CN105301135A - Method for detecting chiral isomer content of ticagrelor by high performance liquid chromatography - Google Patents
Method for detecting chiral isomer content of ticagrelor by high performance liquid chromatography Download PDFInfo
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- CN105301135A CN105301135A CN201510812061.2A CN201510812061A CN105301135A CN 105301135 A CN105301135 A CN 105301135A CN 201510812061 A CN201510812061 A CN 201510812061A CN 105301135 A CN105301135 A CN 105301135A
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- ticagrelor
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Abstract
The invention discloses a method for determining ticagrelor and its chiral isomer by high performance liquid chromatography. The method adopts chiral column separation to determine the chiral isomer, and employs a main component self contrast technique without correction factor to conduct quantification on impurities. The method is simple and feasible to operate. The experimental results prove that the selected chromatographic conditions can well separate the principal component and its chiral isomer and better control the mass of ticagrelor crude drug, and also provide reference for preparation quality study.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, be specifically related to a kind of high performance liquid chromatography and be separated the method detecting chiral isomer in ticagrelor bulk drug.
Background technology
Ticagrelor (ticagrelor) is that the one developed by AstraZeneca drugmaker of Britain (AstraZeneca) has selective therapy acute coronary syndrome (acutecoronarysyndrome, ACS) new small molecule anticoagulation medicine, first oral reversibility adenosine diphosphate (ADP) (ADP) receptor antagonist, can the crucial target acceptor P2Y of Selective depression adenosine diphosphate (ADP)
12.Ticagrelor contains 6 chiral centers, have 64 chiral isomers, according to U.S. food Drug Administration (FDA) to the technical requirement with chiral center medicine, need to control the chiral isomer of medicine, but have no the report about ticagrelor isomeride analytical approach at present.
Summary of the invention
For ensureing the security of clinical application, inventor developed a kind of high performance liquid chromatography and be separated the method detecting chiral isomer in ticagrelor bulk drug, isomeride in ticagrelor bulk drug is analyzed, thus ensures Drug safety, quality controllability.
The object of this invention is to provide the method for chiral isomer in a kind of high performance liquid chromatography separation and detection ticagrelor bulk drug, the method that the present invention sets up accurately, favorable reproducibility, achieve the effective monitoring to ticagrelor chiral isomer impurity.
The present invention is achieved by the following technical solutions:
The invention provides the method for separating and detecting of the high performance liquid chromatography of a kind of ticagrelor bulk drug and chiral isomer thereof, it comprises the following steps:
1) the ticagrelor bulk drug got containing chiral isomer is appropriate, makes every 1ml about containing the sample solution of 2.0mg with ethanol;
2) get step 1) in ticagrelor sample solution appropriate, make every 1ml about containing the contrast solution of 4.0 μ g with ethanol;
3) get 1), 2) solution 10 μ l, inject high performance liquid chromatograph, complete the mensuration of ticagrelor isomeride;
Wherein, described high-efficient liquid phase chromatogram condition is as follows:
With the chromatographic column that polysaccharide derivates coating-type chiral chromatographic column is filler, preferably described chromatographic column is AD-H chromatographic column, 250mm × 4.6mm × 5 μm; Chromatographic column column temperature 38 ~ 42 DEG C;
Using the mixed solvent of normal hexane, ethanol, trifluoroacetic acid as mobile phase, the volume ratio of the normal hexane preferably in mobile phase, ethanol, trifluoroacetic acid is 82 ~ 84:16 ~ 18:0.6 ~ 0.8; Flow rate of mobile phase is 0.9 ~ 1.1ml/min;
Adopt UV-detector, determined wavelength is set to 250 ~ 260nm;
Here, described chiral isomer is the material shown in following seven kinds of structures:
The method for separating and detecting of the high performance liquid chromatography of above-mentioned ticagrelor bulk drug provided by the invention and chiral isomer thereof, test findings shows, chiral isomer impurity Y3, Y4, Y3 ', Y2, Y4 ', Y1, Y2 ' be respectively 1.1,1.0,1.0,1.0,1.0,0.9 relative to the correction factor of ticagrelor, correction factor, all within 0.9 ~ 1.1 scope, can adopt not correction up factor major component Self-control method to calculate.
