CN112326836A - Method for quantitatively determining dimer impurities in ticagrelor intermediate TKG - Google Patents
Method for quantitatively determining dimer impurities in ticagrelor intermediate TKG Download PDFInfo
- Publication number
- CN112326836A CN112326836A CN202011223651.9A CN202011223651A CN112326836A CN 112326836 A CN112326836 A CN 112326836A CN 202011223651 A CN202011223651 A CN 202011223651A CN 112326836 A CN112326836 A CN 112326836A
- Authority
- CN
- China
- Prior art keywords
- tkg
- solution
- impurity
- dimer
- quantitatively determining
- 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.)
- Pending
Links
- 239000012535 impurity Substances 0.000 title claims abstract description 87
- 239000000539 dimer Substances 0.000 title claims abstract description 74
- 238000000034 method Methods 0.000 title claims abstract description 20
- PYEJQVYISBUGDU-UHFFFAOYSA-N 2-(3,4-difluorophenyl)cyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1C1=CC=C(F)C(F)=C1 PYEJQVYISBUGDU-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000012085 test solution Substances 0.000 claims abstract description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000001514 detection method Methods 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000000523 sample Substances 0.000 claims description 15
- 239000000337 buffer salt Substances 0.000 claims description 12
- 230000014759 maintenance of location Effects 0.000 claims description 6
- 238000010606 normalization Methods 0.000 claims description 5
- 239000012488 sample solution Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 239000003643 water by type Substances 0.000 claims description 4
- 238000012937 correction Methods 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 238000002347 injection Methods 0.000 abstract description 3
- 239000007924 injection Substances 0.000 abstract description 3
- 238000005341 cation exchange Methods 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 239000011550 stock solution Substances 0.000 description 25
- 239000013558 reference substance Substances 0.000 description 17
- 238000011084 recovery Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 5
- 239000012088 reference solution Substances 0.000 description 4
- 239000012490 blank solution Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 2
- 229960002528 ticagrelor Drugs 0.000 description 2
- 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 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Images
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
- G01N30/02—Column 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
- G01N30/60—Construction of the column
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Landscapes
- 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)
- Spectroscopy & Molecular Physics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses a method for quantitatively determining dimer impurities in a ticagrelor intermediate TKG, which adopts a cation exchange chromatographic column and salt-acetonitrile with high acetonitrile ratio as a mobile phase to fuse 4 stereoisomer peaks of the dimer impurities into a symmetrical sharp chromatographic peak, and can conveniently and accurately determine the total content of the dimer impurities. The 4 stereoisomeric impurities are all free of chromophores, a differential refraction detector is adopted, a satisfactory detection effect can be achieved under the concentration and the sample injection volume of the test solution, and the minimum detection reaches 0.004 percent of the concentration of the test solution. Therefore, the content of dimer impurities in TKG can be conveniently and accurately quantitatively determined.
Description
Technical Field
The invention belongs to the field of chemical detection, and relates to a method for quantitatively determining dimer impurities in a ticagrelor intermediate TKG.
Background
TKG: 2- [ [ (3aR,4S,6R,6aS) -6-aminotetrahydro-2, 2-dimethyl-4H-cyclopenteno-1, 3-dioxolan-4-yl ] oxy ] ethanol, an important intermediate of ticagrelor, an anticoagulant, aS shown in formula I below:
dimer impurities similar to bimolecular polymerization are generated during the production process thereof, as shown in the following formula II:
without control, it directly affects the quality of the finished ticagrelor product. The impurities are 4 stereoisomers which are not enantiomers, and an effective detection method is not available at present.
Disclosure of Invention
The invention aims to provide a method for quantitatively determining dimer impurities in a ticagrelor intermediate TKG, which can conveniently and accurately quantitatively determine the content of the dimer impurities in the TKG.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for quantitatively determining dimer impurities in a ticagrelor intermediate TKG, comprising: injecting 20 mu L of test solution into a chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows:
a chromatographic column: waters Spherisorb SCX chromatography column;
mobile phase: buffer salt: and acetonitrile is 55-65: 45-35 (V/V);
flow rate: 0.8-1.2 ml/min;
a detector: a differential refractive detector;
column temperature: 25-35 ℃.
Preferably, the sample is dissolved in water to obtain a solution of 60mg/ml as the sample solution.
