CN105301135B - The method of chiral isomer content in high performance liquid chromatography detection ticagrelor - Google Patents
The method of chiral isomer content in high performance liquid chromatography detection ticagrelor Download PDFInfo
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- CN105301135B CN105301135B CN201510812061.2A CN201510812061A CN105301135B CN 105301135 B CN105301135 B CN 105301135B CN 201510812061 A CN201510812061 A CN 201510812061A CN 105301135 B CN105301135 B CN 105301135B
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Abstract
The invention discloses a kind of ticagrelor and its high-efficient liquid phase chromatogram process measuring method of chiral isomer, the present invention is quantified using its chiral isomer of chiral column separation determination using the principal component Self-control method for being not added with correction factor to impurity.This method is easy to operation, and the chromatographic condition that experiment results proved is selected can preferably separate principal component and its chiral isomer, the quality of ticagrelor bulk drug be better controled over, while also providing reference for the quality research of preparation.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, and in particular to a kind of high performance liquid chromatography separation detection ticagrelor
The method of chiral isomer in bulk drug.
Background technology
Ticagrelor (ticagrelor) is one developed by AstraZeneca drugmaker of Britain (AstraZeneca)
The new small molecule with selective therapy acute coronary syndrome (acute coronary syndrome, ACS) is planted to resist
Blood-clotting agent, is first oral invertibity adenosine diphosphate (ADP) (ADP) receptor antagonist, can be with selective depression adenosine diphosphate (ADP)
Crucial target acceptor P2Y12.Ticagrelor contains 6 chiral centres, 64 chiral isomers is had, according to U.S.'s food and medicine
Surveillance Authority (FDA) to the technical requirements with chiral centre medicine, it is necessary to be controlled to the chiral isomer of medicine, but
It is to have no the report on ticagrelor isomers analysis method at present.
The content of the invention
It is auspicious for lattice inventor developed a kind of high performance liquid chromatography separation detection to ensure the security of clinical application
The method of chiral isomer in the bulk drug of Lip river, is analyzed the isomers in ticagrelor bulk drug, so as to ensure medicine
Security, quality controllability.
It is an object of the invention to provide chiral different in a kind of separation of high performance liquid chromatography and detection ticagrelor bulk drug
The method of structure body, the method for the invention set up is accurate, favorable reproducibility, realizes to the effective of ticagrelor chiral isomer impurity
Monitoring.
The present invention is achieved by the following technical solutions：
The invention provides a kind of separation of ticagrelor bulk drug and its high performance liquid chromatography of chiral isomer inspection
Survey method, it comprises the following steps：
1) take the ticagrelor bulk drug containing chiral isomer appropriate, samples of every 1ml containing about 2.0mg is made of ethanol
Solution；
2) take step 1) in ticagrelor sample solution it is appropriate, contrast solutions of every 1ml containing about 4.0 μ g is made of ethanol；
3) the μ l of solution 10 1), 2) are taken, high performance liquid chromatograph is injected, the measure of ticagrelor isomers is completed；
Wherein, the high-efficient liquid phase chromatogram condition is as follows：
Using polysaccharide derivates coating-type chiral chromatographic column as the chromatographic column of filler, preferably described chromatographic column is AD-H chromatograms
Post, 250mm × 4.6mm × 5 μm；38~42 DEG C of chromatographic column column temperature；
Using n-hexane, ethanol, trifluoroacetic acid mixed solvent as mobile phase, n-hexane, second preferably in mobile phase
Alcohol, the volume ratio of trifluoroacetic acid are 82~84:16~18:0.6~0.8；Flow rate of mobile phase is 0.9~1.1ml/min；
Using UV-detector, Detection wavelength is set to 250~260nm；
Here, the chiral isomer is the material shown in following seven kinds of structures：
Above-mentioned ticagrelor bulk drug and its separation inspection of the high performance liquid chromatography of chiral isomer that the present invention is provided
Survey method, result of the test shows, chiral isomer impurity Y3, Y4, Y3 ', Y2, Y4 ', Y1, Y2 ' relative to the correction of ticagrelor
The factor is respectively 1.1,1.0,1.0,1.0,1.0,0.9, and correction factor can use within the scope of 0.9~1.1 and be not added with school
Positive divisor principal component Self-control method is calculated.
