CN106645528B - A kind of high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content - Google Patents
A kind of high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content Download PDFInfo
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Abstract
The invention discloses the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content, it uses with Silica Surface binding fibers element three (3,5 diChloroaniline carbamates) be filler chiral chromatographic column, using the mixed solution of grade alkane lower alcohol as mobile phase A, using dichloromethane and/or chloroform as Mobile phase B.The present invention is bonded with cellulose iii (3 using Silica Surface, 5 diChloroaniline carbamates) it is the chiral chromatographic column of filler and gradient elution is mutually carried out using Suitable flow, fast and effeciently disposably detach all chiral isomer impurity of ticagrelor, effective detection method is provided for prosecution ticagrelor isomers, ensure that ticagrelor product quality and drug safety；The quantitative determination of impurity is carried out using Self-control method, easy to operate, testing cost is low and with good sensitivity, linear, specificity, precision, accuracy, stability and durability, is the effective detection method for controlling content of isomer.
Description
Technical field
The invention belongs to the research and application technical fields in pharmaceutical chemistry, more particularly, are related to a kind of ticagrelor hand
The high-efficiency liquid chromatography method for detecting of property content of isomer.
Background technology
Ticagrelor (ticagrelor) is a kind of novel, tool researched and developed by Astrazeneca AB (AstraZeneca)
Selective small molecule anticoagulant, chemical structural formula is as shown in following formula 1：
Contain 6 asymmetric carbon atoms in ticagrelor molecular structure, in practical building-up process and can be produced in storage
Raw impurity, wherein chiral isomer impurity is one of its major impurity, and conventional analyzing detecting method is difficult that separation is numerous
Chiral isomer impurity.Have document or patent report uses cellulose family (or polysaccharide derivates) for the chiral chromatogram of filler
The method of post detection, but be the pillar of Silica Surface coated fiber element class (or polysaccharide derivates), such pillar equilibration time
It is longer, stability is bad, reproducibility is poor, the pillar service life is shorter, and can not use dichloromethane, chloroform equal solvent be stream
Dynamic phase.
Invention content
In order to solve the problems in the existing technology, the object of the present invention is to provide one kind can effectively detect it is auspicious for lattice
In Lip river chiral isomer content and ensure drug safety and reliability ticagrelor chiral isomer content it is efficient
Liquid chromatography detecting method.
The invention discloses a kind of high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content, use with silicon
Glue surface bond cellulose-three (3,5- diChloroaniline carbamate) is the chiral chromatographic column of filler, rudimentary with lower paraffin hydrocarbon-
The mixed solution of alcohol is mobile phase A, using dichloromethane and/or chloroform as Mobile phase B.
According to one embodiment of the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content of the present invention, institute
It states detection method and specifically includes following steps：
A) ticagrelor reference substance and ticagrelor chiral isomer reference substance are weighed respectively, simultaneously using absolute ethyl alcohol dissolving
Dilution is made in every 1ml containing about the system suitability solution of ticagrelor 1mg, 2 μ g of each chiral isomer；
B) ticagrelor sample is weighed, the test sample that the ticagrelor containing 1mg in every 1ml is configured to using absolute ethyl alcohol is molten
Liquid；
C) utilize absolute ethyl alcohol that the test solution is diluted 1000 times of solution as a contrast；
D) each 10 μ l of solution for taking step a), step b), step c) respectively, are injected separately into high performance liquid chromatograph and carry out
It measures, records chromatogram, the measurement of ticagrelor chiral isomer is completed, using main composition Self-control method to ticagrelor hand
The content of property isomers is calculated；
According to one embodiment of the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content of the present invention, stream
The flow velocity of dynamic phase is 0.8~1.2ml/min, and chromatographic column column temperature is 22~28 DEG C；Detector is UV detector, and Detection wavelength is
250~350nm.
According to one embodiment of the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content of the present invention, institute
It is at least one of n-hexane, pentane, hexamethylene and normal heptane to state lower paraffin hydrocarbon, and the lower alcohol is isopropanol, methanol
At least one of with ethyl alcohol, the volume ratio of lower paraffin hydrocarbon and lower alcohol is in the mixed solution of the lower paraffin hydrocarbon-lower alcohol
100:10~120:10.
