CN110763790A - Method for controlling ticagrelor isomer impurities by high performance liquid chromatography - Google Patents
Method for controlling ticagrelor isomer impurities by high performance liquid chromatography Download PDFInfo
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Abstract
The enantiomers of the drug have obvious differences in metabolic pathways, pharmacological activity, toxic and side effects and the like under most conditions in vivo, and the expression forms are as follows: the enantiomer has no obvious pharmacological action; enantiomers have equivalent or similar pharmacological effects; the enantiomer has stronger toxic and side effects or antagonism; enantiomers have completely different physiological activities. In order to ensure the quality of ticagrelor raw materials, the method has the important significance of establishing a chiral analysis method with high sensitivity and good specificity. The invention provides a method for chiral resolution of ticagrelor isomer by using high performance liquid chromatography, which can shorten analysis time, ensure the stability during detection and the accuracy of a detection result, realize effective separation of ticagrelor and isomer, accurately measure the limit of isomer, and has the advantages of strong specificity, high sensitivity, simple operation method, simplicity and convenience and rapidness.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis, and particularly relates to a method for controlling ticagrelor isomer impurities by using high performance liquid chromatography.
Background
Ticagrelor (ticagrelor) is sold under the trade name of blindar, is a platelet aggregation inhibitor, developed by eastern american limited and is used mainly to prevent thrombotic events (vascular death, myocardial infarction, stroke) in patients with non-ST or ST-elevation coronary syndromes. The drug belongs to a novel cyclopentyl triazolopyrimidine reversible P2Y12 receptor antagonist, effectively inhibits formation of atherothrombosis by inhibiting formation of new blood clots, and makes up the defects of slow effect of anti-platelet effect, large individual difference and the like of clopidogrel.
The chemical name of ticagrelor is 2- (1S, 2S,3R, 5S) -3- [7- { [ (1R, 2S) -2- (3, 4-difluorophenyl) propylamine]Amino } -5- (propylsulfanyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-3-yl]-5- (2-hydroxyethoxy) cyclopentane-1, 2-diol having the molecular formula C23H28F2N6O4S, the specific structure is shown in figure 1, 6 chiral centers exist, 64 chiral isomers exist theoretically, and three isomers are mainly controlled in the quality control of a finished product in practice: enantiomer J, diastereomer H, I.
Disclosure of Invention
The enantiomers of the drug have obvious differences in metabolic pathways, pharmacological activity, toxic and side effects and the like under most conditions in vivo, and the expression forms are as follows: the enantiomer has no obvious pharmacological action; enantiomers have equivalent or similar pharmacological effects; the enantiomer has stronger toxic and side effects or antagonism; enantiomers have completely different physiological activities. In order to ensure the quality of ticagrelor raw materials, the method has the important significance of establishing a chiral analysis method with high sensitivity and good specificity. In the research process, the inventor finds that relevant documents exist for an analysis method for controlling ticagrelor isomer impurities, but finds that the analysis time of the document [1] is too long (more than 75 min), and the figure is shown in figure 2; the relative correction factors of isomer impurities and ticagrelor in the document [2] are greatly different and contradict the relative correction factor in the document [1 ]; therefore, the invention develops a method for chiral resolution of ticagrelor isomer by using high performance liquid chromatography, which shortens the analysis time, is close to the relative correction factor of impurities in the document 1, can ensure the stability during detection and the accuracy of a detection result, can realize effective separation of ticagrelor and isomer, can accurately determine the limit of the isomer, and has the advantages of strong specificity, high sensitivity, simple operation method, simplicity and rapidness. The method comprises the following steps:
1) the mobile phase is the mixed solution of normal hexane, methyl tert-butyl ether and tetrahydrofuran,
2) the additives are diethylamine and triethylamine, the addition amount is 0.1-0.2%, and the addition amount is 0.02-0.1%
3) The column used Chiralpak AD-H (4.6X 250mm,5.0um), Chiralpak IC (4.6X 250mm,5.0 um);
4) the sample injection volume for detection by a high performance liquid chromatography system is 20-50 mu L, the flow rate of a mobile phase is 0.9-1.1 ml/min, and the column temperature of a chromatographic column is 30-40 ℃.
5) The detector of the high performance liquid chromatography system is a DAD detector with a detection wavelength of 254nm
6) Ticagrelor impurity H, I, J stock solution: weighing impurity H in a 100mL volumetric flask, adding mobile phase to dissolve to prepare about 100ug of impurity H stock solution per 1mL, and preparing I, J stock solution by the same method.