In embodiments of the invention, the present invention is provided ticagrelor bulk drug and its efficient liquid of chiral isomer
The method for separating and detecting of phase chromatography, wherein, the volume ratio of n-hexane, ethanol, trifluoroacetic acid in the mobile phase is more excellent
Selection of land is 83: 17：0.7.
In embodiments of the invention, the present invention is provided ticagrelor bulk drug and its efficient liquid of chiral isomer
The method for separating and detecting of phase chromatography, wherein, the flow rate of mobile phase is more preferably 1ml/min.
In embodiments of the invention, the present invention is provided ticagrelor bulk drug and its efficient liquid of chiral isomer
The method for separating and detecting of phase chromatography, wherein, the Detection wavelength is 255nm.
In embodiments of the invention, the present invention is provided ticagrelor bulk drug and its efficient liquid of chiral isomer
The method for separating and detecting of phase chromatography, wherein, the chromatographic column column temperature is 38 DEG C, 40 DEG C or 42 DEG C.
Analyzed according to the design feature of the synthetic route of ticagrelor in the prior art and compound, ticagrelor
Need to control 7 isomer impurities, the present invention determines its chiral isomer using chiral column high performance liquid chromatography separation, using not
The principal component Self-control method of the correction up factor is quantified to impurity；This method is easy to operation, experiment results proved choosing
Chromatographic condition can preferably separate principal component and its chiral isomer, preferably monitor the quality of ticagrelor bulk drug,
Also provide reference for the quality research of preparation simultaneously.
Brief description of the drawings
Fig. 1 is the high-efficient liquid phase chromatogram of the ticagrelor separating degree solution of the embodiment of the present invention 3.
Fig. 2 is the high-efficient liquid phase chromatogram of the ticagrelor separating degree solution of comparative example 1 of the present invention.
Embodiment
To make the object, technical solutions and advantages of the present invention of greater clarity, with reference to embodiment, to this
Invention is further described.It should be understood that these descriptions are merely illustrative, and it is not intended to limit the scope of the present invention.
Embodiment 1
Instrument and chromatographic condition
The high performance liquid chromatographs of Agilent 1260；Chromatographic column is AD-H chromatographic columns, 250mm × 4.6mm × 5 μm, chromatographic column
40 DEG C of column temperature；Using n-hexane, ethanol, trifluoroacetic acid mixed solvent as mobile phase, n-hexane, ethanol in mobile phase, trifluoro second
The volume ratio of acid is 83:17:0.7, flow rate of mobile phase is 1.0ml/min；Using UV-detector, Detection wavelength is set to 255nm.
Experimental procedure
Take ticagrelor reference substance, chiral isomer impurity Y3, Y4, Y3 ', Y2, Y4 ', Y1, Y2 ' in right amount, is dissolved with ethanol
And it is respectively 200 μ g mixed solution that dilution, which is made in every 1ml containing about each impurity and ticagrelor, is storeed as linear test
Liquid.Precision measures linear test stock solution 0.4ml, 1.0ml, 1.6ml, 2.0ml, 2.4ml, 3.0ml, 4.0ml and puts 10ml respectively
In volumetric flask, scale is diluted to ethanol, is shaken up, linear test serial solution is used as.Precision measures linear test serial solution
Each 10 μ l, are injected separately into high performance liquid chromatograph, are determined by described chromatographic condition, record chromatogram.With sample concentration (μ g/
Ml it is) that abscissa, peak area are that ordinate calculates ticagrelor and the regression equation of each known impurities.As a result it see the table below:
Result of the test shows, impurity Y3, Y4, Y3 ', Y2, Y4 ', Y1, Y2 ' distinguish relative to the correction factor of ticagrelor
For 1.1,1.0,1.0,1.0,1.0,0.9, correction factor, can be using being not added with correction factor master within the scope of 0.9~1.1
Composition Self-control method is calculated.