Preferably, the specifications of the Waters Spherisorb SCX chromatography column are: 4.6X 250mm, 5 μm.
Preferably, the mobile phase has a buffer salt of 0.25mol/L potassium dihydrogen phosphate, and the pH is adjusted to 2.5 with phosphoric acid.
Preferably, the volume ratio of the buffer salt to the acetonitrile in the mobile phase is 60: 40.
preferably, the column flow rate is 1 ml/min.
Preferably, the column temperature is 30 ℃.
Preferably, the reference cell and the detection cell of the differential refraction detector are both at a temperature of 40 ℃.
Preferably, the main peak (TKG peak) is retained for 4-6min, and an impurity peak (dimer peak) with a relative retention time of about 1.7 is detected in the chromatogram of the test solution.
Preferably, the dimer impurity content is calculated using an area normalization method without the addition of a correction factor.
The invention has the following beneficial effects:
the invention adopts a cation exchange chromatographic column, salt-acetonitrile with high acetonitrile ratio is taken as a mobile phase, so that 4 stereoisomer peaks of dimer impurities are fused into a symmetrical sharp chromatographic peak, and the total content of the dimer impurities can be conveniently and accurately measured. The 4 stereoisomeric impurities have no chromophore, and the invention adopts a refractive index detector, and can achieve satisfactory detection effect (the minimum detection reaches 0.004 percent of the concentration of the test solution) under the concentration of the test solution and the sample injection volume. Therefore, the content of dimer impurities in TKG can be conveniently and accurately quantitatively determined.
Drawings
FIG. 1 is a chromatogram of a control solution of dimeric impurity in an example of the present invention.
FIG. 2 is a chromatogram of a sample solution in an example of the present invention.
FIG. 3 is a regression curve of a dimer impurity control solution in accordance with an example of the present invention.
FIG. 4 shows the regression curve of TKG control solution in the examples of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Examples
One, special property
1. Preparation of solutions
Blank solution: and (3) water.
Dimer impurity control stock solution: and (3) taking a proper amount of TKG dimer impurity reference substance, and adding water to dissolve to prepare a solution of about 0.6 mg/ml.
Test solution: taking a proper amount of the product, and adding water to dissolve the product to prepare a solution with the concentration of about 60 mg/ml.
2. Respectively adding the blank solution, the TKG dimer impurity reference solution and the test solution, and recording chromatograms, wherein the results are as follows:
TABLE 1 results of the specificity test
| Name of solution | Components | Retention time/min |
| Blank solution | TKG-IP-2 | ＜3 |
| TKG dimer impurity reference stock solution | TKG dimer | 7.774 |
| Test solution | TKG-base | 4.566 |
Therefore, blank, TKG and other impurities do not interfere with the determination of TKG dimer impurities, and the method is good in specificity.
Two, LOD/LOQ
1. Preparation of solutions
LOD solution: an appropriate amount of dimer impurity control was taken and dissolved in water to make a solution of about 0.0024 mg/ml.
LOQ solution: a proper amount of dimer impurity control is taken and dissolved in water to prepare a solution with the concentration of about 0.0096 mg/ml.
2. Noise determination
20 mul of precision water is injected into a chromatograph, a chromatogram is recorded, noise is measured near the appearance peak of the TKG dimer impurity, and the measurement is repeated for 3 times, and the results are as follows:
TABLE 2 noise measurement results
| NO. | 1 | 2 | 3 | Average |
| Detection time/min | 7.5-8.5 | 7.5-8.5 | 7.5-8.5 | 7.5-8.5 |
| Measurement results | 0.01 | 0.01 | 0.01 | 0.01 |
3. LOD determination
Precisely measuring 20 mul of LOD solution, injecting into a chromatograph, recording a chromatogram, measuring the main peak height, calculating the signal-to-noise ratio, and repeatedly measuring for 3 times, wherein the results are as follows:
TABLE 3 LOD measurement of dimer impurity
4. LOQ determination
Precisely measuring 20 mul of LOQ solution, injecting into a chromatograph, recording a chromatogram, measuring the main peak height, calculating the signal-to-noise ratio, and repeatedly measuring for 6 times, wherein the result is as follows:
TABLE 4 determination of dimer impurity LOQ
Three, linear
3.1TKG dimer impurity linearity
1) Preparation of solutions
Taking a proper amount of dimer impurity reference substance, adding water for dissolving, and preparing into about 0.6mg/ml solution as stock solution. Precisely measuring 1, 2, 3, 4, 5, 6, 7.5 and 9ml of stock solutions respectively, and diluting to 50ml with water to obtain 20%, 40%, 60%, 80%, 100%, 120%, 150% and 180% dimer impurity reference solutions.