In embodiments of the invention, the method for separating and detecting of the high performance liquid chromatography of ticagrelor bulk drug provided by the invention and chiral isomer thereof, wherein, the volume ratio of the normal hexane in described mobile phase, ethanol, trifluoroacetic acid is more preferably 83: 17:0.7.
In embodiments of the invention, the method for separating and detecting of the high performance liquid chromatography of ticagrelor bulk drug provided by the invention and chiral isomer thereof, wherein, described flow rate of mobile phase is more preferably 1ml/min.
In embodiments of the invention, the method for separating and detecting of the high performance liquid chromatography of ticagrelor bulk drug provided by the invention and chiral isomer thereof, wherein, described determined wavelength is 255nm.
In embodiments of the invention, the method for separating and detecting of the high performance liquid chromatography of ticagrelor bulk drug provided by the invention and chiral isomer thereof, wherein, described chromatographic column column temperature is 38 DEG C, 40 DEG C or 42 DEG C.
Analyze according to the synthetic route of ticagrelor in prior art and the design feature of compound, ticagrelor needs control 7 isomer impurities, the present invention adopts its chiral isomer of chiral column high performance liquid chromatography separation determination, adopts the major component Self-control method of the not correction up factor to carry out quantitatively to impurity; The method is easy to operation, and the chromatographic condition that experiment results proved is selected can be separated major component and chiral isomer thereof preferably, monitors the quality of ticagrelor bulk drug better, simultaneously also for the quality research of preparation provides reference.
Accompanying drawing explanation
Fig. 1 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 3 ticagrelor degree of separation solution.
Fig. 2 is the high-efficient liquid phase chromatogram of comparative example 1 ticagrelor degree of separation solution of the present invention.
Embodiment
For making the object, technical solutions and advantages of the present invention clearly understand, below in conjunction with embodiment, the present invention is described in more detail.Should be appreciated that, these describe just exemplary, and do not really want to limit the scope of the invention.
Embodiment 1
Instrument and chromatographic condition
Agilent1260 high performance liquid chromatograph; Chromatographic column is AD-H chromatographic column, 250mm × 4.6mm × 5 μm, chromatographic column column temperature 40 DEG C; Using the mixed solvent of normal hexane, ethanol, trifluoroacetic acid as mobile phase, the volume ratio of the normal hexane in mobile phase, ethanol, trifluoroacetic acid is 83:17:0.7, and flow rate of mobile phase is 1.0ml/min; Adopt UV-detector, determined wavelength is set to 255nm.
Experimental procedure
Get ticagrelor reference substance, chiral isomer impurity Y3, Y4, Y3 ', Y2, Y4 ', Y1, Y2 ' is appropriate, dissolves and dilute to make in every 1ml about to contain the mixed solution that each impurity and ticagrelor are respectively 200 μ g, as linear test stock solution with ethanol.Precision measures linear test stock solution 0.4ml, 1.0ml, 1.6ml, 2.0ml, 2.4ml, 3.0ml, 4.0ml and puts respectively in 10ml volumetric flask, is diluted to scale, shakes up with ethanol, as linear test serial solution.Precision measures each 10 μ l of linear test serial solution, injects high performance liquid chromatograph respectively, measures by described chromatographic condition, record chromatogram.With sample concentration (μ g/ml) be horizontal ordinate, peak area is the regression equation that ordinate calculates ticagrelor and each known impurities.The results are shown in following table:
Test findings shows, impurity Y3, Y4, Y3 ', Y2, Y4 ', Y1, Y2 ' be respectively 1.1,1.0,1.0,1.0,1.0,0.9 relative to the correction factor of ticagrelor, correction factor, all within 0.9 ~ 1.1 scope, can adopt not correction up factor major component Self-control method to calculate.
Embodiment 2
Instrument and chromatographic condition are with embodiment 1
Experimental procedure
The preparation of accuracy test stock solution: Example 1 neutral line test stock solution 5.0ml, puts in same 50ml measuring bottle, adds thinning agent and be diluted to scale, shake up, to obtain final product.
The preparation of accuracy test solution sees the following form:
Accurately pipetting 1ml accuracy stock solution by upper table puts in 10ml measuring bottle respectively, respectively adds about 20mg test sample in corresponding measuring bottle, adds that appropriate amount of ethanol is ultrasonic makes dissolving, is cooled to room temperature, is diluted to scale with ethanol, shake up, obtain accuracy test solution.The parallel preparation of each concentration level 3 parts of accuracy test solution.
