CN108344832A - A kind of detection method of principal component and its separated from impurities - Google Patents
A kind of detection method of principal component and its separated from impurities Download PDFInfo
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- CN108344832A CN108344832A CN201711471312.0A CN201711471312A CN108344832A CN 108344832 A CN108344832 A CN 108344832A CN 201711471312 A CN201711471312 A CN 201711471312A CN 108344832 A CN108344832 A CN 108344832A
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- 239000012535 impurity Substances 0.000 title claims abstract description 35
- 238000001514 detection method Methods 0.000 title claims abstract description 29
- 239000000243 solution Substances 0.000 claims abstract description 28
- 239000012071 phase Substances 0.000 claims abstract description 17
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 239000000337 buffer salt Substances 0.000 claims abstract description 9
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 7
- 239000007791 liquid phase Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
- 239000000523 sample Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000012488 sample solution Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 239000008363 phosphate buffer Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 125000005594 diketone group Chemical group 0.000 claims description 2
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
- 238000012360 testing method Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 11
- 239000012490 blank solution Substances 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 230000003252 repetitive effect Effects 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 238000012795 verification Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012496 blank sample Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Classifications
-
- 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
- G01N30/89—Inverse chromatography
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses the detection methods of a kind of principal component and its separated from impurities, it is characterised in that：Using reversed-phased high performace liquid chromatographic, with phenyl liquid-phase chromatographic column, using diode array detector, using gradient elution program, using one sodium salt of a certain proportion of buffer salt solution, one organic phase as mobile phase.It is an advantage of the invention that：The method of the present invention specificity is strong, and accuracy is high, easy to operate.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of detection method of principal component and its separated from impurities.
Background technology
2- [(2R) -2- hydroxyls -3- [[4- (3- oxo -4- morpholinyls) phenyl] amino] propyl] -1H- iso-indoles -1,3
(2H)-diketone (principal component) is in production using 4- (4- aminophenyls) morpholine -3- ketone and (S)-(+)-N- (2,3- ethoxy-cs
Base) phthalimide reaction generation.There is impurity to remain and during synthesizing main composition in both starting materials
By-product can be generated, the residual of these impurity need to be controlled in detection process.Existing 2- [(2R) -2- hydroxyls -3- [[4- (3-
Oxo -4- morpholinyls) phenyl] amino] propyl] -1H- iso-indoles -1,3 (2H)-diketone and its separated from impurities detection side
Method, specificity is not strong, accuracy bottom, complicated for operation.Therefore, it should a kind of new technical solution be provided and solved the above problems.
Invention content
The object of the present invention is to provide the detection methods of a kind of principal component and its separated from impurities.
To achieve the above object, the technical solution adopted by the present invention is：
A kind of detection method of principal component and its separated from impurities, using reversed-phased high performace liquid chromatographic, with phenyl liquid
Phase chromatographic column, using diode array detector, using gradient elution program, with one sodium salt one of a certain proportion of buffer salt solution
Organic phase is mobile phase.
Further technical solution：
Chromatographic column is selected from Agilent ZORBAX-SB, 250mm*4.6mm*5 μm.
The organic phase is one kind in methanol, acetonitrile, propyl alcohol, isopropanol.
Preferably, the organic phase is methanol.
The buffer salt solution is one kind in phosphate, formates, acetate, citrate, perchlorate.
Preferably, the buffer salt solution is phosphate, and buffer salt solution pH is 6.8.
The sodium salt is one kind in sodium hydroxide, sodium acetate, sodium sulphate.
Preferably, the sodium salt is sodium hydroxide.
A kind of 2- [(2R) -2- hydroxyls -3- [[4- (3- oxo -4- morpholinyls) phenyl] amino] propyl] -1H- iso-indoles -
The detection method of 1,3 (2H)-diketone and its separated from impurities, including following steps,
1) 2- [(2R) -2- hydroxyls -3- [[4- (3- oxo -4- morpholinyls) phenyl] amino] propyl] -1H- iso-indoles -, is taken
1,3 (2H)-diketone sample is appropriate, uses methanol sample dissolution respectively, is configured to every lmL [(2R) -2- hydroxyls -3- [[4- (3- containing 2-
Oxo -4- morpholinyls) phenyl] amino] propyl] -1H- iso-indoles -1,3 (2H) -0.1~1.5mg of diketone sample solution；
2), setting flow rate of mobile phase is 0.5~1.5mL/min, and Detection wavelength is 200~240nm, chromatographic column column temperature box temperature
Degree is 20~40 DEG C, and sample size is 5~30 μ L；
3), mobile phase A is pH6.8 phosphate buffers, methanol 95：5, Mobile phase B is methanol, gradient elution program
For：
Further, it is 1.0ml/min that the Detection wavelength described in step 2), which is 220nm flow velocitys, and chromatographic column column oven is 30
DEG C, sample size is 10 μ L
It is an advantage of the invention that：The method of the present invention specificity is strong, and accuracy is high, easy to operate.