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Example 1
Instrument and chromatographic conditions:
a Thermo Ultimate 3000 high performance liquid chromatograph; the chromatographic column was Chiralpak IC (4.6 x 250mm,5.0 um); the column temperature of the chromatographic column is 35 ℃; the mobile phase is methyl tert-butyl ether: n-hexane: tetrahydrofuran: glacial acetic acid = 65: 25: 10: 0.1. detecting with high performance liquid chromatography system with sample volume of 50 μ L; the flow rate is 1.0 ml/min; a DAD detector is adopted; the detection wavelength is 254 nm; the running time is 35 min; the mobile phase is used as a diluent.
Experimental procedure
1) Preparation of system suitability solution: precisely weighing 10mg of ticagrelor in a 10ml measuring flask, adding a mobile phase for dissolution, and taking out the H, I, J stock solution of the impurity obtained in the step 6), so as to prepare about 1.0mg of ticagrelor and 1 mu g of ticagrelor isomer H, I, J in each 1 ml.
2) Preparation of self-control solution: weighing ticagrelor sample, adding mobile phase for dissolving, and making into sample solution containing 1.0ug per 1ml
3) Preparation of a test solution: ticagrelor samples were weighed and dissolved with mobile phase to make up a sample solution containing about 1.0mg per 1 ml.
4) Taking blank solvent, system applicability solution, self-control solution and sample solution, respectively, injecting 50 μ L of sample, measuring, and recording chromatogram.
The experimental results show that the separation between impurity H, I, J and ticagrelor is satisfactory, but all peaks are severely smeared.
Example 2
Instrument and chromatographic conditions:
a Thermo Ultimate 3000 high performance liquid chromatograph; the chromatographic column was Chiralpak IC (4.6 x 250mm,5.0 um); the column temperature of the chromatographic column is 35 ℃; the mobile phase is methyl tert-butyl ether: n-hexane: tetrahydrofuran: trifluoroacetic acid = 65: 25: 10: 0.1. detecting with high performance liquid chromatography system with sample volume of 50 μ L; the flow rate is 1.0 ml/min; a DAD detector is adopted; the detection wavelength is 254 nm; the running time is 35 min; the mobile phase is used as a diluent.
Experimental procedure
1) Preparation of system suitability solution: precisely weighing 10mg of ticagrelor in a 10ml measuring flask, adding a mobile phase for dissolving, taking 0.1ml of the impurity H, I, J stock solution obtained in the step 6), and metering by using the mobile phase to prepare 1.0mg of ticagrelor and 1 mu g of ticagrelor isomer H, I, J in each 1 ml.
2) Preparation of self-control solution: weighing ticagrelor sample, dissolving with mobile phase to obtain sample solution containing 1.0mg per 1ml
3) Preparation of a test solution: ticagrelor samples were weighed and dissolved with mobile phase to make up a sample solution containing about 1.0mg per 1 ml.
4) Taking blank solvent, system applicability solution, self-control solution and sample solution, respectively, injecting 50 μ L of sample, measuring, and recording chromatogram.
The experimental results show that the separation between impurity H, I, J and ticagrelor is satisfactory, but all peaks are severely smeared.
Example 3
Instrument and chromatographic conditions:
a Thermo Ultimate 3000 high performance liquid chromatograph; the chromatographic column was Chiralpak IC (4.6 x 250mm,5.0 um); the column temperature of the chromatographic column is 35 ℃; the mobile phase is methyl tert-butyl ether: n-hexane: tetrahydrofuran: diethylamine = 65: 25: 10: 0.1. detecting with high performance liquid chromatography system with sample volume of 50 μ L; the flow rate is 1.0 ml/min; a DAD detector is adopted; the detection wavelength is 254 nm; the running time is 35 min; the mobile phase is used as a diluent.
Experimental procedure
1) Preparation of system suitability solution: precisely weighing 10mg of ticagrelor in a 10ml measuring flask, adding a mobile phase for dissolving, taking 0.1ml of the impurity H, I, J stock solution obtained in the step 6), and metering by using the mobile phase to prepare 1.0mg of ticagrelor and 1 mu g of ticagrelor isomer H, I, J in each 1 ml.
2) Preparation of self-control solution: weighing ticagrelor sample, dissolving with mobile phase to obtain sample solution containing 1.0mg per 1ml
3) Preparation of a test solution: ticagrelor samples were weighed and dissolved with mobile phase to make up a sample solution containing about 1.0mg per 1 ml.
