that detection method of the present invention uses in embodiments is Shimadzu high performance liquid chromatograph, chromatographic column
For Waters Symmetry C18 (4.6 × 100mm, 3.5 μm).
Below in conjunction with embodiment, the present invention is expanded on further.
Embodiment 1: the chromatographic condition of detection method of the present invention and chromatographic system
Instrument: Shimadzu high performance liquid chromatograph
Chromatographic column: Waters Symmetry C18 (4.6 × 100mm, 3.5 μm)
Mobile phase A: pH3.0 phosphate buffer (take 2.72g potassium dihydrogen phosphate, be dissolved in water and be diluted to 1000ml, with
Phosphorus acid for adjusting pH value is to 3.0)；Mobile phase B: acetonitrile: ethanol=60:40；Detection wavelength: 250nm；Flow velocity: 1.0ml/min；Enter
Sample amount: 20 μ l；Column temperature: 35 DEG C
Table 1: elution program
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 65 | 35 |
| 10 | 50 | 50 |
| 26 | 50 | 50 |
| 27 | 65 | 35 |
| 45 | 65 | 35 |
Prepared by need testing solution: take Sorafenib Tosylate about 27.4mg, put in 100ml measuring bottle, adds mixed solution and fits
Amount, ultrasonic is that it dissolves, and lets cool, by diluted to scale, shakes up, as need testing solution；Prepared by contrast solution: accurate
Measure need testing solution 1ml, put in 100ml measuring bottle, by diluted to scale, shake up, then precision measures 1ml, puts 10ml
In measuring bottle, it is diluted to scale with dilute solution, shakes up, as contrast solution.Molten to test sample respectively according to above-mentioned chromatographic condition
Liquid and contrast solution carry out HPLC detection, then with the main constituent Self-control method computing formula of the correction up factor: there is related substance
Content=F × (A confession/A to) × 0.1%, calculate and obtain the content having related substance；Wherein, F is the relative correction having related substance
The factor, A for there being the peak area of related substance for need testing solution, and A is to for contrast solution main peak peak area, described relative correction factor
It is the slope ratio with the slope of the equation of linear regression having related substance of main composition equation of linear regression.It is respectively arranged with the phase of related substance
Retention time and relative correction factor are shown in Table 2
Table 2: be respectively arranged with relative retention time and the relative correction factor of related substance
| Compound | Relative retention time | Relative correction factor | Control limit |
| Impurity A | 0.12 | 1.05 | ≤ 0.1% |
| Impurity B | 0.32 | 0.88 | ≤ 0.1% |
| Impurity C | 0.57 | 0.80 | ≤ 0.1% |
| Impurity D | 0.83 | 0.67 | ≤ 0.1% |
| Impurity E | 0.91 | 0.69 | ≤ 0.1% |
| Impurity F | 0.97 | 0.71 | ≤ 0.1% |
Embodiment 2: detection method system suitability of the present invention detects
Diluent: mobile phase A-Mobile phase B (1:3) (V/V)；Blank solution: diluent
Impurity stock solution: take each about 20mg of impurity A, impurity B, impurity C, impurity D, impurity E and impurity F, accurately weighed,
Putting in 100ml measuring bottle, add diluent appropriate, ultrasonic make dissolving, let cool, by diluted to scale, shake up, precision measures
5ml, puts in 50ml measuring bottle, by diluted to scale, shakes up, as reference substance stock solution；
System suitability solution: separately take Sorafenib Tosylate reference substance about 27.5mg, accurately weighed, put
In 100ml measuring bottle, add diluent appropriate, ultrasonic make dissolving, more accurate add above-mentioned stock solution 1ml, by diluted to carving
Degree, shakes up, as system suitability solution.
According to embodiment 1 chromatographic condition sample introduction blank solution, separating degree solution respectively, record chromatogram, see that description is attached
Fig. 1 and 2, accordingly result is shown in Table 3.