Description of the drawings
Fig. 1：Specificity-blank solution chromatogram
Fig. 2：Specificity -4- nitrones positioning solution chromatogram
Fig. 3：Specificity-imines positioning solution chromatogram
Fig. 4：The main composition positioning solution chromatogram of specificity-
Fig. 5：Specificity-two replaces positioning solution chromatogram
Fig. 6：System suitability solution chromatogram
Fig. 7：Quantitative limit test chromatogram
Fig. 8：Detection limit test chromatogram
Fig. 9：Sample introduction precision test chromatogram
Figure 10：Repetitive test chromatogram
Figure 11：Intermediate precision test chromatogram
Figure 12：Durability-does not change chromatogram
Figure 13：Durability-pH-6.6 chromatograms
Figure 14：Durability-pH-7.0 chromatograms
Figure 15：Durability-wavelength -218nm chromatograms
Figure 16：Durability-wavelength -222nm chromatograms
Figure 17：Durability-flow velocity -0.8ml/min chromatograms
Figure 18：Durability-flow velocity -1.2ml/min chromatograms
Figure 19：Durability--28 DEG C of column temperature chromatogram
Figure 20：Durability--32 DEG C of column temperature chromatogram
Specific implementation mode
2- [(2R) -2- hydroxyls -3- [[4- (3- oxo -4- morpholinyls) phenyl] amino] propyl] -1H- iso-indoles -1,3
(2H)-diketone (hereinafter referred to as principal component) is in production using 4- (4- aminophenyls) morpholine -3- ketone and (S)-(+)-N- (2,3-
Ethoxycarbonyl propyl) phthalimide reaction generation.There is impurity to remain in both starting materials and is synthesizing main composition
During can generate by-product, the residual of these impurity need to be controlled in detection process.
This method is limited to consider 4 kinds of impurity, and the impurity title and structural formula that need to be controlled are shown in Table 1：
1 impurity structure of table and source
The main composition purity verification method that need to be verified：
Purity detecting condition to be verified：
Chromatographic column：Agilent ZORBAX-SB 250mm*4.6mm*5um
Sample size：10ul, flow velocity：1.0ml/min, column temperature：30 DEG C, wavelength：220nm flows phase composition：
Mobile phase A：Ph6.8 phosphate buffers (the hydroxide of the potassium dihydrogen phosphate+0.188g containing 1.36g in 1L water
Sodium)：Methanol=95:5, Mobile phase B：Methanol
| t/min | A% | B% |
| 0.0 | 95 | 5 |
| 20.0 | 90 | 10 |
| 37.0 | 65 | 35 |
| 42.0 | 65 | 35 |
| 43.0 | 95 | 5 |
| 55.0 | 95 | 5 |
The methodology validation of chromatographic process
Specificity is tested：
Principal component positioning solution/sample concentration (500ug/ml)：
Precision weighs in 25mg this product to 50ml volumetric flasks, and purified water is used after 10ml methanol and appropriate purifying water dissolution is added
It is settled to scale, mixing.
4- ammonia ketone mother liquors：
Precision weighs in 25mg to 50ml volumetric flasks, and purified water constant volume is used after 10ml methanol and appropriate purifying water dissolution is added
To scale, mixing.
4- nitrone mother liquors：
Precision weighs in 25mg to 50ml volumetric flasks, and purified water constant volume is used after 10ml methanol and appropriate purifying water dissolution is added
To scale, mixing.
Imines mother liquor：
Precision weighs in 25mg to 50ml volumetric flasks, and purified water constant volume is used after 10ml methanol and appropriate purifying water dissolution is added
To scale, mixing.
Two substitution mother liquors：
Precision weighs in 100mg to 100ml volumetric flasks, is determined with purified water after 20ml methanol and appropriate purifying water dissolution is added
Hold to scale, mixing.
Blank solution (20% methanol aqueous solution)：
It is added in 50ml volumetric flasks after 10ml methanol and is settled to scale, mixing with purified water dilution.Specificity experiment is molten
Liquid：
It is each appropriate that precision pipettes each impurity mother liquor, principal component mother liquor, until in same volumetric flask, be configured to each impurity and it is main at
Point it is the mixed solution of 50ug/ml, mixing.For investigating specificity, separating degree.
Each impurity and principal component position solution：
Precision pipettes each impurity and principal component mother liquor is appropriate, is configured to the positioning solution of 50ug/ml respectively.
Blank solution, specificity testing liquid, principal component positioning solution, 4- ammonia ketone positioning solution, 4- nitrones are determined
Position solution, imines positioning solution, two substitution positioning are injected separately into liquid chromatograph with solution, record chromatogram.