According to one embodiment of the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content of the present invention, institute
State the mixed solution that mobile phase A is n-hexane-isopropanol-methanol, wherein the volume ratio of n-hexane-isopropanol-methanol is (300
~330):(17~12):(17~12).
According to one embodiment of the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content of the present invention, institute
Stating chiral chromatographic column isIC、IA andIB chiral chromatographic columns
In one kind.
According to one embodiment of the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content of the present invention, press
It is eluted according to gradient shown in following table：
。
According to one embodiment of the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content of the present invention, replace
The chiral isomer of Ge Ruiluo is substance shown in seven kinds of structures listed in Table：
。
According to one embodiment of the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content of the present invention, stream
The flow velocity of dynamic phase is 1ml/min, Detection wavelength 300nm, and chiral chromatographic column isIC, chromatographic column column temperature
It is 22 DEG C, 25 DEG C or 28 DEG C.
The present invention detaches ticagrelor chiral isomer using high performance liquid chromatography and using chiral chromatographic column,
The compound chromatography peak energy of ticagrelor is effective in formula 1 and its seven kinds of chiral isomers realize separation, and right using itself
The quantitative determination of impurity is carried out according to method, easy to operate, testing cost is low and with good sensitivity, linear, specificity, precision
Degree, accuracy, stability and durability are a kind of effective detection methods for controlling ticagrelor isomers, to protect
Ticagrelor product quality and patient medication safety are demonstrate,proved.
Description of the drawings
Fig. 1 shows that detection method using the present invention schemes the HPLC that system suitability solution detects in embodiment 1.
Fig. 2 shows the HPLC figures that detection method using the present invention in embodiment 1 detects test solution.
Fig. 3 shows that detection method schemes the HPLC that system suitability solution detects in comparative example 1.
Fig. 4 shows that detection method schemes the HPLC that system suitability solution detects in comparative example 2.
Fig. 5 shows that detection method schemes the HPLC that system suitability solution detects in comparative example 3.
Fig. 6 shows that detection method schemes the HPLC that system suitability solution detects in comparative example 4.
Specific implementation mode
All features disclosed in this specification or disclosed all methods or in the process the step of, in addition to mutually exclusive
Feature and/or step other than, can combine in any way.
Any feature disclosed in this specification unless specifically stated can be equivalent or with similar purpose by other
Alternative features are replaced.That is, unless specifically stated, each feature is an example in a series of equivalent or similar characteristics
.
The high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content of the present invention will be carried out in detail below
Explanation.
Exemplary embodiment according to the present invention, the present invention are used with plain-three (3, the 5- dichloro-benzenes of Silica Surface binding fibers
Carbamate) be filler chiral chromatographic column, using the mixed solution of lower paraffin hydrocarbon-lower alcohol as mobile phase A, with dichloromethane
Alkane and/or chloroform are Mobile phase B.The present invention is by using more stable plain-three (the 3,5- diChloroanilines of Silica Surface binding fibers
Carbamate) be filler chiral chromatographic column, solve silica gel show coated fiber element class (or polysaccharide derivates) the chromatographic column longevity
Order short, easy that (class requirement of reagent is higher) is damaged by reagent, the poor problem of durability.Although coating-type chromatographic column and key
Mould assembly chromatographic column is only that the fixed form of its stationary phase has differences, but it is apparent poor to the selectivity presence of compound
It is different, thus belong to entirely different chromatographic column.Contain 6 asymmetric carbon atoms in ticagrelor molecular structure, was actually synthesizing
In journey and impurity is will produce in storage, wherein chiral isomer impurity is one of its major impurity, and conventional analysis inspection
Survey method is difficult the numerous chiral isomer impurity of separation.And chiral separation chromatographic column is numerous, mainly cellulose family, albumen
Class, polysaccharide, crown ether-like.Cellulose chromatography column is broadly divided into coating-type and bonding type chromatographic column, and replaces the chirality sides Ge Ruiluo at present
Method is mainly coating-type chromatographic column, and such chromatographic column solvent compatibility is narrow, there is larger limitation to solvent and diluent；Convection current
Dynamic equal levels are more demanding, and part domestic manufacturer reagent cannot be satisfied analysis and require；Service life is shorter, to cause chromatographic column to replace
Durability it is poor.Bonding type chromatographic column is relative to coating-type chromatographic column, the solvent type newly increased, gives Bonded Phase special choosing
Select ability.Therefore our company develops Bonded Phase and replaces Ge Ruiluo chirality development approaches, has expanded solvent type, can be compatible with dichloro
Most of organic solvents such as methane and/or chloroform, therefore the dissolubility of compound is not only improved, while also increasing to compound
Unique selectivity, so the numerous isomer impurities of ticagrelor can be efficiently separated.And intrinsic steady of bonded-phase chromatography column
It is qualitative and and durability, further increase the stability and reproducibility of detection method, to make the present invention be much better than at present using apply
The type of applying chromatography column method.
Wherein, the chemical structural formula of ticagrelor is as shown in following formula 1：
Also, the chiral isomer of ticagrelor is substance shown in seven kinds of structures listed by the following table 1：
Seven kinds of chiral isomer structures of 1 ticagrelor of table
Lower paraffin hydrocarbon can be at least one of n-hexane, pentane, hexamethylene and normal heptane, and lower alcohol can be different
At least one of propyl alcohol, methanol and ethyl alcohol, the volume of lower paraffin hydrocarbon and lower alcohol in the mixed solution of lower paraffin hydrocarbon-lower alcohol
Than being 100:10~120:10.According to a preferred embodiment of the invention, the mobile phase A used is n-hexane-isopropanol-methanol
Mixed solution, wherein the volume ratio of n-hexane-isopropanol-methanol is (300~330):(17~12):(17~12).
The present invention uses plain-three (the 3,5- diChloroanilines carbamates) of Silica Surface binding fibers for the chiral color of filler
Compose column (such as：IC、IA andAppointing in IB chiral chromatographic columns
What is a kind of).
Specifically, detection method of the invention can specifically include following steps：
A) ticagrelor reference substance and ticagrelor chiral isomer reference substance are weighed respectively, simultaneously using absolute ethyl alcohol dissolving
Dilution is made in every 1ml containing about the system suitability solution of ticagrelor 1mg, 2 μ g of each chiral isomer；
B) ticagrelor sample is weighed, the test sample that the ticagrelor containing 1mg in every 1ml is configured to using absolute ethyl alcohol is molten
Liquid；
C) utilize absolute ethyl alcohol that the test solution is diluted 1000 times of solution as a contrast；
D) each 10 μ l of solution for taking step a), step b), step c) respectively, are injected separately into high performance liquid chromatograph and carry out
It measures, records chromatogram, the measurement of ticagrelor chiral isomer is completed, using main composition Self-control method to ticagrelor hand
The content of property isomers is calculated；
Wherein, the testing conditions of high performance liquid chromatography are specially：The flow velocity of mobile phase is 0.8~1.2ml/min, chromatographic column
Column temperature is 22~28 DEG C；Detector is UV detector, and Detection wavelength is 250~350nm.It is further preferred that mobile phase
Flow velocity is 1ml/min, Detection wavelength 300nm, and chiral chromatographic column isIC, chromatographic column column temperature are 25 DEG C.
When elution, eluted preferably by gradient shown in the following table 2.
2 elution program of table
According to the existing stability feature for wanting ticagrelor production line and compound, 7 kinds of chiral isomers are mainly controlled
Impurity, the present invention are detached using high performance liquid chromatography and in conjunction with particular chiral chromatographic column, the chemical combination of ticagrelor in formula 1
It looks for spectral peak effectively can realize separation with its 7 kinds of chiral isomers, is quantitatively surveyed moreover, carrying out impurity using Self-control method
It is fixed, it is easy to operate, testing cost is low and has good sensitivity and specificity, it is auxiliary control ticagrelor chiral isomer
Effective detection method of content, to ensure that the product quality and patient medication safety of ticagrelor.
Below in conjunction with specific embodiment and test example to the efficient liquid phase of ticagrelor chiral isomer content of the present invention
The preparation method of chromatographic detection method is described further.
Embodiment 1：
Detecting instrument：Shimadzu LC-2030 high performance liquid chromatographs.
Chromatographic condition：Chromatographic column isIC columns (250 × 4.6mm, 5 μm), chromatographic column column temperature are 25
℃；Using UV detector, Detection wavelength is set as 300nm；Flow rate of mobile phase is 1.0ml/min；With n-hexane-isopropanol-
Methanol (330:15:15) it is mobile phase A, using dichloromethane as Mobile phase B, elution requirement is as shown in table 3 below：
The elution requirement of 3 embodiment 1 of table
Experimental procedure：
Take ticagrelor sample appropriate, add absolute ethyl alcohol to dissolve and dilute be made it is molten containing about 1mg ticagrelors in every 1ml
Liquid, as test solution；It is appropriate to measure test solution, is made in every 1ml containing about 1 μ g ticagrelors with absolute ethyl alcohol dilution
Solution solution as a contrast；Separately weigh ticagrelor chiral isomer reference substance：Isomers A+ isomers B, isomer C+different
Structure body D, isomers E, isomers F and isomers G are each appropriate, be separately added into absolute ethyl alcohol dissolve and dilute be made it is certain density
Stock solution, separately weighs that ticagrelor reference substance is appropriate, and the stock solution that above-mentioned each impurity reference substance is added in precision is appropriate, with anhydrous second
Alcohol, which is dissolved and diluted, to be made containing about the solution of ticagrelor 1mg, 2 μ g of Isomers in every 1ml, as system suitability solution.
10 μ l of each solution are taken respectively and inject liquid chromatograph, are detected using above-mentioned chromatographic test strip part, and chromatogram is recorded.
Fig. 1 shows that detection method using the present invention schemes the HPLC that system suitability solution detects in embodiment 1, and Fig. 2 shows
Go out detection method using the present invention in embodiment 1 to scheme the HPLC that test solution detects.As depicted in figs. 1 and 2,
Ticagrelor and each chiral photo-isomerisation physical efficiency efficiently separate under the chromatographic condition of the present invention and the minimum of adjacent chiral isomers is divided
It is 1.64 from degree, without other chiral isomer impurity Interference Detections in ticagrelor.
Comparative example 1：
Detecting instrument：Shimadzu LC-2030 high performance liquid chromatographs.
Chromatographic condition：Chromatographic column isAD-H columns (250 × 4.6mm, 5 μm)；It is anhydrous with n-hexane-
Ethyl alcohol (80:20) it is mobile phase；Chromatographic column column temperature is 30 DEG C；Using UV detector；Detection wavelength is set as 300nm；Flowing
Phase flow velocity is 1.0ml/min.
Experimental procedure：By 1 method compounding system applicability solution of implementation steps.
10 μ l of system suitability solution are taken, liquid chromatograph is injected, record chromatogram 3.It can be seen from chromatogram 3
Ticagrelor and adjacent chiral isomer separating degree only have 1.15 under the chromatographic condition, and have isomers and peak position weight
Folded and equilibration time is longer.
Comparative example 2：
Detecting instrument：Shimadzu LC-2030 high performance liquid chromatographs.
Chromatographic condition：Chromatographic column isIC columns (250 × 4.6mm, 5 μm), chromatographic column column temperature are 21
℃；Using UV detector, Detection wavelength is set as 300nm；Flow rate of mobile phase is 1.0ml/min；With the anhydrous second of n-hexane-
Alcohol-isopropanol (85:10:5) it is mobile phase；
Experimental procedure：By 1 method compounding system applicability solution of implementation steps.
10 μ l of system suitability solution are taken, liquid chromatograph is injected, record chromatogram 4.It can be seen from chromatogram 4
There is isomers not detached at ticagrelor appearance under the chromatographic condition, adjacent isomers separating degree only has 1.18.
Comparative example 3：
Detecting instrument：Shimadzu LC-2030 high performance liquid chromatographs.
Chromatographic condition：Chromatographic column isIC columns (250 × 4.6mm, 5 μm), chromatographic column column temperature are 30
℃；Using UV detector, Detection wavelength is set as 300nm；Flow rate of mobile phase is 1.0ml/min；With n-hexane-isopropanol-
Methanol (330:15:15) it is mobile phase A, using dichloromethane as Mobile phase B, elution requirement is as shown in table 4 below：
The elution requirement of 4 comparative example 3 of table
Experimental procedure：By 1 method compounding system applicability solution of implementation steps.
Take 10 μ l of system suitability solution, inject liquid chromatograph, record chromatogram 5, it can be seen from chromatogram 5
Ticagrelor peak type is deteriorated under the chromatographic condition, response is lower, and the separating degree of itself and adjacent chiral isomers only has
1.157, not up to 1.5 separating degree.
Comparative example 4：
Detecting instrument：Shimadzu LC-2030 high performance liquid chromatographs.
Chromatographic condition：Chromatographic column isIC columns (250 × 4.6mm, 5 μm), chromatographic column column temperature are 30
℃；Using UV detector, Detection wavelength is set as 300nm；Flow rate of mobile phase is 1.0ml/min；It is flowing with absolute ethyl alcohol
Phase A, using dichloromethane as Mobile phase B, elution requirement is as shown in table 5 below：
The elution requirement of 5 comparative example 4 of table
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 60 | 80 | 20 |
Experimental procedure：By 1 method compounding system applicability solution of implementation steps.
10 μ l of system suitability solution are taken, liquid chromatograph is injected, record chromatogram 6, from chromatogram 6 it can be seen that at this
Under chromatographic condition, the retention time of ticagrelor is too short and only 3.818, and it can not achieve with chiral isomer impurity
Effect separation.
Advantageous effect in order to further illustrate the present invention, the present invention provide following tests example.
Test example is mainly used for carrying out the methodological study of detection method, wherein various experiments in this test example
It is all made of following condition：
Chromatographic column：IC, 250 × 4.6mm, 5 μm；Chromatographic column column temperature is 30 DEG C；Using ultraviolet detection
Device, Detection wavelength are set as 300nm；Flow rate of mobile phase is 1.0ml/min；Using absolute ethyl alcohol as mobile phase A, it is with dichloromethane
Mobile phase B, elution requirement are as shown in table 6 below：
The elution requirement of 6 test example of table
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 93 | 7 |
| 20 | 86 | 14 |
| 40 | 70 | 30 |
| 45 | 70 | 30 |
| 45.01 | 93 | 7 |
| 60 | 93 | 7 |
Solvent：Absolute ethyl alcohol；Sampling volume：10μl.
Specificity is tested
It takes and carries out sour (0.1mol/L 2 days), alkali (0.1mol/L 2 days), oxidation (3% hydrogen peroxide 2 for Luo Ruiluo samples
It), strong light (5000LX 30 days), ultraviolet light (30 days), high temperature (at 60 DEG C 30 days), the pressures such as high humidity (92.5% lower 30 days)
The test solution of about 1mg ticagrelors in every 1ml is configured to after Degrading experiment with absolute ethyl alcohol.Precision measures 10 μ l, injection
Liquid chromatograph records chromatogram.As a result it see the table below shown in 7：
Specificity test result in 7 test example of table
The test result of table 7 shows that the impurity for not generating interference chiral isomer detection after sample broke occurs, after destruction
The isomery physical efficiency of generation effectively detects under the testing conditions of the present invention.
In conclusion the present invention is using high performance liquid chromatography and utilizes chiral chromatographic column to ticagrelor chiral isomer
It is detached, the compound chromatography peak energy of ticagrelor is effective in formula 1 and its seven kinds of chiral isomers realize separation, and adopts
Carry out the quantitative determination of impurity with Self-control method, easy to operate, testing cost is low and with good sensitivity, linear, specially
Attribute, precision, accuracy, stability and durability are the effective detection sides of one kind for controlling ticagrelor isomers
Method, to ensure that ticagrelor product quality and patient medication safety.
The invention is not limited in specific implementation modes above-mentioned.The present invention, which expands to, any in the present specification to be disclosed
New feature or any new combination, and disclose any new method or process the step of or any new combination.
Claims (6)
1. a kind of high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content, which is characterized in that use with silica gel
Surface bond cellulose-three (3,5- diChloroaniline carbamate) is the chiral chromatographic column of filler, with lower paraffin hydrocarbon-lower alcohol
Mixed solution be mobile phase A, using dichloromethane as Mobile phase B, wherein the mobile phase A be n-hexane-isopropanol-methanol
Mixed solution, the volume ratio of n-hexane-isopropanol-methanol is 300~330:17~12:17~12, according to Gradient into
Row elution：
At 0 minute, mobile phase A is 91~95% and Mobile phase B is 9~5%；At 20 minutes, mobile phase A is 84~88% and flows
Dynamic phase B is 16~12%；At 40 minutes, mobile phase A is 68~72% and Mobile phase B is 32~28%；At 45 minutes, mobile phase
A is 68~72% and Mobile phase B is 32~28%；At 45.01 minutes, mobile phase A be 91~95% and Mobile phase B be 9~
5%；At 60 minutes, mobile phase A is 91~95% and Mobile phase B is 9~5%.
2. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content, feature exist according to claim 1
In the detection method specifically includes following steps：
A) ticagrelor reference substance and ticagrelor chiral isomer reference substance are weighed respectively, are dissolved and are diluted using absolute ethyl alcohol
It is made in every 1ml containing about the system suitability solution of ticagrelor 1mg, 2 μ g of each chiral isomer；
B) ticagrelor sample is weighed, the test solution of the ticagrelor containing 1mg in every 1ml is configured to using absolute ethyl alcohol；
C) utilize absolute ethyl alcohol that the test solution is diluted 1000 times of solution as a contrast；
D) each 10 μ l of solution for taking step a), step b), step c) respectively, are injected separately into high performance liquid chromatograph and are surveyed
It is fixed, chromatogram is recorded, the measurement of ticagrelor chiral isomer is completed, using main composition Self-control method to ticagrelor chirality
The content of isomers is calculated.
3. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 1 or claim 2, feature
It is, the flow velocity of mobile phase is 0.8~1.2ml/min, and chromatographic column column temperature is 22~28 DEG C；Detector is UV detector, inspection
Survey wavelength is 250~350nm.
4. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 1 or claim 2, feature
It is, the chiral chromatographic column isIC、IA andIB hands
One kind in property chromatographic column.
5. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 1 or claim 2, feature
It is, the chiral isomer of ticagrelor is substance shown in following seven kinds of structures：
The structure of isomers A is：
The structure of isomers B is：
The structure of isomer C is：
The structure of isomers D is：
The structure of isomers E is：
The structure of isomers F is：
The structure of isomers G is：
6. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 1 or claim 2, feature
It is, the flow velocity of mobile phase is 1ml/min, Detection wavelength 300nm, and chiral chromatographic column isIC, chromatography
Column column temperature is 25 DEG C.
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| CN112666269B (en) * | 2019-10-16 | 2022-12-30 | 北京联馨药业有限公司 | Method for detecting isomer in SAR107375 by using high performance liquid chromatography |
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| CN105092721A (en) * | 2014-05-21 | 2015-11-25 | 天津市汉康医药生物技术有限公司 | High performance liquid chromatography detection analysis method for controlling ticagrelor isomer |
| CN105301135B (en) * | 2015-11-20 | 2017-08-01 | 扬子江药业集团有限公司 | The method of chiral isomer content in high performance liquid chromatography detection ticagrelor |
| CN105510482B (en) * | 2016-01-29 | 2018-02-02 | 成都百裕制药股份有限公司 | The detection method of isomer impurities content in a kind of ticagrelor raw material |
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