Embodiment 2
Instrument and chromatographic condition be the same as Example 1
Experimental procedure
The preparation of accuracy test stock solution：Linear test stock solution 5.0ml in Example 1, puts same 50ml amounts
In bottle, plus diluent is diluted to scale, shakes up, produces.
The preparation of accuracy test solution see the table below：
1ml degrees of accuracy stock solution is accurately pipetted by upper table to put respectively in 10ml measuring bottles, it is each in corresponding measuring bottle to add about
20mg test samples, plus appropriate amount of ethanol ultrasound make dissolving, are cooled to room temperature, and scale is diluted to ethanol, shake up, and produce degree of accuracy examination
Test solution.Each concentration level is parallel to prepare 3 parts of accuracy test solution.
Precision measures each 10 μ l of above-mentioned accuracy test need testing solution, injects liquid chromatograph, records chromatogram.Using
The degree of accuracy for the method for detecting impurities that recovery test evaluation is set up, it is as a result as follows：
Impurity Y3Accuracy test result：
Impurity Y4Accuracy test result：
Impurity Y3' accuracy test result：
Impurity Y2' accuracy test result：
Impurity Y2Accuracy test result：
Impurity Y4' accuracy test result：
Impurity Y1Accuracy test result：
Conclusion：Impurity Y3Accuracy test solution R1~R3 average recovery rates are in 98.8%~100.5%, impurity Y4Accurately
Testing liquid R1~R3 average recovery rates are spent in 99.8%~101.0%, impurity Y3' accuracy test solution R1~R3 averagely returns
Yield is in 103.3%~111.4%, impurity Y2' degree of accuracy solution R1~R3 average recovery rates are miscellaneous 112.4%~117.7%
Matter Y2Degree of accuracy solution R1~R3 average recovery rates are in 92.5%~95.7%, impurity Y4' degree of accuracy solution R1~R3 averagely reclaims
Rate is in 89.3%~91.3%, impurity Y1Degree of accuracy solution R1~R3 average recovery rates meet the requirements 87.3%~94.5%
(80.0%~120.0%).
Impurity Y3、Y4、Y3’、Y2’、Y2、Y4’、Y1The RSD values of 9 rate of recovery data be respectively：1.04%th, 0.88%,
3.44%th, 2.80%, 2.67%, 1.49%, 4.08%, meet the requirements (RSD must not exceed 10.0%).
Embodiment 3
Chromatographic condition
AD-H chromatographic columns, 250mm × 4.6mm × 5 μm, 40 DEG C of chromatographic column column temperature；With n-hexane, ethanol, trifluoroacetic acid
Mixed solvent is as mobile phase, and the volume ratio of n-hexane, ethanol, trifluoroacetic acid in mobile phase is 83:17:0.7, mobile phase
Flow velocity is 1.0ml/min；Using UV-detector, Detection wavelength is set to 255nm.
Experimental procedure
Take impurity Y1、Y2、Y2' each 10mg and impurity Y3+Y4、Y3’+Y4' each 40mg, put in 50ml measuring bottles, plus appropriate amount of ethanol,
Ultrasound makes dissolving, is cooled to room temperature, and scale is diluted to ethanol, shakes up.Precision measures sample solution 1ml and put in 100ml measuring bottles,
Scale is diluted to ethanol, is shaken up, impurity stock solution is used as.Ticagrelor about 20mg is taken, is put in 10ml measuring bottles, plus ethanol in proper amount
Dissolving, adds 1.0ml impurity stock solutions, is diluted to scale with ethanol, shakes up, be used as separating degree testing liquid.