2) Respectively and precisely measuring 20 mu l of each dimer impurity reference substance solution, injecting the solution into a chromatograph, recording a chromatogram, fitting a regression curve by taking the solution concentration as a horizontal coordinate and the main peak area as a vertical coordinate, and obtaining the following results:
TABLE 5 dimer impurity linearity test results
As shown in FIG. 3, it can be seen that the dimer impurity is in good linear relationship in the range of 0.016% (LOQ) -0.18% of the concentration of the test solution, the correlation coefficient is not lower than 0.995, and the ratio of the intercept to the peak area of 100% solution is not more than 10%.
3.2TKG Linearity
1) Preparation of solutions
Dissolving the product in water to obtain solutions of 0.6, 6, 12, 30, 48, 60, and 72mg/ml as TKG reference solutions of 1%, 10%, 20%, 50%, 80%, 100%, and 120%.
2) Respectively and precisely measuring 20 mu l of each TKG reference substance solution, injecting the TKG reference substance solution into a chromatograph, recording a chromatogram, fitting a regression curve by taking the solution concentration as a horizontal coordinate and the main peak area as a vertical coordinate, and obtaining the following results:
TABLE 6 TKG Linear test results
The regression curve is shown in FIG. 4, it can be seen that TKG has good linear relationship in the range of 1% -180% of the concentration of the test solution, the correlation coefficient is not lower than 0.995, and the ratio of the intercept to the peak area of 100% solution is not more than 10%.
Four, relative response factor
According to the linear result, the slope ratio of the regression curve is the ratio of the response factors, the relative corresponding factor of the dimer impurity is calculated to be 1.08 by taking the TKG relative corresponding factor as 1, and therefore the content of the dimer impurity in the test sample is calculated by adopting an area normalization method without a correction factor.
Fifth, sample recovery rate
1. Preparation of solutions
Dimer impurity control stock solution: the appropriate amount of dimer impurity as a control was weighed out accurately and dissolved in water to make a solution of about 0.6 mg/ml.
Dimer impurity control solution: precisely measuring 1ml of dimer impurity reference stock solution, and adding water to dilute to 10 ml.
Background solution: 0.6g of the product is precisely weighed, dissolved by adding water and diluted to 10 ml.
Sample application recovery rate solution:
50% sample recovery solution: precisely weighing 1.0g of the product, placing the product in a 10ml measuring flask, precisely adding 0.5ml of dimer impurity reference substance stock solution, adding water to dissolve and dilute the dimer impurity reference substance stock solution to a scale, and uniformly mixing. 3 parts are prepared in parallel.
80% sample recovery solution: precisely weighing 1.0g of the product, placing the product in a 10ml measuring flask, precisely adding 0.8ml of dimer impurity reference substance stock solution, adding water to dissolve and dilute the dimer impurity reference substance stock solution to a scale, and uniformly mixing. 3 parts are prepared in parallel.
100% sample recovery solution: precisely weighing 1.0g of the product, placing the product in a 10ml measuring flask, precisely adding 1ml of dimer impurity reference substance stock solution, adding water to dissolve and dilute the dimer impurity reference substance stock solution to a scale, and uniformly mixing. 3 parts are prepared in parallel.
Solution at 120% sample recovery: precisely weighing 1.0g of the product, placing the product in a 10ml measuring flask, precisely adding 1.2ml of dimer impurity reference stock solution, adding water to dissolve and dilute the dimer impurity reference stock solution to a scale, and uniformly mixing. 3 parts are prepared in parallel.
150% sample recovery solution: precisely weighing 1.0g of the product, placing the product in a 10ml measuring flask, precisely adding 1.5ml of dimer impurity reference stock solution, adding water to dissolve and dilute the dimer impurity reference stock solution to a scale, and uniformly mixing. 3 parts are prepared in parallel.