4) Taking blank solvent, system applicability solution, self-control solution and sample solution, respectively, injecting 50 μ L of sample, measuring, and recording chromatogram.
The experimental results show that the separation between impurity H, I, J and ticagrelor is satisfactory, but all peaks are severely smeared.
Example 4
Instrument and chromatographic conditions:
a Thermo Ultimate 3000 high performance liquid chromatograph; the chromatographic column was Chiralpak IC (4.6 x 250mm,5.0 um); the column temperature of the chromatographic column is 35 ℃; the mobile phase is methyl tert-butyl ether: n-hexane: tetrahydrofuran: triethylamine = 65: 25: 10: 0.1. detecting with high performance liquid chromatography system with sample volume of 50 μ L; the flow rate is 1.0 ml/min; a DAD detector is adopted; the detection wavelength is 254 nm; the running time is 35 min; the mobile phase is used as a diluent.
Experimental procedure
1) Preparation of system suitability solution: precisely weighing 10mg of ticagrelor in a 10ml measuring flask, adding a mobile phase for dissolving, taking 0.1ml of the impurity H, I, J stock solution obtained in the step 6), and metering by using the mobile phase to prepare 1.0mg of ticagrelor and 1 mu g of ticagrelor isomer H, I, J in each 1 ml.
2) Preparation of self-control solution: weighing ticagrelor sample, dissolving with mobile phase to obtain sample solution containing 1.0mg per 1ml
3) Preparation of a test solution: ticagrelor samples were weighed and dissolved with mobile phase to make up a sample solution containing about 1.0mg per 1 ml.
4) Taking blank solvent, system applicability solution, self-control solution and sample solution, respectively, injecting 50 μ L of sample, measuring, and recording chromatogram.
The experimental results show that the separation between impurity H, I, J and ticagrelor is satisfactory, but all peaks are severely smeared.
Example 5
Instrument and chromatographic conditions:
a Thermo Ultimate 3000 high performance liquid chromatograph; the chromatographic column was Chiralpak IC (4.6 x 250mm,5.0 um); the column temperature of the chromatographic column is 35 ℃; the mobile phase is methyl tert-butyl ether: n-hexane: tetrahydrofuran: diethylamine: glacial acetic acid = 65: 25: 10: 0.1: 0.1. detecting with high performance liquid chromatography system with sample volume of 50 μ L; the flow rate is 1.0 ml/min; a DAD detector is adopted; the detection wavelength is 254 nm; the running time is 35 min; the mobile phase is used as a diluent.
Experimental procedure
1) Preparation of system suitability solution: precisely weighing 10mg of ticagrelor in a 10ml measuring flask, adding a mobile phase for dissolving, taking 0.1ml of the impurity H, I, J stock solution obtained in the step 6), and metering by using the mobile phase to prepare 1.0mg of ticagrelor and 1 mu g of ticagrelor isomer H, I, J in each 1 ml.
2) Preparation of self-control solution: weighing ticagrelor sample, dissolving with mobile phase to obtain sample solution containing 1.0mg per 1ml
3) Preparation of a test solution: ticagrelor samples were weighed and dissolved with mobile phase to make up a sample solution containing about 1.0mg per 1 ml.
4) Taking blank solvent, system applicability solution, self-control solution and sample solution, respectively, injecting 50 μ L of sample, measuring, and recording chromatogram.
The test results show that impurity H, I is disturbed before the peak and cannot be completely separated.
Example 6
Instrument and chromatographic conditions:
a Thermo Ultimate 3000 high performance liquid chromatograph; the chromatographic column was Chiralpak IC (4.6 x 250mm,5.0 um); the column temperature of the chromatographic column is 35 ℃; the mobile phase is methyl tert-butyl ether: n-hexane: tetrahydrofuran: diethylamine: glacial acetic acid = 65: 25: 10: 0.1: 0.05. detecting with high performance liquid chromatography system with sample volume of 50 μ L; the flow rate is 1.0 ml/min; a DAD detector is adopted; the detection wavelength is 254 nm; the running time is 35 min; the mobile phase is used as a diluent.
Experimental procedure
1) Preparation of system suitability solution: precisely weighing 10mg of ticagrelor in a 10ml measuring flask, adding a mobile phase for dissolving, taking 0.1ml of the impurity H, I, J stock solution obtained in the step 6), and metering by using the mobile phase to prepare 1.0mg of ticagrelor and 1 mu g of ticagrelor isomer H, I, J in each 1 ml.
