CN109870521B - Method for separating oseltamivir phosphate enantiomers by normal phase chromatography - Google Patents
Method for separating oseltamivir phosphate enantiomers by normal phase chromatography Download PDFInfo
- Publication number
- CN109870521B CN109870521B CN201910263858.XA CN201910263858A CN109870521B CN 109870521 B CN109870521 B CN 109870521B CN 201910263858 A CN201910263858 A CN 201910263858A CN 109870521 B CN109870521 B CN 109870521B
- Authority
- CN
- China
- Prior art keywords
- oseltamivir phosphate
- enantiomers
- solution
- separating
- oseltamivir
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000004587 chromatography analysis Methods 0.000 title claims abstract description 9
- 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 15
- 229960002194 oseltamivir phosphate Drugs 0.000 claims abstract description 38
- 238000001514 detection method Methods 0.000 claims abstract description 17
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 11
- KBRZBBOTZJFKFH-UHFFFAOYSA-N (3,5-dichlorophenyl) carbamate Chemical compound NC(=O)OC1=CC(Cl)=CC(Cl)=C1 KBRZBBOTZJFKFH-UHFFFAOYSA-N 0.000 claims abstract description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 239000000741 silica gel Substances 0.000 claims abstract description 4
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 46
- 239000003085 diluting agent Substances 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012085 test solution Substances 0.000 claims description 12
- 239000000523 sample Substances 0.000 claims description 7
- 238000012360 testing method Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 239000012488 sample solution Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000013558 reference substance Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229960003752 oseltamivir Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000007983 Tris buffer Substances 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 239000011248 coating agent Substances 0.000 abstract 1
- 238000000576 coating method Methods 0.000 abstract 1
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical class OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 60
- 239000011550 stock solution Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 238000007865 diluting Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- -1 ethanol-methanol-trifluoroacetic acid-diethylamine Chemical compound 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 208000002979 Influenza in Birds Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 206010064097 avian influenza Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940126532 prescription medicine Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000004086 separation measurement method Methods 0.000 description 1
- 229940061367 tamiflu Drugs 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a high performance liquid chromatography method for separating oseltamivir phosphate and enantiomers thereof by normal phase chromatography, which comprises the steps of coating a silica gel surface with a cellulose-tris (3, 5-dichlorophenyl carbamate) column, wherein a mobile phase is n-hexane-absolute ethyl alcohol-methanol-trifluoroacetic acid-diethylamine with a volume ratio of (90:8:2:0.4:0.2), the column temperature is 30-40 ℃, the detection wavelength is 240nm, and the flow rate is 0.9-1.1 ml per minute. The method can separate the enantiomers of oseltamivir phosphate and oseltamivir phosphate, is simple and accurate, has high sensitivity, and can be used for detecting the enantiomers in oseltamivir phosphate production.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating oseltamivir phosphate enantiomers by normal phase chromatography.
Background
Oseltamivir phosphate (seltamivir phosphate), chemical name: (R, 4R, 5S) 4-acetamide-5-amido-3 (-propoxyethyl) 1-cyclohexane-1 carboxylic acid ethyl ester phosphate, the chemical structural formula is:
oseltamivir phosphate, tradename tamiflu, an antiviral compound for the prevention or treatment of avian influenza that was successfully developed in 1996 by Gilead Sciences Inc. The medicine has the characteristics of specificity, high efficiency, safety, small drug resistance and the like for target treatment of influenza viruses, is approved to be sold on the market in multiple countries, is the most effective anti-influenza virus medicine at present, and is also one of the most common prescription medicines.