2 specificity verification experimental verification result of table
Conclusion：1. each peak-to-peak separating degree meets preset requirement；2. theoretical cam curve meets preset requirement；3. each peak peak purity
Less than purity threshold value.
Sample introduction precision test：
Precision weighs in this product 49.05mg to 100ml volumetric flasks, with pure after addition 20ml methanol and appropriate purifying water dissolution
Change water dilution and is settled to scale.Blank solution is prepared with method.
Blank solution and sample feeding repetitive test solution are injected separately into liquid chromatograph, record chromatogram.
3 each impurity of table and main composition sample introduction Precision test result
Conclusion：4- ammonia ketone, 4- nitrones, imines, principal component, disubstituted RSD be 2.06%, 2.38%, 0.52%,
0.12%, 3.10%；Maximum single miscellaneous RSD is 0.36%, but the unknown impuritie that relative retention time is 0.34 is in gradually to increase
The RSD of trend, RSD 57.93%, principal component meets the requirements.Solution need to now with it is existing into.
Quantitative limit is tested：
According to the signal-to-noise ratio at each peak of system suitability solution, calculates thus signal-to-noise ratio and be directly diluted to 10:It is required when 1
Dilute volume, dilution obtain quantitative limit testing liquid.
The ratio between each chromatographic peak signal strength and baseline noise are about 10:1.
4 each impurity of table and main composition quantitative limit test result
Detection limit experiment：
Quantitative limit testing liquid is diluted 3 times, obtains detection limit testing liquid.
The ratio between each chromatographic peak signal strength and baseline noise are about 3:1.
5 each impurity of table limits test result with main ingredient analysis
Main composition linear test：
Linear solvent 6 (150%)：Precision weighs in 37.5mg this product to 50ml volumetric flasks, and 10ml methanol and appropriate is added
After purifying water dissolution scale, mixing are settled to purified water.
Linear solvent 5 (100%)：Precision weighs in 25mg this product to 50ml volumetric flasks, and 10ml methanol and appropriate pure is added
After change water dissolution scale, mixing are settled to purified water.
Linear solvent 4 (70%)：Precision pipettes in linear solvent 5 (100%) 7ml to 10ml volumetric flasks, with 20% methanol
Aqueous solution is settled to scale.
Linear solvent 3 (50%)：Precision pipettes in linear solvent 5 (100%) 5ml to 10ml volumetric flasks, with 20% methanol
Aqueous solution is settled to scale.
Linear solvent 2 (20%)：Precision pipettes in linear solvent 5 (100%) 2ml to 10ml volumetric flasks, with 20% methanol
Aqueous solution is settled to scale.
Linear solvent 1 (2%)：Precision pipettes in linear solvent 2 (20%) 1ml to 10ml volumetric flasks, with 20% methanol-water
Solution is settled to scale.
6 parts of linear solvents are injected separately into liquid chromatograph, record chromatogram, with the actual concentrations of principal component for horizontal seat
Mark carries out linear regression analysis, principal component linearly dependent coefficient (R using the peak area of principal component as ordinate2) should be greater than
0.999。
6 main composition linear test result of table
Conclusion：Good linear relationship, linear equation y=is presented in principal component between 0.01mg/ml~0.69mg/ml
56407x+296.58 coefficient R2It is 0.9997.
Repetitive test：
Prepare 6 parts of sample solutions respectively, now match it is existing into.Blank solution is prepared with method.
Principal component RSD≤2.0%.
7 each impurity of table and main composition repetitive test result
Conclusion：The RSD of principal component meets the requirements.
Intermediate precision is tested：
The chromatographic column with model difference lot number is used by different personnel using different manufacturers instrument in different time, is matched respectively
Make 6 parts of sample solutions, now match it is existing into.Blank solution is prepared with method.
The repeatability of principal component is compared with the 12 of Intermediate precision groups of data, RSD≤2.0% of purity detecting result.
8 main composition of table and impurity Intermediate precision test result
Conclusion：The repeatability of principal component is 0.036% with the RSD of 12 groups of data of Intermediate precision.It meets the requirements.
Serviceability test：
Change flow velocity (0.9ml/min, 1.1ml/min), wavelength (218nm, 222nm), column temperature (28 DEG C, 32 DEG C), flowing
The pH (6.6,7.0) of phase detects this product principal component purity afterwards, is compared with the testing result for not changing condition.
Prepare sample solution, now match it is existing into.Blank solution is prepared with method.
Testing result after change condition is compared with the testing result for change, RSD≤2.0% of principal component purity.
9 serviceability test result of table
Conclusion：This method is to the pH value good tolerance of flow velocity, column temperature, Detection wavelength, mobile phase, and nothing between each impurity
Interference, separating degree are more than 1.5.