Precision measures each 10 μ l of above-mentioned accuracy test need testing solution, injection liquid chromatography, record chromatogram.The accuracy of the method for detecting impurities adopting recovery test evaluation to set up, result is as follows:
Impurity Y
3accuracy test result:
Impurity Y
4accuracy test result:
Impurity Y
3' accuracy test result:
Impurity Y
2' accuracy test result:
Impurity Y
2accuracy test result:
Impurity Y
4' accuracy test result:
Impurity Y
1accuracy test result:
Conclusion: impurity Y
3accuracy test solution R1 ~ R3 average recovery rate 98.8% ~ 100.5%, impurity Y
4accuracy test solution R1 ~ R3 average recovery rate 99.8% ~ 101.0%, impurity Y
3' accuracy test solution R1 ~ R3 average recovery rate 103.3% ~ 111.4%, impurity Y
2' accuracy solution R1 ~ R3 average recovery rate 112.4% ~ 117.7%, impurity Y
2accuracy solution R1 ~ R3 average recovery rate 92.5% ~ 95.7%, impurity Y
4' accuracy solution R1 ~ R3 average recovery rate 89.3% ~ 91.3%, impurity Y
1accuracy solution R1 ~ R3 average recovery rate is 87.3% ~ 94.5%, and meet the requirements (80.0% ~ 120.0%).
Impurity Y
3, Y
4, Y
3', Y
2', Y
2, Y
4', Y
1the RSD value of 9 recovery data be respectively: 1.04%, 0.88%, 3.44%, 2.80%, 2.67%, 1.49%, 4.08%, all meet the requirements (RSD must not more than 10.0%).
Embodiment 3
Chromatographic condition
AD-H chromatographic column, 250mm × 4.6mm × 5 μm, chromatographic column column temperature 40 DEG C; Using the mixed solvent of normal hexane, ethanol, trifluoroacetic acid as mobile phase, the volume ratio of the normal hexane in mobile phase, ethanol, trifluoroacetic acid is 83:17:0.7, and flow rate of mobile phase is 1.0ml/min; Adopt UV-detector, determined wavelength is set to 255nm.
Experimental procedure
Get impurity Y
1, Y
2, Y
2' each 10mg and impurity Y
3+ Y
4, Y
3'+Y
4' each 40mg, put in 50ml measuring bottle, add appropriate amount of ethanol, ultrasonicly make dissolving, be cooled to room temperature, be diluted to scale with ethanol, shake up.Precision measures sample solution 1ml and puts in 100ml measuring bottle, is diluted to scale with ethanol, shakes up, as impurity stock solution.Get ticagrelor and be about 20mg, put in 10ml measuring bottle, add ethanol in proper amount and dissolve, then add 1.0ml impurity stock solution, be diluted to scale with ethanol, shake up, as degree of separation testing liquid.
Get ticagrelor and be about 20mg, put in 10ml measuring bottle, add appropriate amount of ethanol, ultrasonicly make dissolving, be cooled to room temperature, be diluted to scale with ethanol, shake up, as sample solution.Precision measures sample solution 1ml and puts in 100ml measuring bottle, is diluted to scale with ethanol, shakes up.Precision measures 2ml, puts in 10ml measuring bottle, is diluted to scale with ethanol, shake up, in contrast solution.
Precision measures blank solvent (ethanol), degree of separation testing liquid, sample solution, each 10 μ L of contrast solution, and sample introduction measures, record chromatogram.Test findings shows, does not detect isomer impurities in sample, and the degree of separation between each composition of degree of separation solution is all greater than 1.5.
Embodiment 4
Chromatographic condition
AD-H chromatographic column, 250mm × 4.6mm × 5 μm, chromatographic column column temperature 38 DEG C; Using the mixed solvent of normal hexane, ethanol, trifluoroacetic acid as mobile phase, the volume ratio of the normal hexane in mobile phase, ethanol, trifluoroacetic acid is 83:17:0.7, and flow rate of mobile phase is 1.0ml/min; Adopt UV-detector, determined wavelength is set to 255nm.
All the other operation stepss and condition are all with embodiment 3.
Test findings shows, does not detect isomeride in sample, and the degree of separation between each composition of degree of separation solution is all greater than 1.5.