Oseltamivir phosphate has three chiral centers, so that 7 opposite chiral isomers exist, wherein enantiomers (SSR-isomer) of oseltamivir phosphate are difficult to separate due to the similar physicochemical properties of the isomers and the oseltamivir phosphate, so that the purity and the quality of a final medicament are influenced. Therefore, achieving separation and determination of oseltamivir phosphate and its enantiomers is very important for quality control of oseltamivir phosphate. At present, the prior pharmacopoeia methods do not control the oseltamivir phosphate enantiomer. The prior literature, "guo na, the enantiomer separation method and pharmacokinetic study of several chiral drugs [ D ], shenyang pharmaceutical university, 2008" refers to the research of the oseltamivir phosphate enantiomer, but the mobile phase system of the method is n-hexane and isopropanol, and oseltamivir phosphate is almost insoluble in n-hexane and isopropanol, so the separation of oseltamivir phosphate from the enantiomer cannot be realized well in practice by the method. In addition, no other literature reports on the separation of oseltamivir phosphate enantiomers have been found. Oseltamivir phosphate is used frequently in daily life as a common drug for treating influenza, and an analytical determination method for accurately and effectively determining oseltamivir phosphate enantiomers is researched and developed in order to ensure the quality of drug development and production, so that the method has very important significance for quality control of drug products.
Disclosure of Invention
The invention aims to provide a simple and accurate method for effectively separating and determining oseltamivir phosphate and enantiomers thereof.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a method for separating oseltamivir phosphate enantiomers by normal phase chromatography comprises the following steps:
(1) high performance liquid chromatography conditions:
a chromatographic column: the silica gel surface was coated with a cellulose-tris (3, 5-dichlorophenyl carbamate) column (4.6 mm. times.250 mm, 5 μm);
detection wavelength: 240 nm;
flow rate: 0.9-1.1 ml/min;
column temperature: 33-37 ℃;
sample introduction amount: 25 mul;
mobile phase: the volume ratio of n-hexane-anhydrous ethanol-methanol-trifluoroacetic acid-diethylamine is (90:7:3:0.4:0.2) ~ (90:9:1:0.4:0.2)
Diluent agent: the volume ratio of n-hexane to absolute ethyl alcohol to methanol is 1:1:3
(2) Preparing a system suitability solution;
(3) preparing a test solution;
(4) the determination method comprises the following steps: respectively and precisely measuring a test solution and a system applicability solution, injecting the test solution and the system applicability solution into a liquid chromatograph, recording a chromatogram, and calculating the contents of the oseltamivir phosphate enantiomer and the test solution according to peak areas.
The structures of the enantiomers of oseltamivir phosphate and oseltamivir phosphate are respectively shown as a molecular formula I and a molecular formula II:
the method for preparing the test solution and the system applicability solution comprises the following steps: adding a diluent into a test sample to prepare a test sample solution, taking an oseltamivir phosphate working reference substance, and adding the diluent into an oseltamivir phosphate enantiomer to prepare a system applicability solution. The volume ratio of n-hexane-absolute ethyl alcohol-methanol-trifluoroacetic acid-diethylamine in the mobile phase is 90:8:2:0.4:0.2, the flow rate is 1.0ml/min, the column temperature is 35 ℃, and the wavelength is 240 nm. The method can be applied to the detection of oseltamivir phosphate enantiomers.
The invention has the following beneficial effects: the method is simple and convenient, good in reproducibility and high in sensitivity, the separation degree of oseltamivir phosphate and the enantiomer can reach more than 4.0, and the oseltamivir phosphate enantiomer can be effectively separated and determined and can be used for detection and monitoring in the oseltamivir phosphate production process.
Drawings
FIG. 1 separation chromatogram of an oseltamivir phosphate system applicability solution;
FIG. 2 Oseltamivir phosphate enantiomer detection chromatogram;
FIG. 3 LOD plots of oseltamivir phosphate and the enantiomers;
FIG. 4 LOQ diagram of oseltamivir phosphate and enantiomers.
Detailed Description
The invention will be further described with reference to specific embodiments, but the scope of the invention is not limited thereto.