Verified main composition method for detecting purity
Detection method：
Chromatographic column：Agilent ZORBAX-SB 250mm*4.6mm*5um
Sample size：10ul, flow velocity：1.0ml/min, column temperature：30 DEG C, wavelength：220nm flows phase composition：
Mobile phase A：Ph6.8 phosphate buffers：Methanol=95:5, Mobile phase B：Methanol
| t/min | A% | B% |
| 0.0 | 95 | 5 |
| 20.0 | 90 | 10 |
| 37.0 | 65 | 35 |
| 42.0 | 65 | 35 |
| 43.0 | 95 | 5 |
| 55.0 | 95 | 5 |
Main composition purity detecting result
Claims (10)
1. the detection method of a kind of principal component and its separated from impurities, it is characterised in that：Using reversed-phased high performace liquid chromatographic,
With phenyl liquid-phase chromatographic column, using diode array detector, using gradient elution program, with a certain proportion of buffer salt solution
One sodium salt, one organic phase is mobile phase.
2. the detection method of a kind of principal component and its separated from impurities according to claim 1, it is characterised in that：Chromatography
Column is selected from Agilent ZORBAX-SB, 250mm*4.6mm*5 μm.
3. the detection method of a kind of principal component and its separated from impurities according to claim 1, it is characterised in that：It is described
Organic phase is one kind in methanol, acetonitrile, propyl alcohol, isopropanol.
4. the detection method of a kind of principal component and its separated from impurities according to claim 1, it is characterised in that：It is described
Organic phase is methanol.
5. the detection method of a kind of principal component and its separated from impurities according to claim 1, it is characterised in that：It is described
Buffer salt solution is one kind in phosphate, formates, acetate, citrate, perchlorate.
6. the detection method of a kind of principal component and its separated from impurities according to claim 5, it is characterised in that：It is described
Buffer salt solution is phosphate, and buffer salt solution pH is 6.8.
7. the detection method of a kind of principal component and its separated from impurities according to claim 1, it is characterised in that：It is described
Sodium salt is one kind in sodium hydroxide, sodium acetate, sodium sulphate.
8. the detection method of a kind of principal component and its separated from impurities according to claim 7, it is characterised in that：It is described
Sodium salt is sodium hydroxide.
9. the detection method of a kind of principal component and its separated from impurities according to claim 1, it is characterised in that：Including
Following steps,
1) 2- [(2R) -2- hydroxyls -3- [[4- (3- oxo -4- morpholinyls) phenyl] amino] propyl] -1H- iso-indoles -1,3, is taken
(2H)-diketone sample is appropriate, uses methanol sample dissolution respectively, is configured to every lmL [(2R) -2- hydroxyls -3- [[4- (3- oxygen containing 2-
Generation -4- morpholinyls) phenyl] amino] propyl] -1H- iso-indoles -1,3 (2H) -0.1~1.5mg of diketone sample solution；
2), setting flow rate of mobile phase is 0.5~1.5mL/min, and Detection wavelength is 200~240nm, and chromatographic column column oven temperature is
20~40 DEG C, sample size is 5~30 μ L；
3), mobile phase A is pH6.8 phosphate buffers, methanol 95：5, Mobile phase B is methanol, and gradient elution program is：
10. the detection method of a kind of principal component and its separated from impurities according to the 9 of claim, it is characterised in that：
Detection wavelength described in step 2) is that 220nm flow velocitys are 1.0ml/min, and chromatographic column column oven is 30 DEG C, and sample size is 10 μ L.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111721858A (en) * | 2020-06-03 | 2020-09-29 | 杭州华东医药集团新药研究院有限公司 | Method for determining genotoxic impurities in rivaroxaban |
| CN114216976A (en) * | 2021-11-30 | 2022-03-22 | 江苏中邦制药有限公司 | Method for determining potential genotoxic impurities in rivaroxaban by high performance liquid chromatography |
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| CN111721858A (en) * | 2020-06-03 | 2020-09-29 | 杭州华东医药集团新药研究院有限公司 | Method for determining genotoxic impurities in rivaroxaban |
| CN111721858B (en) * | 2020-06-03 | 2022-07-01 | 杭州华东医药集团新药研究院有限公司 | Method for determining genotoxic impurities in rivaroxaban |
| CN114216976A (en) * | 2021-11-30 | 2022-03-22 | 江苏中邦制药有限公司 | Method for determining potential genotoxic impurities in rivaroxaban by high performance liquid chromatography |
| CN114216976B (en) * | 2021-11-30 | 2024-04-30 | 江苏中邦制药有限公司 | Method for determining potential genotoxic impurities in rivaroxaban by high performance liquid chromatography |
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