Embodiment 5
Chromatographic condition
AD-H chromatographic column, 250mm × 4.6mm × 5 μm, chromatographic column column temperature 42 DEG C; Using the mixed solvent of normal hexane, ethanol, trifluoroacetic acid as mobile phase, the volume ratio of the normal hexane in mobile phase, ethanol, trifluoroacetic acid is 83:17:0.7, and flow rate of mobile phase is 1.0ml/min; Adopt UV-detector, determined wavelength is set to 255nm.
All the other operation stepss and condition are all with embodiment 3.
Test findings shows, does not detect isomeride in sample, and the degree of separation between each composition of degree of separation solution is all greater than 1.5.
Comparative example 1
Chromatographic condition
AD-H chromatographic column, 250mm × 4.6mm × 5 μm, chromatographic column column temperature 40 DEG C; Using the mixed solvent of normal hexane, ethanol, trifluoroacetic acid as mobile phase, the volume ratio of the normal hexane in mobile phase, ethanol, trifluoroacetic acid is 80:20:0.5, and flow rate of mobile phase is 1.0ml/min; Adopt UV-detector, determined wavelength is set to 255nm.
Degree of separation testing liquid preparation reference example 3.
Precision measures blank solvent, each 10 μ L of degree of separation testing liquid, and sample introduction measures, record chromatogram.Test findings shows, degree of separation solution major component peak is less with impurity peaks degree of separation afterwards, can not baseline separation, and has two impurity peaks to overlap.
Although describe embodiments of the present invention in detail, it should be understood that when without departing from the spirit and scope of the present invention, various change, replacement and change can be made to embodiments of the present invention.
Claims (7)
1. detect a high performance liquid chromatography method for chiral isomer in ticagrelor bulk drug, comprise the following steps:
1) the ticagrelor bulk drug got containing chiral isomer is appropriate, makes every 1ml about containing the sample solution of 2.0mg with ethanol;
2) get step 1) in ticagrelor sample solution appropriate, make every 1ml about containing the contrast solution of 4.0 μ g with ethanol;
3) get 1), 2) each 10 μ l of solution, inject high performance liquid chromatograph respectively, by described chromatographic condition measure, record chromatogram, complete the mensuration of ticagrelor chiral isomer;
4) the chiral content of isomer of major component Self-control method of the not correction up factor is adopted to calculate;
Wherein, described high-efficient liquid phase chromatogram condition is as follows:
With the chromatographic column that polysaccharide derivates coating-type chiral chromatographic column is filler, chromatographic column column temperature 38 ~ 42 DEG C; Using the mixed solvent of normal hexane, ethanol, trifluoroacetic acid as mobile phase; Flow rate of mobile phase is 0.9 ~ 1.1ml/min; Adopt UV-detector, determined wavelength is set to 250 ~ 260nm;
Wherein, described chiral isomer is the material shown in following seven kinds of structures:
2. high effective liquid chromatography for detecting according to claim 1, wherein, the volume ratio of the normal hexane in mobile phase, ethanol, trifluoroacetic acid is 82 ~ 84:16 ~ 18:0.6 ~ 0.8.
3. high effective liquid chromatography for detecting according to claim 2, wherein, the volume ratio of the normal hexane in mobile phase, ethanol, trifluoroacetic acid is 83: 17:0.7.
4. high effective liquid chromatography for detecting according to claim 1, wherein, flow rate of mobile phase is 1ml/min.
5. high effective liquid chromatography for detecting according to claim 1, wherein, determined wavelength is 255nm.
6. high effective liquid chromatography for detecting according to claim 1, wherein, chromatographic column column temperature is 38 DEG C, 40 DEG C or 42 DEG C.
7. high effective liquid chromatography for detecting according to claim 6, wherein, chromatographic column column temperature is 40 DEG C.
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| CN106645528A (en) * | 2016-11-25 | 2017-05-10 | 成都欣捷高新技术开发股份有限公司 | High performance liquid chromatography detection method of content of chiral isomers of ticagrelor |
| 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 |
| 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 |
| CN112557520A (en) * | 2019-09-25 | 2021-03-26 | 北京济美堂医药研究有限公司 | Method for detecting TGR-1-corresponding isomer in TGR-1 |
| CN114689761A (en) * | 2022-05-31 | 2022-07-01 | 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 |
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| CN114689761A (en) * | 2022-05-31 | 2022-07-01 | 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 |
| 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 |
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