EXAMPLE 1 isolation assay of Oseltamivir phosphate and its enantiomers in a test article
1. Instruments and reagents:
agilent 1260 liquid chromatograph and configured G1314F ultraviolet detector and analytical instrument configured HPLC chromatographic workstation.
n-Hexane (HPLC), anhydrous ethanol (HPLC), methanol (HPLC), trifluoroacetic acid (TFA) (HPLC), diethylamine (AR)
2. Chromatographic conditions are as follows:
a chromatographic column: the surface of the silica gel is coated with a cellulose-tri (3, 5-dichlorophenyl carbamate) column (4.6mm multiplied by 250mm, 5 mu m);
detection wavelength: 240 nm;
flow rate: 0.9-1.1 ml/min;
column temperature: 33 to 37 ℃;
sample injection amount: 25 μ l
Mobile phase: the volume ratio of n-hexane-anhydrous ethanol-methanol-trifluoroacetic acid-diethylamine is (90:8:2:0.4:0.2)
Diluent agent: the volume ratio of n-hexane to absolute ethyl alcohol to methanol is 1:1:3
3. Preparation of related solution:
(1) oseltamivir phosphate enantiomer stock solution: taking about 20mg of oseltamivir phosphate enantiomer (source: self-made) reference substance, precisely weighing, placing into a 10ml measuring flask, adding about 2/3 measuring flask volume of diluent for ultrasonic dissolution, diluting with diluent to scale, shaking up, precisely weighing 1ml, placing into a 10ml measuring flask, diluting with diluent to scale, shaking up (concentration: 0.2 mg/ml).
(2) Test solution: about 40mg of oseltamivir phosphate is precisely weighed and placed in a 20ml measuring flask, diluent with about 2/3 measuring flask volume is added for ultrasonic dissolution, the mixture is diluted to the scale by the diluent, and the mixture is shaken up (concentration: 2 mg/ml).
(3) System applicability solution: about 40mg of oseltamivir phosphate working reference substance (source: self-made) is taken, precisely weighed and placed in a 20ml measuring flask, a diluent with the volume of about 2/3 measuring flasks is added for ultrasonic dissolution, 2ml of enantiomer stock solution is precisely measured and placed in the same measuring flask, the solution is diluted to scale by the diluent, and shaking is carried out uniformly (the oseltamivir phosphate concentration: 2mg/ml, and the enantiomer concentration: 20 mu g/ml).
4. Separation measurement method
Precisely measuring 25 μ l of each of the system applicability solution (3) and the sample solution (2) under the preparation items of the related solutions, respectively injecting into a liquid chromatograph for isocratic elution, recording chromatogram, and showing the measurement results in table 1 and the chromatogram in fig. 1 and 2. And calculating the content of each component according to the peak area of the chromatogram.
TABLE 1 results of the resolution test
| Name (R) | Relative retention time | Degree of separation | Number of theoretical plates |
| Oseltamivir phosphate enantiomers | 0.76 | ___ | 8567 |
| Oseltamivir phosphate | 1.00 | 5.70 | 5888 |
The detection result shows that the separation degree between the main peak and the enantiomer peak is more than 1.5, which indicates that the method has better specificity.
Example 2: methodology validation
1. Quantitative and detection limits
Precisely measuring 1ml of each of the solutions (1) to (2) under the preparation items of the related solutions, putting the solutions into a same 100ml measuring flask, diluting the solution to a scale mark by using a diluent, and shaking the solution uniformly to obtain a stock solution (A).
Detection limiting solution: 1ml of the stock solution (A) was precisely measured, placed in a 50ml measuring flask, diluted to the mark with a diluent, and shaken (equivalent to 0.02% of the concentration of the sample solution).
Quantitative limiting solution: 1ml of the stock solution (A) was precisely measured, placed in a 20ml measuring flask, diluted to the mark with a diluent, and shaken (equivalent to 0.05% of the concentration of the sample solution).
The detection limit solution and the quantification limit solution were precisely measured in an amount of 25. mu.l each, and the solutions were injected into a liquid chromatograph, and the chromatogram, the measurement results of which are shown in Table 2, is shown in FIGS. 3 and 4.