Ticagrelor about 20mg is taken, is put in 10ml measuring bottles, plus appropriate amount of ethanol, ultrasound makes dissolving, is cooled to room temperature, uses ethanol
Scale is diluted to, is shaken up, sample solution is used as.Precision measures sample solution 1ml and put in 100ml measuring bottles, and quarter is diluted to ethanol
Degree, shakes up.Precision measures 2ml, puts in 10ml measuring bottles, scale is diluted to ethanol, shake up, be used as contrast solution.
Precision measures each 10 μ L of blank solvent (ethanol), separating degree testing liquid, sample solution, contrast solution, and sample introduction is surveyed
It is fixed, record chromatogram.Result of the test shows, does not detect the separation between isomer impurities, each composition of separating degree solution in sample
Degree is all higher than 1.5.
Embodiment 4
Chromatographic condition
AD-H chromatographic columns, 250mm × 4.6mm × 5 μm, 38 DEG C of chromatographic column column temperature；With n-hexane, ethanol, trifluoroacetic acid
Mixed solvent is as mobile phase, and the volume ratio of n-hexane, ethanol, trifluoroacetic acid in mobile phase is 83:17:0.7, mobile phase
Flow velocity is 1.0ml/min；Using UV-detector, Detection wavelength is set to 255nm.
Remaining operating procedure and the equal be the same as Example 3 of condition.
Result of the test shows, does not detect that the separating degree between isomers, each composition of separating degree solution is all higher than in sample
1.5。
Embodiment 5
Chromatographic condition
AD-H chromatographic columns, 250mm × 4.6mm × 5 μm, 42 DEG C of chromatographic column column temperature；With n-hexane, ethanol, trifluoroacetic acid
Mixed solvent is as mobile phase, and the volume ratio of n-hexane, ethanol, trifluoroacetic acid in mobile phase is 83:17:0.7, mobile phase
Flow velocity is 1.0ml/min；Using UV-detector, Detection wavelength is set to 255nm.
Remaining operating procedure and the equal be the same as Example 3 of condition.
Result of the test shows, does not detect that the separating degree between isomers, each composition of separating degree solution is all higher than in sample
1.5。
Comparative example 1
Chromatographic condition
AD-H chromatographic columns, 250mm × 4.6mm × 5 μm, 40 DEG C of chromatographic column column temperature；With n-hexane, ethanol, trifluoroacetic acid
Mixed solvent is as mobile phase, and the volume ratio of n-hexane, ethanol, trifluoroacetic acid in mobile phase is 80:20:0.5, mobile phase
Flow velocity is 1.0ml/min；Using UV-detector, Detection wavelength is set to 255nm.
Separating degree testing liquid prepares reference implementation example 3.
Precision measures each 10 μ L of blank solvent, separating degree testing liquid, and sample introduction is determined, and records chromatogram.Result of the test table
Bright, separating degree solution principal component peak and impurity peaks separating degree afterwards are smaller, it is impossible to baseline separation, and have two impurity peaks weights
Close.
Although embodiments of the present invention are described in detail, it should be understood that, without departing from the present invention's
In the case of spirit and scope, embodiments of the present invention can be made with various changes, replace and change.