2. Respectively and precisely measuring 20 mul of each of the impurity reference solution, the background solution and each sample adding recovery rate solution, injecting the solution into a chromatograph, recording a chromatogram, calculating the amount of dimer impurities in the background and each sample adding recovery rate solution according to an external standard method, and calculating the recovery rate, wherein the results are as follows:
TABLE 7 sample recovery test results
The recovery rate is between 90% and 108%, the RSD of 15 results is not more than 3%, and the method has good accuracy.
Sixthly, repeatability
1. Preparation of solutions
Dimer impurity control stock solution: the appropriate amount of dimer impurity as a control was weighed out accurately and dissolved in water to make a solution of about 0.6 mg/ml.
Test solution: precisely weighing 1.0g of the product, placing the product in a 10ml measuring flask, precisely adding 1ml of dimer impurity reference substance stock solution, adding water to dissolve and dilute the dimer impurity reference substance stock solution to a scale, and uniformly mixing. 6 parts are prepared in parallel.
2. Precisely measuring 20 μ l of each sample solution, injecting into chromatograph, recording chromatogram, and calculating dimer impurity by area normalization method
The results of mass content were as follows:
TABLE 8 results of the repeatability tests
| NO. | 1 | 2 | 3 | 4 | 5 | 6 | RSD％ |
| Dimer% | 0.119 | 0.121 | 0.118 | 0.121 | 0.12 | 0.117 | 1.4 |
The result RSD of 6 test articles is 1.4%, and the method has good repeatability.
Seven, durability
1. Preparation of solutions
Dimer impurity control stock solution: the appropriate amount of dimer impurity as a control was weighed out accurately and dissolved in water to make a solution of about 0.6 mg/ml.
Test solution: precisely weighing 1.0g of the product, placing the product in a 10ml measuring flask, precisely adding 1ml of dimer impurity reference substance stock solution, adding water to dissolve and dilute the dimer impurity reference substance stock solution to a scale, and uniformly mixing.
2. Under the condition of slightly changing chromatographic parameters, the dimer impurity in the same test sample solution is measured according to an area normalization method, and the result is as follows:
TABLE 9 durability test results
Compared with the normal condition, the measurement results have no obvious difference, and the method has good durability.
Eight, RRT
The retention time of the dimeric impurity relative to TKG was measured under normal conditions and each durability condition, and the results were as follows:
TABLE 10 retention time of dimer impurities relative to TKG under different conditions
| Chromatographic conditions | RRT |
| Normal condition | 1.71 |
| Column temperature 25 deg.C | 1.72 |
| Column temperature 35 deg.C | 1.71 |
| Flow rate 0.8ml/min | 1.71 |
| Flow rate 1.2ml/min | 1.71 |
| Buffer salt pH2.3 | 1.75 |
| Buffer salt pH2.7 | 1.75 |
| Buffer salt: ACN 65: 35 | 1.77 |
| Buffer salt: ACN 55: 45 | 1.67 |
| Buffer salt concentration 0.24mol | 1.78 |
| Buffer salt concentration 0.26mol | 1.69 |
| Changing chromatographic columns of different batch numbers of the same manufacturer | 1.67 |
Compared with the normal condition, the RRT of each condition does not change by more than +/-10 percent, and the provisional RRT is 1.7.
Ninth, solution stability
1. Preparation of solutions
Dimer impurity control stock solution: the appropriate amount of dimer impurity as a control was weighed out accurately and dissolved in water to make a solution of about 0.6 mg/ml.
Test solution: precisely weighing 1.0g of the product, placing the product in a 10ml measuring flask, precisely adding 1ml of dimer impurity reference substance stock solution, adding water to dissolve and dilute the dimer impurity reference substance stock solution to a scale, and uniformly mixing. 6 parts are prepared in parallel.
2. After the test solution is placed at room temperature for 24 hours, sample injection is carried out, and compared with 0 hour, the results are as follows:
TABLE 11 test results of stability of test solutions
| Name (R) | Dimer impurity content% | Whether or not to produceChromatographic peak for interference generation dimer impurity detection |
| Test solution (0h) | 0.12％ | Whether or not |
| Test solution (24h) | 0.12％ | Whether or not |
It can be seen that the test solution is stable for at least 24 hours at room temperature.
