CN113866337A - Mass analysis method for separating and determining oseltamivir phosphate isomers - Google Patents
Mass analysis method for separating and determining oseltamivir phosphate isomers Download PDFInfo
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- CN113866337A CN113866337A CN202111240912.2A CN202111240912A CN113866337A CN 113866337 A CN113866337 A CN 113866337A CN 202111240912 A CN202111240912 A CN 202111240912A CN 113866337 A CN113866337 A CN 113866337A
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- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical class CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 title claims abstract description 64
- 238000004458 analytical method Methods 0.000 title claims abstract description 21
- 239000012535 impurity Substances 0.000 claims abstract description 40
- 229960002194 oseltamivir phosphate Drugs 0.000 claims abstract description 33
- 239000012085 test solution Substances 0.000 claims abstract description 15
- 239000012088 reference solution Substances 0.000 claims abstract description 10
- 238000001514 detection method Methods 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 48
- 239000013558 reference substance Substances 0.000 claims description 25
- 239000000523 sample Substances 0.000 claims description 18
- 239000011550 stock solution Substances 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- 238000005303 weighing Methods 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KBRZBBOTZJFKFH-UHFFFAOYSA-N (3,5-dichlorophenyl) carbamate Chemical compound NC(=O)OC1=CC(Cl)=CC(Cl)=C1 KBRZBBOTZJFKFH-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 5
- 239000012488 sample solution Substances 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007983 Tris buffer Substances 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 4
- 229960003752 oseltamivir Drugs 0.000 description 10
- 230000035945 sensitivity Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 241000712431 Influenza A virus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 208000037798 influenza B Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- 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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a mass analysis method for separating and determining oseltamivir phosphate isomers, relates to the technical field of mass analysis, and aims to solve the problem that the existing oseltamivir phosphate related substance detection method cannot effectively separate the isomers. The invention prepares a test solution, a reference solution and an impurity reference solution, and the oseltamivir phosphate isomers RSS, SRR, SSS, RRR, SSR and SRS are detected by a high performance liquid chromatograph. Can accurately separate the oseltamivir phosphate isomer. The invention is applied to the field of quality analysis.
Description
Technical Field
The invention relates to the technical field of mass analysis, in particular to a mass analysis method for separating and determining oseltamivir phosphate isomers.
Background
Oseltamivir phosphate (seltamivirphosphate), chemical name: (r, 4r, 5s) 4-acetamide-5-amino-3 (-propoxyethyl) 1-cyclohexane-1 carboxylic acid ethyl ester phosphate. Oseltamivir phosphate is an antiviral drug and is mainly used for preventing or treating influenza A and B viruses. Has obvious effect of resisting influenza A virus for adults and children over 1 year old.
During the preparation and synthesis of oseltamivir phosphate, impurities I, II, III and isomers may be generated. Wherein the impurities I, II and III are degradation impurities, and the impurities I, II and III are determined by high performance liquid chromatography in the current Chinese pharmacopoeia 2020 edition. And the isomers of oseltamivir phosphate have no quality control requirements and no related detection method. Therefore, it is very important to realize the separation and determination of oseltamivir phosphate and isomers for the quality control of oseltamivir phosphate. Oseltamivir phosphate is frequently used in daily life as a common drug for treating influenza, and a quality analysis method for separating and determining oseltamivir phosphate isomers is developed in order to ensure the quality of the drug and the production research.
Disclosure of Invention
The invention aims to provide a mass analysis method for separating and determining oseltamivir phosphate isomers, which aims to solve the problem that the existing oseltamivir phosphate related substance detection method cannot effectively separate the isomers.