Claims (6)
1. a kind of high performance liquid chromatography method for detecting chiral isomer in ticagrelor bulk drug, comprises the following steps：
1) take the ticagrelor bulk drug containing chiral isomer appropriate, samples of every 1ml containing about 2.0mg is made of ethanol molten
Liquid；
2) take step 1) in ticagrelor sample solution it is appropriate, contrast solutions of every 1ml containing about 4.0 μ g is made of ethanol；
3) each 10 μ l of solution 1), 2) are taken, high performance liquid chromatograph is injected separately into, determined by described chromatographic condition, color is recorded
Spectrogram, completes the measure of ticagrelor chiral isomer；
4) calculated using the chiral content of isomer of principal component Self-control method for being not added with correction factor；
Wherein, the high-efficient liquid phase chromatogram condition is as follows：
AD-H chromatographic columns, 38~42 DEG C of chromatographic column column temperature；Using n-hexane, ethanol, trifluoroacetic acid mixed solvent as mobile phase,
The volume ratio of n-hexane, ethanol, trifluoroacetic acid in mobile phase is 82~84:16~18:0.6~0.8；Flow rate of mobile phase is
0.9~1.1ml/min；Using UV-detector, Detection wavelength is set to 250~260nm；
Wherein, the chiral isomer is impurity Y1, Y2, Y2 ', Y3, Y4, Y3 ' and Y4 '：
Impurity Y1 structure is：
Impurity Y2 structure is：
Impurity Y2 ' structure is：
Impurity Y3 structure is：
Impurity Y4 structure is：
Impurity Y3 ' structure is：
Impurity Y4 ' structure is：
2. the high performance liquid chromatography method of chiral isomer in ticagrelor bulk drug is detected according to claim 1, its
In, the volume ratio of n-hexane, ethanol, trifluoroacetic acid in mobile phase is 83: 17：0.7.
3. the high performance liquid chromatography method of chiral isomer in ticagrelor bulk drug is detected according to claim 1, its
In, flow rate of mobile phase is 1ml/min.
4. the high performance liquid chromatography method of chiral isomer in ticagrelor bulk drug is detected according to claim 1, its
In, Detection wavelength is 255nm.
5. the high performance liquid chromatography method of chiral isomer in ticagrelor bulk drug is detected according to claim 1, its
In, chromatographic column column temperature is 38 DEG C, 40 DEG C or 42 DEG C.
6. the high performance liquid chromatography method of chiral isomer in ticagrelor bulk drug is detected according to claim 5, its
In, chromatographic column column temperature is 40 DEG C.
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| CN107778312A (en) * | 2016-08-30 | 2018-03-09 | 重庆植恩药业有限公司 | Ticagrelor impurity and its production and use |
| CN106645528B (en) * | 2016-11-25 | 2018-08-31 | 成都欣捷高新技术开发股份有限公司 | A kind of high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content |
| CN109856255B (en) * | 2017-11-30 | 2022-04-05 | 四川海思科制药有限公司 | Analysis method for controlling isomer impurity content of ticagrelor intermediate |
| CN112557520B (en) * | 2019-09-25 | 2023-06-30 | 北京济美堂医药研究有限公司 | Method for detecting TGR-1-corresponding isomer in TGR-1 |
| CN114689761B (en) * | 2022-05-31 | 2023-03-03 | 天津市汉康医药生物技术有限公司 | Method for detecting parecoxib sodium positional isomer through liquid chromatography |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2589587A1 (en) * | 2011-11-04 | 2013-05-08 | Chemo Ibérica, S.A. | Synthesis of nitrogen substituted cyclopropanes |
| CN104634887A (en) * | 2013-11-11 | 2015-05-20 | 广东东阳光药业有限公司 | Method for separating and measuring ticagrelor and optical isomer of ticagrelor |
| CN104640864A (en) * | 2012-07-04 | 2015-05-20 | 力奇制药公司 | Ticagrelor adducts with divalent metal salts |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2589587A1 (en) * | 2011-11-04 | 2013-05-08 | Chemo Ibérica, S.A. | Synthesis of nitrogen substituted cyclopropanes |
| CN104640864A (en) * | 2012-07-04 | 2015-05-20 | 力奇制药公司 | Ticagrelor adducts with divalent metal salts |
| CN104634887A (en) * | 2013-11-11 | 2015-05-20 | 广东东阳光药业有限公司 | Method for separating and measuring ticagrelor and optical isomer of ticagrelor |
Non-Patent Citations (1)
| Title |
|---|
| 王曼曼 等;犬血浆中替格瑞洛及其活性代谢产物的LC-MS/MS法测定;《中国医药工业杂志》;20141231;第45卷(第11期);全文 * |
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