TABLE 2 results of quantitative limit and detection limit measurements
| Name (R) | Detection limit signal-to-noise ratio (S/N) | Detection quantity (ng) | Quantitative limited signal-to-noise ratio (S/N) | Quantitative (ng) |
| Oseltamivir phosphate enantiomers | 5.8 | 10.1 | 15.5 | 25.2 |
| Oseltamivir phosphate | 7.7 | 9.9 | 14.6 | 24.7 |
The above results show that: the minimum detection concentration of the oseltamivir phosphate enantiomer is 0.02 percent, the quantitative limit detection concentration of the oseltamivir phosphate enantiomer is 0.05 percent, and the detection of 25 mul of oseltamivir phosphate sample injection volume can be met.
2. Linearity and range
Precisely measuring 1ml of each of the solutions (1) to (2) under the preparation items of the related solutions, putting the solutions into a same 100ml measuring flask, diluting the solutions to a scale with a diluent, and shaking the solutions uniformly to obtain linear stock solutions.
Linear solution: the linear stock solution is precisely measured according to the following table, placed in a corresponding measuring flask, diluted to the scale by the diluent and shaken up.
TABLE 3 preparation of Linear solutions
Remarking: l6 is linear stock solution.
The measuring method comprises the following steps: injecting an L1-L6 solution. The results are shown in tables 4 and 5.
TABLE 4 Oseltamivir phosphate enantiomer linearity results
TABLE 5 Oseltamivir phosphate Linear results
The above results show that: when the concentration of oseltamivir phosphate and the enantiomer is in the range of 0.05% -1.0% of the concentration of the test solution, the peak area and the concentration are in good linear relation; the correlation coefficients are all larger than 0.990; the Y-intercepts were all within 25% of the 100% response values, and the response factors RSD (n =6) were all less than 10%.
3. Accuracy of
(1) Oseltamivir phosphate enantiomer stock solution 1: 1ml of the solution (1) under the preparation item of the above-mentioned related solution was precisely measured, placed in a 100ml measuring flask, diluted to the scale with a diluent, and shaken up (concentration: 20. mu.g/ml).
(2) Oseltamivir phosphate enantiomer stock solution 2: precisely measuring 1ml of the solution (1) under the preparation item of the related solution, placing the solution in a 10ml measuring flask, diluting the solution to the scale with a diluent, and shaking up (concentration: 0.2 mg/ml).
(3) Oseltamivir phosphate enantiomer control solution: 2ml of oseltamivir phosphate enantiomer stock solution 1 is precisely measured, placed in a 20ml measuring flask, diluted to the mark with a diluent, and shaken up (concentration: 2. mu.g/ml).
(4) Accuracy solution: accurately weighing a proper amount of oseltamivir phosphate according to the following table, placing the proper amount of oseltamivir phosphate into a corresponding measuring flask, adding about 2/3 measuring flasks of diluent for ultrasonic dissolution, diluting the mixture to a scale by using the diluent, taking 10 parts in total, taking 1 part as a matrix sample, accurately transferring 9 parts into oseltamivir phosphate enantiomer stock solutions 1 and 2, diluting the mixture to the scale by using the diluent, and shaking the mixture uniformly to obtain an accurate solution. The specific formulation is shown in Table 6.
TABLE 6 preparation of oseltamivir phosphate enantiomer accuracy solutions
Note: SSR-isomer refers to oseltamivir phosphate enantiomer
The determination method comprises the following steps: and (3) sampling solutions (3) - (4) under the accuracy item, wherein the solution (3) is continuously sampled for 3 needles, and the accuracy measurement results of the oseltamivir phosphate enantiomers are shown in table 7.
TABLE 7 Oseltamivir phosphate enantiomer accuracy determination results
Results and analysis: calculated according to an external standard method, the recovery rate of oseltamivir phosphate enantiomer is between 83.4% and 96.1%, RSD (n =9) is 5.43%, the method meets the requirement, and the accuracy of the method meets the requirement.