Table 3: system suitability result
| Chemical combination name | Retention time (min) | Tailing factor | Separating degree | Number of theoretical plate |
| P-methyl benzenesulfonic acid | 1.494 | 1.716 | -- | 975.127 |
| Impurity A | 1.962 | 1.332 | 1.926 | 709.058 |
| Impurity B | 5.256 | 1.115 | 10.721 | 4324.884 |
| Unknown impuritie | 5.791 | 1.107 | 1.764 | 6537.141 |
| Impurity C | 9.439 | 1.011 | 13.547 | 22438.586 |
| Impurity D | 13.746 | 1.061 | 17.739 | 55405.555 |
| Impurity E | 15.163 | 0.986 | 5.892 | 60236.461 |
| Impurity F | 16.200 | 0.996 | 4.309 | 76297.460 |
| Sorafenib | 16.659 | 1.056 | 1.926 | 76123.594 |
| Unknown impuritie | 27.565 | 1.120 | 27.155 | 38524.188 |
According to Figure of description 1,2 and the result of table 3, before Sorafenib and its peak, the minimum at other impurities F peak is divided
It is about 1.9 from degree, meets system suitability requirement, and peak shape is preferable, and the most noiseless peak in blank solution, compare existing side
Before the main peak of method appearance and its peak, the separating degree between other impurities F peak and between p-methyl benzenesulfonic acid peak and impurity A is poor, this
Bright described detection method is more beneficial for the detection of impurity, and precision is inherently derived large increase.
Embodiment 3: detection method specificity of the present invention detects
Strong Degrading experiment is at simulation strong acid, highly basic, oxidation, high temperature and the strong degradation condition of illumination, p-methyl benzenesulfonic acid rope
La Feini destroys, it is therefore an objective to by investigating catabolite and the separation situation of main peak and known impurities of sample, contrast
The growing amount of impurity and the decrement of main composition, carry out the efficiency and applicability of analysis and assessment method with this.Use DAD inspection simultaneously
Survey device, carry out Peak homogeneity: in the collection of illustrative plates of Degrading experiment gained, when the purity factor of main composition is more than threshold value, then can sentence
This chromatographic peak disconnected does not comprise other impurity peaks, and chromatographic peak purity meets the requirements, and concrete result of the test is shown in Table 4, corresponding chromatogram
Figure of description 3-8.
Table 4: specificity result of the test
Result according to table 4 is it is apparent that under strong Degrading experiment, detection method of the present invention still can be complete
Isolating well each peak shape, it is ensured that occur without the situation at coincidence peak, and the purity factor of main peak is all higher than threshold value, conformance with standard is wanted
Ask.
Embodiment 4: detection method quantitative limit of the present invention and the detection of detection limit
For there being related substance, detection limit (LOD) and quantitative limit (LOQ) determine according to signal to noise ratio method.Embodiment 2
Knowing that the impurity storing solution of concentration is diluted to the sample of low concentration, the signal measured compares with baseline noise, and calculating energy quilt can
By least concentration or the percentage ratio of detection, the results are shown in Table 5.
Table 5: quantitative limit and detection limit result
Note: the percentage ratio being equivalent to sample concentration is to have the detection of related substance to limit concentration or quantitative limit concentration than upper test sample
The concentration of solution
In the data of quantitative limit, be equivalent to the relevant material sample signal to noise ratio of sample concentration 0.02% more than 10, protect
In card sample, the related substance that has of more than 0.02% can be with detection by quantitative；In the data of detection limit, be equivalent to sample concentration
The impurity sample signal to noise ratio of 0.007% is more than 3, it is ensured that in sample, the related substance that has of more than 0.007% can be detected, card
The sensitivity of the bright present invention is the highest.
Embodiment 5: the linear and range detection of detection method of the present invention
Impurity each for Sorafenib Tosylate, in the scope being equivalent to need testing solution concentration 0.02% to 0.15%
Inside take 6 concentration point to study.Linear relationship is with function construction to analyte concentration of the peak area that records, with a young waiter in a wineshop or an inn
Multiplication carries out linear regression, it is desirable to the numerical value of this linear regression coeffficient r should the results are shown in Table 6～12 not less than 0.990.Be equivalent to
The percentage ratio of sample concentration is the concentration concentration than upper need testing solution of each linear scale solution having related substance.
Table 6: impurity A linear determination result
Table 7: impurity B linear determination result
Table 8: impurity C linear determination result
Table 9: impurity D linear determination result
Table 10: impurity E linear determination result
Table 11: impurity F linear determination result
Table 12: Sorafenib Tosylate linear determination result
From the result of above-mentioned each table, invent described detection method and all meet for the range of linearity of each impurity and at least exist
Standard in the range of LOQ value～index 150%, and regression coefficient is all more than 0.9995, it was demonstrated that in good linear relationship.