Claims (10)
1. A method for quantitatively determining dimer impurities in a ticagrelor intermediate TKG, comprising: injecting 20 mu L of test solution into a chromatograph, and recording a chromatogram, wherein the chromatogram conditions are as follows:
a chromatographic column: waters Spherisorb SCX chromatography column;
mobile phase: buffer salt: and acetonitrile is 55-65: 45-35;
flow rate: 0.8-1.2 ml/min;
a detector: a differential refractive detector;
column temperature: 25-35 ℃.
2. The method for quantitatively determining the dimer impurity in the ticagrelor intermediate TKG as claimed in claim 1, wherein the sample is dissolved in water to prepare a solution of 60mg/ml as the sample solution.
3. The method for quantitative determination of dimeric impurities in the ticagrelor intermediate TKG as claimed in claim 1, wherein the Waters Spherisorb SCX chromatography column is of the following specifications: 4.6X 250mm, 5 μm.
4. The method for quantitatively determining the dimer impurity in the ticagrelor intermediate TKG as claimed in claim 1, wherein the buffer salt is 0.25mol/L potassium dihydrogen phosphate and the ph is adjusted to 2.5 with phosphoric acid in the mobile phase.
5. The method for quantitatively determining the dimeric impurity in the ticagrelor intermediate TKG as claimed in claim 1, wherein the volume ratio of the buffer salt to the acetonitrile in the mobile phase is 60: 40.
6. the method for quantitatively determining the dimeric impurity in the ticagrelor intermediate TKG as claimed in claim 1, wherein the flow rate of the chromatographic column is 1 ml/min.
7. The method for quantitatively determining the dimeric impurity in the ticagrelor intermediate TKG as claimed in claim 1, wherein the column temperature is 30 ℃.
8. The method for quantitatively determining the dimeric impurity in the ticagrelor intermediate TKG as claimed in claim 1, wherein the temperature of the reference cell and the detection cell of the differential refraction detector are both 40 ℃.
9. The method for quantitatively determining the dimer impurity in the ticagrelor intermediate TKG as claimed in any one of claims 1 to 8, wherein the retention time of the main peak is 4-6min, and the impurity peak with the relative retention time of 1.7 in the chromatogram of the test solution is the dimer impurity peak.
10. The method for quantitatively determining the dimeric impurity in the ticagrelor intermediate TKG as claimed in claim 9, wherein the dimeric impurity content is calculated by area normalization without adding a correction factor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011223651.9A CN112326836A (en) | 2020-11-05 | 2020-11-05 | Method for quantitatively determining dimer impurities in ticagrelor intermediate TKG |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011223651.9A CN112326836A (en) | 2020-11-05 | 2020-11-05 | Method for quantitatively determining dimer impurities in ticagrelor intermediate TKG |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112326836A true CN112326836A (en) | 2021-02-05 |
Family
ID=74316009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011223651.9A Pending CN112326836A (en) | 2020-11-05 | 2020-11-05 | Method for quantitatively determining dimer impurities in ticagrelor intermediate TKG |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112326836A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262346A (en) * | 2014-09-17 | 2015-01-07 | 广东众生药业股份有限公司 | Preparation method of bromfenac sodium dimer impurity |
| CN105092768A (en) * | 2014-05-21 | 2015-11-25 | 天津市汉康医药生物技术有限公司 | Method for analyzing and separating isomer impurity of ticagrelor intermediate |
| CN105424822A (en) * | 2015-10-29 | 2016-03-23 | 成都百裕科技制药有限公司 | Method for detecting (1R,2S)-2-(3,4-diflurophenyl) cyclopropylamine in ticagrelor |
| CN105606741A (en) * | 2016-03-10 | 2016-05-25 | 天津红日药业股份有限公司 | Method for detecting content of relevant substances of Ticagrelor |
| CN107827840A (en) * | 2017-11-10 | 2018-03-23 | 成都美域高制药有限公司 | A kind of preparation method and applications of acotiamide hydrochloride hydrate dimer impurity |
| CN108037209A (en) * | 2017-12-25 | 2018-05-15 | 浙江天宇药业股份有限公司 | The liquid phase chromatography analytical method of ticagrelor chiral intermediate |
