CN104359993B - A kind of detection method of ambrisentan related substance - Google Patents
A kind of detection method of ambrisentan related substance Download PDFInfo
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Abstract
The present invention relates to analytical chemistry field, specifically disclose a kind of detection method of ambrisentan related substance.Detection method of the present invention gets ambrisentan product to be tested preparation need testing solution, need testing solution is diluted 100 times of product solution in contrast, then take trifluoroacetic acid aqueous solution as mobile phase A, with trifluoroacetic acid acetonitrile solution for Mobile phase B carries out HPLC detection respectively, record the content of related substance according to the major component Self-control method of the correction up factor.The present invention adopts acetonitrile-water-trifluoroacetic acid gradient elution system, make the chromatographic peak of ambrisentan can be higher with other related substance peak degree of separation, and peak type symmetry is higher, be beneficial to detecting of related substance, there is higher system flexibility, in specificity, quantitative limit, detectability, 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, relate to a kind of detection method of ambrisentan related substance in particular.
Background technology
Ambrisentan, English Ambrisentan by name, indication is the patients with pulmonary hypertension being applicable to treat WHOII level or III level symptom, in order to improve locomitivity and to delay clinical deterioration rates.This medicine as requiring during drug use that the content of ambrisentan is not less than 98.5%, and has made strict restriction to its related substances wherein.
The related substance that mainly contains that ambrisentan is known is at present SRS1, SRS2, SRS3, SRS4 and DP1, and come from synthesis material, resolution reagent, intermediate and catabolite, structural formula is as follows:
In view of current to the strict demand of ambrisentan product, after synthesis ambrisentan, need the detection carrying out its related substances, to reaching standard-required.
Document " QualitySpecificationforImportDrugs-CompoundAmbrisentanta blets " (import drugs quality standard---ambrisentan sheet, [S] .JX20090317.) in, ambrisentan sheet import drugs registered standard adopts acetonitrile-phosphate-buffered salt gradient elution, but there is ghost peak to occur when not sample introduction dry running Gradient program, affect the inspection of impurity.Meanwhile, its phosphate buffered saline pH value is 6.5, and ambrisentan molecule (pKa is 4.0) is separated in the form of an ion on reverse-phase chromatographic column, and the hangover of ambrisentan chromatographic peak is serious, is unfavorable for the detection of content of material.Although document (M.B.V.Narayana1, K.B.ChandrasekharandB.M.Rao.AValidatedSpecificStability-IndicatingRP-HPLCAssayMethodforAmbrisentanandItsRelatedS ubstances [J] .JournalofChromatographicScience, 2013, potassium dihydrogen phosphate pH value is adjusted to 2.5 by the detection method 1-8), but still have ghost peak to occur when not sample introduction dry running Gradient program, affect the inspection of impurity.Such as, and the chromatographic condition adopted in above-mentioned two kinds of detection methods, mobile phase and gradient elution mode etc. all retain more weak to impurity phenyl ethylamine (DP1), do not separate completely, make testing result inaccurate equally with solvent peak.Existing detection method, owing to there is chromatographic condition and method is not good enough, makes it poor in system suitability, repeatability, the range of linearity, quantitative limit, detectability etc.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of detection method of ambrisentan related substance, make it in system suitability, specificity, repeatability, the range of linearity, quantitative limit, detectability etc., meet standard completely and have higher precision.
For achieving the above object, the invention provides following technical scheme:
A detection method for ambrisentan related substance, comprising:
Get ambrisentan product to be tested preparation need testing solution, need testing solution is diluted 100 times of product solution in contrast, then take trifluoroacetic acid aqueous solution as mobile phase A, with trifluoroacetic acid acetonitrile solution for Mobile phase B carries out HPLC detection respectively, record the content of related substance according to the major component Self-control method of the correction up factor.