2) Preparation of self-control solution: weighing ticagrelor sample, dissolving with mobile phase to obtain sample solution containing 1.0mg per 1ml
3) Preparation of a test solution: ticagrelor samples were weighed and dissolved with mobile phase to make up a sample solution containing about 1.0mg per 1 ml.
4) Taking blank solvent, system applicability solution, self-control solution and sample solution, respectively, injecting 50 μ L of sample, measuring, and recording chromatogram.
Test results show that impurity I peak is interfered and can not be completely separated.
Example 7
Instrument and chromatographic conditions:
a Thermo Ultimate 3000 high performance liquid chromatograph; the chromatographic column was Chiralpak IC (4.6 x 250mm,5.0 um); the column temperature of the chromatographic column is 35 ℃; the mobile phase is methyl tert-butyl ether: n-hexane: tetrahydrofuran: diethylamine: glacial acetic acid = 65: 25: 10: 0.1: 0.03. detecting with high performance liquid chromatography system with sample volume of 50 μ L; the flow rate is 1.0 ml/min; a DAD detector is adopted; the detection wavelength is 254 nm; the running time is 35 min; the mobile phase is used as a diluent.
Experimental procedure
1) Preparation of system suitability solution: precisely weighing 10mg of ticagrelor in a 10ml measuring flask, adding a mobile phase for dissolving, taking 0.1ml of the impurity H, I, J stock solution obtained in the step 6), and metering by using the mobile phase to prepare 1.0mg of ticagrelor and 1 mu g of ticagrelor isomer H, I, J in each 1 ml.
2) Preparation of self-control solution: weighing ticagrelor sample, dissolving with mobile phase to obtain sample solution containing 1.0mg per 1ml
3) Preparation of a test solution: ticagrelor samples were weighed and dissolved with mobile phase to make up a sample solution containing about 1.0mg per 1 ml.
4) Taking blank solvent, system applicability solution, self-control solution and sample solution, respectively, injecting 50 μ L of sample, measuring, and recording chromatogram, as shown in FIG. 3.
The test results show that the separation degree between the impurity H, I, J and ticagrelor is satisfactory, but all peaks are relatively symmetrical.
Example 8
Instrument and chromatographic conditions:
a Thermo Ultimate 3000 high performance liquid chromatograph; the chromatographic column was Chiralpak IC (4.6 x 250mm,5.0 um); the column temperature of the chromatographic column is 35 ℃; the mobile phase is methyl tert-butyl ether: n-hexane: tetrahydrofuran: diethylamine: glacial acetic acid = 65: 25: 10: 0.1: 0.01. detecting with high performance liquid chromatography system with sample volume of 50 μ L; the flow rate is 1.0 ml/min; a DAD detector is adopted; the detection wavelength is 254 nm; the running time is 35 min; the mobile phase is used as a diluent.
Experimental procedure
1) Preparation of system suitability solution: precisely weighing 10mg of ticagrelor in a 10ml measuring flask, adding a mobile phase for dissolving, taking 0.1ml of the impurity H, I, J stock solution obtained in the step 6), and metering by using the mobile phase to prepare 1.0mg of ticagrelor and 1 mu g of ticagrelor isomer H, I, J in each 1 ml.
2) Preparation of self-control solution: weighing ticagrelor sample, dissolving with mobile phase to obtain sample solution containing 1.0mg per 1ml
3) Preparation of a test solution: ticagrelor samples were weighed and dissolved with mobile phase to make up a sample solution containing about 1.0mg per 1 ml.
4) Taking blank solvent, system applicability solution, self-control solution and sample solution, respectively, injecting 50 μ L of sample, measuring, and recording chromatogram.
Test results show that impurity I peak is interfered and can not be completely separated.
In summary, embodiment 7 is a preferred embodiment, and the method is validated by specificity, stability (see fig. 4), detection limit, quantification limit (see fig. 5), linearity, durability (wavelength ± 2nm, flow rate ± 0.1mL/min, column temperature ± 5 ℃) (see fig. 6), accuracy and the like, and the result shows that the method can accurately determine the limit of the isomer, and has the advantages of strong specificity, high sensitivity, simple operation method, simplicity, convenience and rapidness.