Embodiment 6: the detection (standard curve method) of each impurity relative correction factor of detection method of the present invention
Take " embodiment 5: the linear and range detection of detection method of the present invention " lower 6 kinds of linear test solution of item, point
Do not test in Shimadzu and Agilent high performance liquid chromatograph, each line taking testing liquid 20 μ l, be injected separately into liquid phase color
Spectrometer, records chromatogram, in solution Sorafenib Tosylate or each impurity concentration as abscissa, Sorafenib or each impurity
Peak area is that vertical coordinate makees regression equation, calculates correction factor.
Computing formula: correction factor F=KSorafenib÷KImpurity
In formula: KSorafenib: toluenesulfonic acid rope draws the slope in regression equation；
KImpurity: the slope in Sorafenib Tosylate each impurity regression equation.
Record in Shimadzu high performance liquid chromatograph the results are shown in Table 11, the result of record in Agilent high performance liquid chromatograph
It is shown in Table 13～19
Table 13: impurity A linear determination result
Table 14: impurity B linear determination result
Table 15: impurity C linear determination result
Table 16: impurity D linear determination result
Table 17: impurity E linear determination result
Table 18: impurity F linear determination result
Table 19: Sorafenib Tosylate linear determination result
According to the linear of described detection method and range detection method, different time difference instrument difference is used to analyze personnel
The result of the test recorded for twice, calculates the relative correction factor of each impurity, the results are shown in Table 20.
Table 20 each impurity relative correction factor measures table
| Instrument | Shimadzu high performance liquid chromatograph | Agilent high performance liquid chromatograph | Averagely |
| Impurity A correction factor | 1.06 | 1.03 | 1.04 |
| Impurity B correction factor | 0.89 | 0.88 | 0.88 |
| Impurity C correction factor | 0.81 | 0.80 | 0.80 |
| Impurity D correction factor | 0.67 | 0.67 | 0.67 |
| Impurity E correction factor | 0.69 | 0.69 | 0.69 |
| Impurity F correction factor | 0.72 | 0.70 | 0.71 |
Embodiment 7: the detection of the repeatability of detection method of the present invention
Take Sorafenib Tosylate sample, be repeated 6 times detection according to the embodiment of the present invention 1 detection method, carry out authentication
Method has good precision, the results are shown in Table 21.
Table 21: reperformance test result
As shown in Table 21,6 detections, the most only detect impurity A and impurity B, and the relative standard deviation of impurity sum
It is 1.26%, it was demonstrated that the method has good precision.
Embodiment 8: the detection of the Intermediate precision test of detection method of the present invention
Take same lot number Sorafenib Tosylate sample, respectively by different people, different instruments, implement according to the present invention
Example 1 detection method measures impurity A, impurity B, impurity C, impurity D, impurity E, the content of impurity F, result of the test table 22.
Table 22 Intermediate precision test result
As shown in Table 22, difference analyze personnel, different instrument in 6 measurement results of different time, the most only detect
Impurity A and impurity B, and the relative standard deviation of impurity sum is 1.29%, it was demonstrated that and the method has good intermediate precision
Degree.
Embodiment 9: the detection of the recovery test of detection method of the present invention
Use sample-adding absorption method to measure, measure impurity A, impurity B, impurity C, impurity D, impurity E, impurity F in loaded sample
Actually measured amount and theoretical amount between ratio (response rate), express with percentage rate %, it is desirable to the response rate 90.0%～
Between 108.0, with substantive approach, there is good accuracy.The results are shown in Table 23～28.
Table 23 impurity A recovery test result
Table 24 impurity B recovery test result
Table 25 impurity C recovery test result
Table 26 impurity D recovery test result
Table 27 impurity E recovery test result
Table 28 impurity F accuracy test result
From table 23-28, the response rate of impurity A, impurity B, impurity C, impurity D, impurity E and impurity F is all 93.9%
～between 107.2%, average recovery rate is respectively 102.7%, 101.0%, 103.7%, 104.4%, 103.4%, 98.8%,
Meet proof scheme and require (90%～108%).Confirm that the method has good accuracy.
Embodiment 9: the detection of the solution stability testing of detection method of the present invention
Take a Sorafenib Tosylate sample, according to the embodiment of the present invention 1 detection method respectively measure placement 0h, 2h,
The need testing solution of 4h, 6h, 8h, 10h, investigates each impurity and the situation of change of total impurities peak area and to calculate relative standard inclined
Difference.The results are shown in Table 29.