Optimize not for existing detection method chromatographic condition, cause the detection of impact to ambrisentan related substance SRS1, SRS2, SRS3, SRS4 and DP1, the present invention adjusts chromatographic condition, based on the major component Self-control method of the correction up factor, provide one complete standard compliant new detection method in system suitability, repeatability, the range of linearity, quantitative limit, detectability etc.Related substance of the present invention refers to SRS1, SRS2, SRS3, SRS4 and DP1 impurity.
As preferably, detection method of the present invention comprises:
Get ambrisentan product to be tested preparation need testing solution, need testing solution is diluted 100 times of product solution in contrast, then take trifluoroacetic acid aqueous solution as mobile phase A, with trifluoroacetic acid acetonitrile solution for Mobile phase B carries out HPLC detection respectively, the major component Self-control method computing formula according to the correction up factor: the content=F × (A of related substance
supply/ A
right) × 1%, calculates the content obtaining related substance;
Wherein, F is the relative correction factor of related substance, A
supplyfor the peak area of need testing solution related substance, A
rightfor contrast solution main peak peak area, described relative correction factor is the ratio of the slope of the slope of major component equation of linear regression and the equation of linear regression of related substance.
Described relative correction factor is relative value, can not become in theory, but because of the existence of experimental error, has subtle change, on final result without impact.Preferably, the relative correction factor of described SRS1, SRS2, SRS3, SRS4 and DP1 is respectively 8.0,1.6,1.2,1.0 and 0.64.
As preferably, the elution program that described HPLC detects is:
0min, wash-out phase A: wash-out phase B volume ratio is 75:25 wash-out, 0-17min, wash-out phase A: wash-out phase B volume ratio linearly fades to 40:60, carries out linear gradient elution; 17-25min, wash-out phase A: wash-out phase B volume ratio is 40:60, carries out isocratic elution; 25-40min, wash-out phase A: wash-out phase B volume ratio linearly fades to 20:80, carries out linear gradient elution; After 40min, wash-out phase A: wash-out phase B volume ratio is that the peak that 20:80 is eluted to related substance all occurs.
As preferably, in described trifluoroacetic acid aqueous solution, the percent by volume of trifluoroacetic acid is 0.01-0.03%, is more preferably 0.02%.
As preferably, in described trifluoroacetic acid acetonitrile solution, the percent by volume of trifluoroacetic acid is 0.005-0.015%, is more preferably 0.01%
As preferably, the chromatographic column that described HPLC detects is WatersAtlantisT3 chromatographic column, and its adopts trifunctional C18 alkyl bonded phase, and make the compound of opposed polarity all have suitable reservation, the degree of separation of ambrisentan and related substance is higher.
As preferably, described preparation need testing solution is adopt wash-out phase A and wash-out phase B to be mixed with the need testing solution that concentration is 0.25mg/mL.More preferably, described preparation need testing solution is:
Get ambrisentan and be about 12.5mg, put in 50ml measuring bottle, add trifluoroacetic acid acetonitrile solution 12.5ml and make dissolving, add trifluoroacetic acid aqueous solution and be diluted to scale, shake up, as need testing solution.
As preferably, the determined wavelength that described HPLC detects is 220nm.
As preferably, the flow velocity that described HPLC detects is 0.9-1.1mL/min, is more preferably 1.0mL/min.
As preferably, the sample size that described HPLC detects is 20 μ l.
As preferably, the column temperature that described HPLC detects is 25-35 DEG C, is more preferably 30 DEG C.
As preferably, the injector temperature that described HPLC detects is 5 DEG C.