Description of the drawings:
fig. 1 is a structural diagram of ticagrelor;
FIG. 2 is a graph of the separation of ticagrelor from isomers of reference [1 ];
FIG. 3 is a system suitability chromatogram of a preferred embodiment of high performance liquid chromatography for controlling ticagrelor isomer impurities of the present invention;
FIG. 4 is stability data for a preferred embodiment of high performance liquid chromatography of the present invention for controlling ticagrelor isomer impurities;
FIG. 5 is a quantitative limit chromatogram of a preferred embodiment of high performance liquid chromatography for controlling ticagrelor isomer impurities of the present invention;
figure 6 is durability data for a preferred embodiment of high performance liquid chromatography of the present invention for controlling ticagrelor isomer impurities.
Claims (9)
1. The enantiomers of the drug have obvious differences in metabolic pathways, pharmacological activity, toxic and side effects and the like under most conditions in vivo, and the expression forms are as follows: the enantiomer has no obvious pharmacological action; enantiomers have equivalent or similar pharmacological effects; the enantiomer has stronger toxic and side effects or antagonism; the method for controlling ticagrelor isomer impurities by using the high performance liquid chromatography is characterized by shortening the analysis time, ensuring the stability during the detection period and the accuracy of the detection result, realizing the effective separation of ticagrelor and the isomer, being capable of accurately measuring the limit of the isomer, and having strong specificity and high sensitivity.
2. The method of claim 1 comprising the steps of:
1) preparing a mixed solution of n-hexane, methyl tert-butyl ether and tetrahydrofuran as a mobile phase;
2) the additives are diethylamine, triethylamine and ethanolamine, the addition amount is 0.1-0.2%, and the addition amount is glacial acetic acid and trifluoroacetic acid, the addition amount is 0.01-0.1%;
3) the column used Chiralpak AD-H (4.6 x 250mm,5.0 um);
4) the sample injection volume detected by a high performance liquid chromatography system is 20-50 mu L, the flow rate of a mobile phase is 0.9-1.1 ml/min, and the column temperature of a chromatographic column is 30-40 ℃;
5) the detector of the high performance liquid chromatography system is a DAD detector, and the detection wavelength is 254 nm;
6) ticagrelor impurity H, I, J stock solution: weighing impurity H in a 100mL volumetric flask, adding mobile phase to dissolve to obtain a stock solution containing about 100ug of impurity H per 1mL, diluting to obtain a control solution containing about 1ug of impurity H per 1mL,
preparing I, J control solution by the same method;
7) ticagrelor test solution: ticagrelor samples were weighed into 10mL volumetric flasks, dissolved with mobile phase to give about 1mg per 1mL of test solution, and diluted to about 1ug per 1mL of self-control solution.
3. The method according to claim 2, wherein the mobile phase is a mixed solution of n-hexane, methyl tert-butyl ether and tetrahydrofuran.
4. The process of claim 2, wherein the additive is diethylamine, triethylamine, ethanolamine in an amount of 0.1% to 0.2% and glacial acetic acid, trifluoroacetic acid in an amount of 0.01% to 0.1%.
5. The process of claim 2, wherein the chromatography column uses Chiralpak AD-H (4.6 x 250mm,5.0 um).
6. The method according to claim 2, wherein the sample volume for detection by the HPLC system is 20-50 μ L, the flow rate of the mobile phase is 0.9-1.1 ml/min, and the column temperature of the chromatographic column is 30-40 ℃.
7. The process of claim 2, wherein the detector of the high performance liquid chromatography system is a DAD detector and the detection wavelength is 254 nm.
8. The process of claim 2, characterized by a stock solution of Gracilostao impurity H, I, J: weighing impurity H in a 100mL volumetric flask, adding mobile phase to dissolve to obtain a stock solution containing about 100ug of impurity H per 1mL, diluting to obtain a control solution containing about 1ug of impurity H per 1mL, and preparing I, J control solution according to the same method.
9. The process of claim 2, wherein the ticagrelor test solution: ticagrelor samples were weighed into 10mL volumetric flasks, dissolved with mobile phase to give about 1mg per 1mL of test solution, and diluted to about 1ug per 1mL of self-control solution.
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| CN113945672A (en) * | 2020-07-17 | 2022-01-18 | 武汉武药科技有限公司 | Method for detecting ticagrelor and related substances thereof |
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| CN113945672A (en) * | 2020-07-17 | 2022-01-18 | 武汉武药科技有限公司 | Method for detecting ticagrelor and related substances thereof |
| CN113945672B (en) * | 2020-07-17 | 2024-03-12 | 武汉武药科技有限公司 | Method for detecting ticagrelor and related substances thereof |
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