The invention relates to a mass analysis method for separating and determining oseltamivir phosphate isomers, which is carried out according to the following steps:
step one, preparing a test solution:
the test solution contains 1-3 mg/mL oseltamivir phosphate; the preparation method comprises the following steps: precisely weighing a sample, placing the sample in a measuring flask, and quantitatively diluting the sample to a scale by adding a mobile phase; shaking, filtering, and collecting the filtrate as sample solution;
step two, preparing a control solution:
the control solution contains 1-3 mug/mL of oseltamivir phosphate; the preparation method comprises the following steps: placing the prepared test solution into a measuring flask, and adding a mobile phase to dilute to a scale; precisely measuring the solution, placing in a measuring flask, adding mobile phase to dilute to scale, shaking, filtering, and taking the filtrate as control solution;
step three, impurity reference substance solution:
the impurity reference substance solution contains 15-25 mu g/mL of impurity reference substance; the preparation method comprises the following steps: respectively taking oseltamivir phosphate isomers RSS, SRR, SSS, RRR, SSR and SRS, precisely weighing, respectively placing in a measuring flask, and quantitatively diluting to a scale by adding a mobile phase to serve as stock solutions of various impurity reference substances; precisely measuring each impurity stock solution, placing the impurity stock solution into a volumetric flask, and adding a mobile phase to dilute the impurity stock solution to a scale; shaking, filtering, and collecting filtrate as impurity reference solution;
step four, analyzing a sample: detecting by using a high performance liquid chromatograph according to the following conditions:
cellulose-tri (3, 5-dichlorophenyl carbamate) or the chromatographic column with equivalent efficiency is covalently bonded on the surface of silica gel; n-hexane-absolute ethyl alcohol-methanol-trifluoroacetic acid-diethylamine with the volume ratio of 900:60:40:4:2 as a mobile phase; the detection wavelength is 240 nm; the column temperature is 35 ℃; the flow rate is 1.0 mL/min; the running time is 60 min; the sample injection volume is 25 mu L; the temperature of the sample bin is controlled to be 4 ℃;
and (3) performing mass analysis on chromatographic peaks of the obtained impurity reference substance solution, the obtained reference solution and the obtained test solution, namely completing the mass analysis method for separating and determining the oseltamivir phosphate isomer.
Further, the concentration of the impurity reference substance solution is 20 mug/mL.
Further, the oseltamivir phosphate is 2 mug/mL.
Further, the oseltamivir phosphate is 2 mg/mL.
Furthermore, the normal hexane, the absolute ethyl alcohol, the methanol, the trifluoroacetic acid and the diethylamine are all chromatographically pure.
Furthermore, cellulose-tris (3, 5-dichlorophenyl carbamate) or a chromatographic column with equivalent performance is covalently bonded on the surface of the silica gel, and the specification of the chromatographic column is 4.6 x 150mm and 3 um.
The invention has the following beneficial effects:
the oseltamivir phosphate has a plurality of isomers, and the isomer peaks are overlapped and cannot be separated when the high performance liquid chromatography reverse C8 chromatographic column detection of 'oseltamivir phosphate related substances' in the 2020 edition of Chinese pharmacopoeia is considered. As six isomers of oseltamivir phosphate (RSR): oseltamivir diastereomer II (SRS), Oseltamivir hydrochloride (SSR), Oseltamivir imprority 46(SSS), Oseltamivir imprority 17(RRR), Oseltamivir imprority 20(RSS) and Oseltamivir imprority 47(SRR) are selected as bases, a high performance liquid chromatography forward chromatographic column is selected for detection, a test sample, a reference substance and an impurity reference substance are prepared, and Oseltamivir phosphate isomers can be accurately separated.
Drawings
FIG. 1 is a liquid chromatogram of example 1.
Detailed Description
To further explain the technical solution of the present invention, detailed description will be made with reference to specific experimental data and attached tables.
The present embodiment relates to a mass analysis method for separating and determining oseltamivir phosphate isomers, which specifically includes the following steps:
firstly, the impurity reference substance solution, the reference solution and the test solution of the invention:
and (3) detecting the impurity reference substance solution, the reference solution and the sample solution by high performance liquid chromatography. Detection conditions are as follows: cellulose-tri (3, 5-dichlorophenyl carbamate) or chromatographic column with equivalent efficiency is covalently bonded on the surface of silica gel; n-hexane-absolute ethyl alcohol-methanol-trifluoroacetic acid-diethylamine (900:60:40:4:2) is used as a mobile phase; the detection wavelength is 240 nm; the column temperature is 35 ℃; the flow rate is 1.0 mL/min; the running time is 60 min; the sample injection volume is 25 mu l; the temperature of the sample bin was controlled at 4 ℃. And (3) carrying out quality analysis on chromatographic peaks of the impurity reference substance solution, the reference solution and the test sample solution.
The impurity reference substance solution is 20 mug/mL of impurity-containing reference substance, and the specific preparation method is as follows: respectively taking 5.0mg of oseltamivir phosphate isomers (RSS), (SRR), (SSS), (RRR), (SSR) and (SRS), precisely weighing, respectively placing into a 25mL measuring flask, and quantitatively diluting to a scale by adding a mobile phase to serve as stock solutions of various impurity reference substances; precisely measuring 1.0mL of each impurity stock solution, placing the impurity stock solution into a 10mL volumetric flask, and adding a mobile phase to dilute the impurity stock solution to a scale; shaking, filtering, and collecting filtrate as impurity control solution.
The test solution contains 2mg/mL oseltamivir phosphate, and the specific preparation method comprises the following steps: precisely weighing 500mg of a test sample, placing the test sample in a 10mL measuring flask, and adding a mobile phase for quantitative dilution to a scale; shaking, filtering, and collecting the filtrate as sample solution.
The above control solution contains oseltamivir phosphate 2 μ g/mL, and the preparation method comprises: taking 1.0mL of the test solution, placing the test solution in a 100mL measuring flask, and adding a mobile phase to dilute the test solution to a scale; precisely measuring 1.0mL of the solution, placing the solution in a 10mL measuring flask, adding a mobile phase to dilute the solution to a scale, shaking up, filtering, and taking a subsequent filtrate as a control solution.
Second, system applicability solution
1. Solution A: oseltamivir hydrochloride (SSR) is precisely weighed to be 5.0mg, placed in a 25mL volumetric flask, dissolved by a mobile phase and fixed to a certain volume to be marked to be used as isomer stock solution.
2. Solution B: accurately weighing 20mg of oseltamivir phosphate reference substance, placing the oseltamivir phosphate reference substance in a 10mL measuring flask, dissolving the oseltamivir phosphate reference substance in 3-4mL of mobile phase, accurately weighing 1.0mL of solution A, placing the solution A in the 10mL measuring flask, fixing the volume to a scale by using the mobile phase, shaking up, filtering, and taking the subsequent filtrate as a separation degree solution.
3. The system applicability solution contains 1mg/mL of oseltamivir phosphate: taking an oseltamivir phosphate reference substance, precisely weighing 10mg, placing the oseltamivir phosphate reference substance in a 10mL measuring flask, fixing the volume to a scale with a mobile phase, shaking up, filtering, and taking a subsequent filtrate as a system applicability solution.
Third, the requirement of applicability of the system
The separation degree of oseltamivir hydrochloride (SSR) and oseltamivir phosphate is not lower than 1.5.
The applicability of the system is that the solution is continuously injected for 5 times, and the peak area RSD of the oseltamivir phosphate is not more than 10.0%.
Fourthly, the sensitivity solution contains 2 mug/mL of oseltamivir phosphate: precisely measuring 1.0mL of the two-system applicability solution item 3 system applicability solution, placing the solution in a 50mL measuring flask, and measuring to scale with constant volume; precisely measuring 1.0mL of the solution, placing the solution in a 10mL measuring flask, fixing the volume to the scale, shaking up, filtering, and taking the subsequent filtrate as a sensitivity solution.
Fifthly, the sensitivity requirement is as follows: the S/N of the sensitivity solution should be greater than 10.
And sixthly, injecting the system applicability solution, the separation degree solution, the sensitivity solution, the reference substance solution, the reference solution and the test solution into a liquid chromatograph respectively, and recording the chromatogram.
Seventhly, calculating a result: a self-control method using oseltamivir phosphate as a main component.
See figure 1 and table 1 for results.
TABLE 1
| Sample name | Retention time | Relative retention time |
| Oseltamivir hydrochloride (SSR) | 6.805 | 0.84 |
| Oseltamivir phosphate (RSR) | 8.117 | 1.00 |
| Oseltamivir impurity 46(SSS) | 8.902 | 1.10 |
| Oseltamivir impurity 17(RRR) | 9.307 | 1.15 |
| Oseltamivir diastereomer II (SRS) | 10.079 | 1.24 |
| Oseltamivir impurity 20(RSS) | 11.322 | 1.39 |
| Oseltamivir impurity 47(SRR) | 11.806 | 1.45 |
The above mentioned is the actual experimental result data of the present invention, and the above mentioned experimental data can not be used to limit the scope of the present invention, and all the improvements and adjustments made on the principle and method of the present invention are considered to be within the protection scope of the present invention.
Claims (6)
1. A mass analysis method for separating and determining oseltamivir phosphate isomers is characterized by comprising the following steps:
step one, preparing a test solution:
the test solution contains 1-3 mg/mL oseltamivir phosphate; the preparation method comprises the following steps: precisely weighing a sample, placing the sample in a measuring flask, and quantitatively diluting the sample to a scale by adding a mobile phase; shaking, filtering, and collecting the filtrate as sample solution;
step two, preparing a control solution:
the control solution contains 1-3 mug/mL of oseltamivir phosphate; the preparation method comprises the following steps: placing the prepared test solution into a measuring flask, and adding a mobile phase to dilute to a scale; precisely measuring the solution, placing in a measuring flask, adding mobile phase to dilute to scale, shaking, filtering, and taking the filtrate as control solution;
step three, impurity reference substance solution:
the impurity reference substance solution contains 15-25 mu g/mL of impurity reference substance; the preparation method comprises the following steps: respectively taking oseltamivir phosphate isomers RSS, SRR, SSS, RRR, SSR and SRS, precisely weighing, respectively placing in a measuring flask, and quantitatively diluting to a scale by adding a mobile phase to serve as stock solutions of various impurity reference substances; precisely measuring each impurity stock solution, placing the impurity stock solution into a volumetric flask, and adding a mobile phase to dilute the impurity stock solution to a scale; shaking, filtering, and collecting filtrate as impurity reference solution;
step four, analyzing a sample: detecting by using a high performance liquid chromatograph according to the following conditions:
cellulose-tri (3, 5-dichlorophenyl carbamate) or the chromatographic column with equivalent efficiency is covalently bonded on the surface of silica gel; n-hexane-absolute ethyl alcohol-methanol-trifluoroacetic acid-diethylamine with the volume ratio of 900:60:40:4:2 as a mobile phase; the detection wavelength is 240 nm; the column temperature is 35 ℃; the flow rate is 1.0 mL/min; the running time is 60 min; the sample injection volume is 25 mu L; the temperature of the sample bin is controlled to be 4 ℃;
and (3) performing mass analysis on chromatographic peaks of the obtained impurity reference substance solution, the obtained reference solution and the obtained test solution, namely completing the mass analysis method for separating and determining the oseltamivir phosphate isomer.
2. The mass analysis method for separating and determining oseltamivir phosphate isomers according to claim 1, wherein the concentration of the impurity control solution is 20 μ g/mL.
3. The mass analysis method for separating and determining oseltamivir phosphate isomers according to claim 1, wherein the oseltamivir phosphate is 2 μ g/mL.
4. The mass analysis method for separating and determining oseltamivir phosphate isomers according to claim 1, wherein the oseltamivir phosphate is 2 mg/mL.
5. The mass analysis method for separating and determining oseltamivir phosphate isomers according to claim 1, wherein the n-hexane, absolute ethyl alcohol, methanol, trifluoroacetic acid and diethylamine are all chromatographically pure.
6. The method according to claim 1, wherein cellulose-tris (3, 5-dichlorophenyl carbamate) or a chromatographic column with equivalent performance is covalently bonded to the surface of silica gel, and the chromatographic column has a specification of 4.6 × 150mm and 3 μm.
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| CN117214369A (en) * | 2023-11-09 | 2023-12-12 | 山东百诺医药股份有限公司 | Liquid chromatography method for detecting related substances of oseltamium phosphate Wei Ganhun suspension |
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