| CN109856255A (en) * | 2017-11-30 | 2019-06-07 | 四川海思科制药有限公司 | A kind of analysis method for the isomer impurities content controlling ticagrelor intermediate |
-
2020
- 2020-11-05 CN CN202011223651.9A patent/CN112326836A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105092768A (en) * | 2014-05-21 | 2015-11-25 | 天津市汉康医药生物技术有限公司 | Method for analyzing and separating isomer impurity of ticagrelor intermediate |
| CN104262346A (en) * | 2014-09-17 | 2015-01-07 | 广东众生药业股份有限公司 | Preparation method of bromfenac sodium dimer impurity |
| CN105424822A (en) * | 2015-10-29 | 2016-03-23 | 成都百裕科技制药有限公司 | Method for detecting (1R,2S)-2-(3,4-diflurophenyl) cyclopropylamine in ticagrelor |
| CN105606741A (en) * | 2016-03-10 | 2016-05-25 | 天津红日药业股份有限公司 | Method for detecting content of relevant substances of Ticagrelor |
| CN107827840A (en) * | 2017-11-10 | 2018-03-23 | 成都美域高制药有限公司 | A kind of preparation method and applications of acotiamide hydrochloride hydrate dimer impurity |
| CN109856255A (en) * | 2017-11-30 | 2019-06-07 | 四川海思科制药有限公司 | A kind of analysis method for the isomer impurities content controlling ticagrelor intermediate |
| CN108037209A (en) * | 2017-12-25 | 2018-05-15 | 浙江天宇药业股份有限公司 | The liquid phase chromatography analytical method of ticagrelor chiral intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 国家药典委员会: "《中华人民共和国药典 2020年版 四部》", 中国医药科技出版社, pages: 514 - 516 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106324141B (en) | A kind of efficient liquid phase detection method of the escitalopram oxalate in relation to substance | |
| CN113125625B (en) | Method for detecting genotoxic impurities in propiofuravir fumarate | |
| CN105334274A (en) | Reversed-phase high performance liquid chromatography determination method for content and related substances of tofacitinib citrate | |
| CN111579704A (en) | Method for detecting content of N, N' -diacetyl-L-cystine in compound amino acid injection | |
| CN112326836A (en) | Method for quantitatively determining dimer impurities in ticagrelor intermediate TKG | |
| CN110133119B (en) | Detection method of L-alpha-glycerophosphorylcholine related substance | |
| CN110988233A (en) | Method for detecting impurity A content of cocarboxylase tetrahydrate | |
| CN113484450B (en) | Derivatization treatment method for detecting drug enantiomer, determination method and application | |
| CN108344832B (en) | Detection method for completely separating main component from impurities thereof | |
| CN113125587B (en) | Tofacitinib intermediate and detection method of enantiomer thereof | |
| CN113655150B (en) | Method for detecting nitroxide free radical piperidinol in betahistine hydrochloride | |
| CN112098562B (en) | Method for measuring contents of six impurities in doxepin hydrochloride and preparation thereof | |
| CN110824059B (en) | Detection method of formyl impurities in febuxostat | |
| CN108760937B (en) | Determination of residual ethylenediamine in caspofungin acetate and application thereof | |
| CN111521693B (en) | Method for detecting isosorbide mononitrate | |
| CN112881538A (en) | Detection method for impurities and enantiomers in fudosteine and fudosteine tablets | |
| CN114113402B (en) | Method for measuring pinanediol content in bortezomib by adopting high performance liquid chromatography | |
| CN116879428B (en) | High performance liquid analysis method for residual content of phosphorylcholine in L-alpha-phosphorylcholine | |
| CN115963217B (en) | Detection method of imidapril intermediate and impurity | |
| CN114295750B (en) | Method for detecting related substances in ursodeoxycholic acid synthesis | |
| CN117890496B (en) | Method for detecting related substances of compound preparation of novel oral solution of guaifenesin | |
| CN118209645A (en) | Method for detecting 2, 4-dimethylbenzene thiophenol related substances | |
| CN113125626B (en) | HPLC method for detecting dextroisomer from levetiracetam oral liquid | |
| CN117723664A (en) | Method for separating and detecting related substances in clotrimazole initial raw material imidazole | |
| CN116818943A (en) | High performance liquid analysis method for measuring content of phosphorylcholine |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210205 |
|
| RJ01 | Rejection of invention patent application after publication |