As preferably, detection method of the present invention is also included in before HPLC detects carries out system flexibility detecting step:
According to the formal chromatographic condition detected, sample introduction blank solution, degree of separation solution respectively, record chromatogram, make noiseless peak in blank solution chromatogram by adjustment chromatographic column and chromatograph, in degree of separation solution chromatogram, ambrisentan and the degree of separation between SRS1, SRS2, SRS3, SRS4, DP1 must not be less than 1.5;
Described blank solution is wash-out phase A: wash-out phase B volume ratio is the mixed solution of 75:25, and described degree of separation solution is formulated by following methods:
Get each 12.5mg of related substance SRS1, SRS2, SRS3, SRS4, DP1 respectively, accurately weighed and be placed in same 100ml measuring bottle, dissolve with blank solution and be diluted to scale, shaking up, obtaining impurity storing solution;
Get ambrisentan and be about 12.5mg, put in 50ml measuring bottle, add 0.01% trifluoroacetic acid acetonitrile solution 12.5ml and make dissolving, then add impurity storing solution 1.0ml, be diluted to scale with 0.02% trifluoroacetic acid aqueous solution, shake up and obtain degree of separation solution.
In the test of system suitability, related substance SRS3 immediate with ambrisentan, it is about 4.5 with the degree of separation of ambrisentan, still be greater than 1.5 of standard-required, what show that detection method of the present invention can be intact isolates each related substance peak and ambrisentan major component peak, noiseless between each peak, be beneficial to detection.
In the test of specificity, in the sample collection of illustrative plates after acid, alkali, oxidation, high temperature, illumination degrading, the purity factor of main peak is all greater than threshold value, meets standard-required.
In the test of quantitative limit, be equivalent to the related substance sample signal to noise ratio (S/N ratio) of sample concentration 0.05% more than 10, ensure that the related substance of in sample more than 0.05% can quantitatively detect; In the test of detectability, be equivalent to the impurity sample signal to noise ratio (S/N ratio) of sample concentration 0.02% more than 3, ensure that the related substance of in sample more than 0.02% can be detected, prove that sensitivity of the present invention is very high.
In the test of the range of linearity, detection method of the present invention all meets the standard at least in the scope of LOQ value ~ index 150% for the range of linearity of each related substance, and regression coefficient is all more than 0.999, proves in good linear relationship.
In repeatability, the impurity peak number measured for 6 times is consistent, and the absolute deviation of impurity sum is 0.02%, is no more than 50% of quality standard limit, confirms that detection method of the present invention has good precision.
From above technical scheme, the present invention adopts acetonitrile-water-trifluoroacetic acid gradient elution system, make the chromatographic peak of ambrisentan can be higher with other related substance peak degree of separation, and peak type symmetry is higher, be beneficial to detecting of related substance, there is higher system flexibility, in specificity, quantitative limit, detectability, the range of linearity and repeatability, all show unrivaled advantage simultaneously, there is higher precision.
Accompanying drawing explanation
Figure 1 shows that ambrisentan Related substances separation blank solution liquid chromatogram;
Figure 2 shows that ambrisentan Related substances separation degree of separation solution liquid chromatographic figure;
Figure 3 shows that without degradation treatment ambrisentan need testing solution liquid chromatogram;
Figure 4 shows that 0.1MHCl degradation treatment ambrisentan need testing solution liquid chromatogram;
Figure 5 shows that 1MNaOH degradation treatment ambrisentan need testing solution liquid chromatogram;
Figure 6 shows that oxidative degradation process ambrisentan need testing solution liquid chromatogram;
Figure 7 shows that high light degradation treatment ambrisentan need testing solution liquid chromatogram;
Figure 8 shows that high temperature degradation process ambrisentan need testing solution liquid chromatogram.
Embodiment
The invention discloses a kind of detection method of ambrisentan related substance.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Detection method of the present invention is described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope methods and applications as herein described are changed or suitably change with combination, realize and apply the technology of the present invention.
According to detection method of the present invention, it is mainly for the detection of known related substance SRS1, SRS2, SRS3, SRS4, DP1, but for the impurity of the unknown, detection method of the present invention also first can suppose that unknown impuritie is consistent with the response of ambrisentan, namely relative correction factor is 1.0, then carry out demonstration test, be assumed to be very by counter the pushing away of the result, thus detect the content of unknown impuritie.
The chromatograph that detection method of the present invention adopts in embodiments is Shimadzu high performance liquid chromatograph, and chromatographic column is WatersAtlantisT3 (4.6 × 250mm, 5 μm).
Below in conjunction with embodiment, set forth the present invention further.
Embodiment 1: detection method of the present invention
Instrument: Shimadzu high performance liquid chromatograph
Chromatographic column: WatersAtlantisT3 (4.6 × 250mm, 5 μm)
Mobile phase A: 0.02% trifluoroacetic acid aqueous solution
Mobile phase B: 0.01% trifluoroacetic acid acetonitrile solution
Determined wavelength: 220nm
Flow velocity: 1.0ml/min
Sample size: 20 μ l
Column temperature: 30 DEG C
Automatic sampler temperature control: 5 DEG C
Elution program is in table 1:
Table 1 elution program
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 75 | 25 4 --> |
| 17 | 40 | 60 |
| 25 | 40 | 60 |
| 40 | 20 | 80 |
| 45 | 20 | 80 |
Need testing solution: get ambrisentan sample 12.5mg, put in 50ml measuring bottle, adds 0.01% trifluoroacetic acid acetonitrile solution 12.5ml and makes dissolving, add 0.02% trifluoroacetic acid aqueous solution and be diluted to scale, shake up, as need testing solution.
Reference substance solution: get need testing solution 1.0ml in 100ml measuring bottle, be diluted to scale with dilute solution, shake up.
Respectively HPLC detection is carried out to need testing solution and reference substance solution according to above-mentioned chromatographic condition, then with the major component Self-control method computing formula of the correction up factor: the content=F × (A of related substance
supply/ A
right) × 1%, calculates the content obtaining related substance;
Wherein, F is the relative correction factor of related substance, A
supplyfor the peak area of need testing solution related substance, A
rightfor contrast solution main peak peak area, described relative correction factor is the ratio of the slope of the main slope of composition equation of linear regression and the equation of linear regression of related substance.
The relative retention time of each related substance and relative correction factor are in table 2
The relative retention time of each related substance of table 2 and relative correction factor
| Compound | Relative retention time | Relative correction factor | Control limit (%) |
| SRS1 | 0.15 | 8.0 | ≤0.1 |
| SRS2 | 0.26 | 1.6 | ≤0.1 |
| Ambrisentan | 1.0 | 1.0 | — |
| SRS3 | 1.04 | 1.2 | ≤0.1 |
| SRS 4 | 1.44 | 1.0 | ≤0.1 |
| DP1 | 1.74 | 0.65 | ≤0.2 |
| Single unknown impuritie | — | 1.0 | ≤0.1 |
| Total impurities | — | — | ≤0.5 |
Embodiment 2: detection method system flexibility of the present invention detects
Dilute solution: 0.01% trifluoroacetic acid acetonitrile solution-0.02% trifluoroacetic acid aqueous solution (25:75) (V/V)
Blank solution: dilute solution
Impurity stock solution: get each 12.5mg of impurity SRS1, SRS2, SRS3, SRS4, dp1, accurately weighed in 100ml measuring bottle, dissolve with dilute solution and be diluted to scale, shaking up.
Degree of separation solution: get ambrisentan and be about 12.5mg, puts in 50ml measuring bottle, adds 0.01% trifluoroacetic acid acetonitrile solution 12.5ml and makes dissolving, then add impurity storing solution 1.0ml, be diluted to scale, shake up with 0.02% trifluoroacetic acid aqueous solution.
According to embodiment 1 chromatographic condition sample introduction blank solution, degree of separation solution respectively, record chromatogram, see Fig. 1 and Fig. 2, accordingly result is in table 3.
Table 3 system flexibility result
| Compound name | Concentration | Retention time (min) | Degree of separation 5--> |
| Impurity SRS1 | 0.482ug/ml | 3.780 | —— |
| Impurity SRS2 | 0.508ug/ml | 5.863 | 15.33 |
| Ambrisentan | 0.2496mg/ml | 21.595 | 22.17 |
| Impurity SRS3 | 0.488ug/ml | 22.695 | 4.50 |
| Impurity SRS4 | 0.491ug/ml | 32.426 | 33.79 |
| Impurity dp1 | 0.502ug/ml | 39.465 | 21.52 |
Note, in table, concentration is actual sample concentration in test, according to objective reality situation, compares with the limiting concentration of aforementioned degree of separation solution the error allowed within 10%.
According to the result of Fig. 1, Fig. 2 and table 3, the minimum separation degree of ambrisentan and each related substance is about 4.5, meet system suitability requirement, and peak shape is better, and also noiseless peak in blank solution, compare the ghost peak that existing method occurs, detection method of the present invention is more conducive to detecting of impurity, and precision is greatly improved naturally.
Embodiment 3: detection method specificity of the present invention detects
Strong Degrading experiment is under the condition that intensity is larger, as the method for strong acid, highly basic, Strong oxdiative, high temperature, intense light irradiation, accelerate to destroy ambrisentan, object is by investigating the catabolite of sample and the separation case of main peak and known impurities, the growing amount of comparison impurity and the reduction of main composition, carry out the efficiency and applicability of analysis and assessment method with this.Adopt DAD detecting device simultaneously, carry out Peak homogeneity: in the collection of illustrative plates of Degrading experiment gained, when the purity factor of main composition is greater than threshold value, then can judge that this chromatographic peak does not comprise other impurity peaks, chromatographic peak purity meets the requirements, and concrete test findings is in table 4, and corresponding chromatogram is shown in Fig. 3-8.
Table 4 specificity test findings
The purity factor and purity threshold value are calculated by software, obtain by comparing the difference of the spectrogram that each time point is corresponding on chromatographic peak, the purity factor is more close to 1000, more illustrate that the spectrogram that on chromatographic peak, each time point is corresponding is consistent, illustrate that this chromatographic peak only represents a kind of material, do not comprise other unsegregated materials.And material balance use the chromatogram total peak area after degraded and than upper without degradation treatment chromatogram total peak area and, ratio, more close to 1, more illustrates that the total material detected by degraded front and back is conservation.
Result according to table 4 can obviously be found out, under strong Degrading experiment, detection method of the present invention still can isolate each peak shape in good condition, ensure the situation not occurring coincidence peak, and the purity factor of main peak is all greater than threshold value, meets standard-required.
Embodiment 4: the detection of detection method quantitative limit of the present invention and detectability
For related substance, detectability (LOD) and quantitative limit (LOQ) are determined according to signal to noise ratio (S/N ratio) method.The impurity storing solution of embodiment 2 concentration known is diluted to the sample of low concentration, the signal measured and baseline noise compare, and calculate and by the least concentration that reliably detects or number percent, can the results are shown in Table 5.
Table 5 quantitative limit and detectability result
Note: the number percent being equivalent to sample concentration is the concentration of need testing solution on the detectability concentration of related substance or quantitative limit concentration ratio
In the data of quantitative limit, be equivalent to the related substance sample signal to noise ratio (S/N ratio) of sample concentration 0.05% more than 10, ensure that the related substance of in sample more than 0.05% can quantitatively detect; In the data of detectability, be equivalent to the impurity sample signal to noise ratio (S/N ratio) of sample concentration 0.02% more than 3, ensure that the related substance of in sample more than 0.02% can be detected, prove that sensitivity of the present invention is very high.
Embodiment 5: the linear and range detection of detection method of the present invention
For related substance, in the scope being equivalent to sample concentration 0.05% to 0.2%, get 5 concentration point study.Linear relationship, with the function construction of the peak area recorded to analyte concentration, carries out linear regression by least square method, requires that the numerical value of this linear regression coeffficient r should be not less than 0.990, the results are shown in Table 6 ~ 11.The number percent being equivalent to sample concentration is the concentration of need testing solution on the detectability concentration of related substance or quantitative limit concentration ratio
Table 6 impurity SRS1 linear determination result
Table 7 impurity SRS2 linear determination result
Table 8 impurity SRS3 linear determination result
Table 9 impurity SRS4 linear determination result
Table 10 impurity DP1 linear determination result
Table 11 ambrisentan linear determination result
From the result of above-mentioned each table, invent described detection method and all meet standard at least in the scope of LOQ value ~ index 150% for the range of linearity of each related substance, and regression coefficient is all more than 0.999, proves in good linear relationship.
Embodiment 6: the detection of the repeatability of detection method of the present invention
Get an ambrisentan sample, repeat 6 times according to the embodiment of the present invention 1 detection method and detect, carry out verification method and have good precision, the absolute deviation of standard-required impurity sum must not exceed 50% of quality standard, the results are shown in Table 12.
Table 12 reperformance test result
As shown in Table 12, detect, be all only tested with related substance DP1 and identical unknown impuritie, and the absolute deviation of impurity sum is 0.02%, exceedes far away 50% of quality standard limit for 6 times, confirm that the method has good precision.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1. a detection method for ambrisentan related substance, is characterized in that, comprising:
Get ambrisentan product to be tested preparation need testing solution, need testing solution is diluted 100 times of product solution in contrast, then take trifluoroacetic acid aqueous solution as mobile phase A, with trifluoroacetic acid acetonitrile solution for Mobile phase B carries out HPLC detection respectively, record the content of related substance according to the major component Self-control method of the correction up factor;
The chromatographic column that described HPLC detects is WatersAtlantisT3 chromatographic column;
In described trifluoroacetic acid aqueous solution, the percent by volume of trifluoroacetic acid is 0.02%; In described trifluoroacetic acid acetonitrile solution, the percent by volume of trifluoroacetic acid is 0.01%;
The elution program that described HPLC detects is:
0min, wash-out phase A: wash-out phase B volume ratio is 75:25 wash-out, 0-17min, wash-out phase A: wash-out phase B volume ratio linearly fades to 40:60, carries out linear gradient elution; 17-25min, wash-out phase A: wash-out phase B volume ratio is 40:60, carries out isocratic elution; 25-40min, wash-out phase A: wash-out phase B volume ratio linearly fades to 20:80, carries out linear gradient elution; After 40min, wash-out phase A: wash-out phase B volume ratio is that the peak that 20:80 is eluted to related substance all occurs;
The determined wavelength that described HPLC detects is 220nm.
2. detection method according to claim 1, is characterized in that, comprising:
Get ambrisentan product to be tested preparation need testing solution, need testing solution is diluted 100 times of product solution in contrast, then take trifluoroacetic acid aqueous solution as mobile phase A, with trifluoroacetic acid acetonitrile solution for Mobile phase B carries out HPLC detection respectively, the major component Self-control method computing formula according to the correction up factor: the content=F × (A of related substance
supply/ A
right) × 1%, calculates the content obtaining related substance;
Wherein, F is the relative correction factor of related substance, A
supplyfor the peak area of need testing solution related substance, A
rightfor contrast solution main peak peak area, described relative correction factor is the ratio of the slope of the main slope of composition equation of linear regression and the equation of linear regression of related substance.
3. detection method according to claim 1 or 2, is characterized in that, described preparation need testing solution is adopt wash-out phase A and wash-out phase B to be mixed with the need testing solution that concentration is 0.25mg/mL.
4. detection method according to claim 3, it is characterized in that, described preparation need testing solution is:
Get ambrisentan and be about 12.5mg, put in 50ml measuring bottle, add trifluoroacetic acid acetonitrile solution 12.5ml and make dissolving, add trifluoroacetic acid aqueous solution and be diluted to scale, shake up, as need testing solution.
5. detection method according to claim 1 or 2, is characterized in that, the flow velocity that described HPLC detects is 0.9-1.1mL/min.
6. detection method according to claim 1 or 2, is characterized in that, the column temperature that described HPLC detects is 25-35 DEG C.
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