Claims (4)
1. A method for separating oseltamivir phosphate enantiomers by normal phase chromatography is characterized in that: the method comprises the following steps:
(1) high performance liquid chromatography conditions:
a chromatographic column: the surface of the silica gel is coated with a cellulose-tri (3, 5-dichlorophenyl carbamate) column with the diameter of 4.6mm multiplied by 250mm and the diameter of 5 mu m;
detection wavelength: 240 nm;
flow rate: 0.9-1.1 ml/min;
column temperature: 33-37 ℃;
sample introduction amount: 25 mul;
mobile phase: the volume ratio of n-hexane-absolute ethyl alcohol-methanol-trifluoroacetic acid-diethylamine is (90:7:3:0.4:0.2) - (90:9:1:0.4: 0.2);
diluent agent: the volume ratio of n-hexane to absolute ethyl alcohol to methanol is 1:1: 3;
(2) preparing a system suitability solution;
(3) preparing a test solution; the method for preparing the test solution and the system applicability solution comprises the following steps: adding a diluent into an oseltamivir test sample to prepare a test sample solution, and respectively adding a oseltamivir phosphate working reference substance and an oseltamivir phosphate enantiomer into the diluent to prepare a system applicability solution;
(4) the measuring method comprises the following steps: respectively and precisely measuring a test solution and a system applicability solution, injecting the test solution and the system applicability solution into a liquid chromatograph, recording a chromatogram, and calculating the contents of oseltamivir phosphate enantiomers and the test solution according to peak areas;
the structures of the enantiomers of oseltamivir phosphate and oseltamivir phosphate are respectively shown as a molecular formula I and a molecular formula II:
2. the method for separating oseltamivir phosphate enantiomers according to the normal phase chromatography of claim 1, characterized in that: the volume ratio of n-hexane-absolute ethyl alcohol-methanol-trifluoroacetic acid-diethylamine in the mobile phase is 90:8:2:0.4: 0.2.
3. The method for separating oseltamivir phosphate enantiomers according to the normal phase chromatography of claim 1, characterized in that: the flow rate was 1.0 ml/min.
4. The method for separating oseltamivir phosphate enantiomers through normal phase chromatography according to claim 1, wherein the method comprises the following steps: the column temperature was 35 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910263858.XA CN109870521B (en) | 2019-04-03 | 2019-04-03 | Method for separating oseltamivir phosphate enantiomers by normal phase chromatography |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910263858.XA CN109870521B (en) | 2019-04-03 | 2019-04-03 | Method for separating oseltamivir phosphate enantiomers by normal phase chromatography |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109870521A CN109870521A (en) | 2019-06-11 |
| CN109870521B true CN109870521B (en) | 2022-09-23 |
Family
ID=66921953
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910263858.XA Active CN109870521B (en) | 2019-04-03 | 2019-04-03 | Method for separating oseltamivir phosphate enantiomers by normal phase chromatography |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109870521B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110988164A (en) * | 2019-11-29 | 2020-04-10 | 南京正济医药研究有限公司 | Detection method for purity of vepatavir |
| CN113866337B (en) * | 2021-10-25 | 2024-03-08 | 哈药集团技术中心 | Mass analysis method for separating and measuring oseltamivir phosphate isomer |
| CN114166983B (en) * | 2021-11-30 | 2023-05-23 | 苏州正济药业有限公司 | Analysis method for separating and detecting oseltamivir phosphate intermediate and impurities thereof |
| CN115266965B (en) * | 2022-07-01 | 2024-04-02 | 苏州博研医药科技有限公司 | High performance liquid chromatography method for detecting oseltamivir phosphate key intermediate specific impurities |
| CN115326999B (en) * | 2022-10-12 | 2022-12-27 | 深圳市海滨制药有限公司 | Detection method of oseltamivir epoxy intermediate and isomer thereof |