Table 29 need testing solution stability test result
| Standing time (h) | Impurity A peak area | Impurity B peak area | Main peak peak area |
| 0 | 3878 | 1226 | 12398452 |
| 2 | 3830 | 1221 | 12457119 |
| 4 | 4051 | 1313 | 12410553 |
| 6 | 4215 | 1203 | 12422474 |
| 8 | 4233 | 1163 | 12445159 |
| 10 | 4180 | 1167 | 12454636 |
| Averagely | 4064.5 | 1216 | 12431399 |
| RSD | 4.32% | 4.49% | 0.20% |
As shown in Table 29, single miscellaneous number and content all do not increase, and total impurities does not increases yet, Sorafenib Tosylate
Need testing solution is stable in 10 hours.
Embodiment 10: the detection of the serviceability test of detection method of the present invention
Assess when condition determination has small variation by the change pH value of mobile phase A, Mobile phase B ratio, column temperature,
The impregnable Bearing degree of measurement result.Durability test the results are shown in Table 30～31.
The parameter of table 30 chromatographic condition variation
| Chromatographic parameter | Setting | Mobility scale |
| Flowing phase pH value | 2.5 | 2.3 and 2.7 |
| Mobile phase B ratio | Acetonitrile: ethanol (60:40) | 58:42 and 62:38 |
| Column temperature | 35℃ | 30℃ |
The flowing of the different pH value of table 31 is relatively about the impact of substance-measuring
The different column temperature of table 32 is on the impact about substance-measuring
The different mobile phase ratio of table 33 is on the impact about substance-measuring
From table 30-33, in the method during chromatographic condition generation small change, single miscellaneous number and content all do not have
Significant change, total impurities does not has significant change, the separating degree between each impurity and other impurities peak to still conform to regulation yet, shows
This method good tolerance.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For Yuan, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (6)
1. a Sorafenib Tosylate has the detection method of related substance, it is characterised in that including: take toluenesulfonic acid Suo Lafei
Buddhist nun's product to be tested preparation need testing solution, using need testing solution dilution 1000 times as contrast solution, then delays with pH3.0 phosphate
Rush liquid (take 2.72g potassium dihydrogen phosphate, be dissolved in water and be diluted to 1000ml, with phosphorus acid for adjusting pH value to 3.0) as mobile phase A,
It is that Mobile phase B carries out HPLC detection respectively, according to the main constituent Self-control method of the correction up factor with acetonitrile-ethanol (60:40)
Record the content of related substance；The chromatographic column of described HPLC detection is C18 chromatographic column；Biphosphate in described phosphate buffer
The amount of the material of potassium is 0.02mol/L；The elution program of described HPLC detection is:
The detection wavelength of described HPLC detection is 250nm.
Detection method the most according to claim 1, it is characterised in that including: take the preparation of Sorafenib Tosylate product to be tested
Need testing solution, using need testing solution dilute 1000 times as contrast solution, then with phosphate buffer as mobile phase A, with
Acetonitrile-ethanol (60:40) mixed solution is that Mobile phase B carries out HPLC detection respectively, according to the main constituent self of the correction up factor
Counter point computing formula: have the content=F of related substance × (A confession/A to) × 0.1%, calculate and obtain the content having related substance；Its
In, F is the relative correction factor having related substance, and A for there being the peak area of related substance for need testing solution, and A is to for contrast solution master
Peak-to-peak area, described relative correction factor is the slope of main composition equation of linear regression and the equation of linear regression having related substance
The ratio of slope.
Detection method the most according to claim 1 or claim 2, it is characterised in that described preparation need testing solution is for using eluting phase A
It is configured to the need testing solution that concentration is 0.2mg/mL with eluting phase B.
Detection method the most according to claim 3, it is characterised in that described preparation need testing solution is: take toluenesulfonic acid rope
La Feiniyue 27.4mg, puts in 100ml measuring bottle, adds mobile phase A: Mobile phase B (1:3) solution makes dissolving in right amount, adds mobile phase A:
Mobile phase B (1:3) is diluted to scale, shakes up, as need testing solution.
Detection method the most according to claim 1 or claim 2, it is characterised in that the flow velocity of described HPLC detection is 0.9-1.1mL/
min。
Detection method the most according to claim 1 or claim 2, it is characterised in that the column temperature of described HPLC detection is 25-35 DEG C.
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