| CN117214369B (en) * | 2023-11-09 | 2024-02-02 | 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047076A (en) * | 2017-12-26 | 2018-05-18 | 杭州新博思生物医药有限公司 | A kind of preparation method of Oseltamivir enantiomter |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPWO2017033946A1 (en) * | 2015-08-25 | 2018-06-07 | 武田薬品工業株式会社 | Heterocyclic compounds |
-
2019
- 2019-04-03 CN CN201910263858.XA patent/CN109870521B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047076A (en) * | 2017-12-26 | 2018-05-18 | 杭州新博思生物医药有限公司 | A kind of preparation method of Oseltamivir enantiomter |
Non-Patent Citations (2)
| Title |
|---|
| Vikto＇ria Hajzer等.Optimization of stereoselective Michael addition of 2-(pentan-3-yloxy)acetaldehyde to N-[(Z)-2-nitroethenyl]acetamide with the aid of design of experiments.《Monatsh Chem》.2015,第146卷 * |
| 几种手性药物的对映体分离方法与药物动力学研究;郭娜;《中国优秀而硕博士学位论文全文数据库（硕士） 医药卫生科技辑》;20081115(第11期);第E079-13页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109870521A (en) | 2019-06-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109870521B (en) | Method for separating oseltamivir phosphate enantiomers by normal phase chromatography | |
| CN109580850B (en) | High performance liquid chromatography method for separating and determining oseltamivir phosphate and specific impurities thereof | |
| CN111983074B (en) | Method for determining peramivir intermediate isomer by using high performance liquid chromatography | |
| CN110501441A (en) | Detection method in relation to substance in a kind of paracetamol tablets | |
| CN115097023A (en) | High performance liquid chromatography detection method for zolmitamine related substances | |
| CN111855842B (en) | Detection method and application of related substances of ozagrel sodium | |
| CN112198260B (en) | Method for detecting content of process impurities in procaterol hydrochloride medicinal preparation | |
| CN107991415B (en) | Simultaneous separation and determination of pyroglutamic acid and methionine sulfoxide impurities in compound amino acid injection 18AA by liquid chromatography | |
| CN108152418B (en) | HPLC detection method for ketorolac tromethamine or/and impurities in preparation of ketorolac tromethamine | |
| CN106198819B (en) | The method of residual solvent in Headspace Gas Chromatography Xi Gelieting bulk pharmaceutical chemicals | |
| CN111721879A (en) | A method for detecting D-3-acetylmercapto-2-methylpropionyl chloride in captopril by gas chromatography-mass spectrometry | |
| CN113866337B (en) | Mass analysis method for separating and measuring oseltamivir phosphate isomer | |
| CN113671077B (en) | Method for detecting acryloyl chloride and related substances | |
| CN104880517B (en) | Method for measuring content of trace components in traditional Chinese medicine preparation | |
| CN114076802A (en) | Analysis method for quantitatively detecting nitrogen and oxygen impurities in pitavastatin calcium | |
| CN113514588B (en) | High performance liquid chromatography analysis method of relevant substances of cysteamine for injection | |
| Thejaswini et al. | Quantitative determination of duloxetine HCL in human plasma by GC-FID method | |
| CN109001342B (en) | High performance liquid chromatography method for detecting N-2, 3-dimethoxybenzyl piperonylethylamine and salt content thereof | |
| CN116265937A (en) | Detection method and application of oseltamivir phosphate related impurities | |
| CN107884496B (en) | Method for determining content of succinic acid in trelagliptin succinate | |
| Nagaraju et al. | Development and validation of chiral hplc method for the identification and quantification of enantiomer in posaconazole drug substance | |
| CN115791999B (en) | Detection method of impurity C in peramivir injection | |
| CN119595796A (en) | Sampling detection method for phenacetin content | |
| CN119395176A (en) | Detection method of optical isomer of citric acid Sha Zuomi | |
| CN114280169A (en) | Determination method of isomers in monatiravir |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |