CN106645528A - High performance liquid chromatography detection method of content of chiral isomers of ticagrelor - Google Patents
High performance liquid chromatography detection method of content of chiral isomers of ticagrelor Download PDFInfo
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G—PHYSICS
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Abstract
The invention discloses a high performance liquid chromatography detection method of the content of chiral isomers of ticagrelor. The high performance liquid chromatography detection method takes cellulose-tri(3,5-dichlorophenylaminoformiate) bonded on the surface of silica gel as a chiral chromatographic column of a filling agent, takes a mixed solution of alkane-low carbon alcohol as a mobile phase A and takes dichloromethane and/or chloroform as a mobile phase B. The cellulose-tri(3,5-dichlorophenylaminoformiate) bonded on the surface of the silica gel is used as the chiral chromatographic column of the filling agent and the suitable mobile phase is used for carrying out gradient elution; all chiral isomer impurities of ticagrelor are rapidly and effectively separated in one step and an effective detection method is provided for detecting and controlling the isomers of ticagrelor, so that the product quality and drug safety of ticagrelor are guaranteed; a self contrast method is used for carrying out quantitative determination of the impurities and the detection method is simple and convenient to operate and low in detection cost, and has good flexibility, linearity, specificity, precision, accuracy, stability and durability; and the detection method is an effective detection method of the content of the isomers.
Description
Technical field
The invention belongs to the research and application technical field in pharmaceutical chemistry, more particularly, is 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 new, the tool researched and developed by Astrazeneca AB (AstraZeneca)
Selective small molecule anticoagulant, its chemical structural formula is as shown in following formula 1：
Contain 6 asymmetric carbon atoms in ticagrelor molecular structure, in actual building-up process and can produce in storage
Raw impurity, wherein chiral isomer impurity is one of its major impurity, and the analyzing detecting method of routine be difficult to separate it is numerous
Chiral isomer impurity.Existing document or patent report adopt cellulose family (or polysaccharide derivates) for the chiral chromatogram of filler
The method of post detection, but it is the pillar of Silica Surface coated fiber element class (or polysaccharide derivates), such pillar equilibration time
Longer, stability is bad, reappearance is poor, the pillar life-span is shorter, and cannot the use of dichloromethane, chloroform equal solvent be stream
Dynamic phase.
The content of the invention
In order to solve problems of the prior art, it is an object of the invention to provide one kind can effective detection for lattice it is auspicious
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, adopts with silicon
Glue surface bond cellulose-three (3,5- diChloroaniline carbamate) for filler chiral chromatographic column, with lower paraffin hydrocarbon-rudimentary
The mixed solution of alcohol is mobile phase A, with 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
State detection method and specifically include following steps：
A) ticagrelor reference substance and ticagrelor chiral isomer reference substance are weighed respectively, using anhydrous alcohol solution simultaneously
Dilution is made in every 1ml containing about ticagrelor 1mg, the system suitability solution of the μ g of each chiral isomer 2；
B) ticagrelor sample is weighed, the test sample for being configured in every 1ml contain 1mg ticagrelors using absolute ethyl alcohol is molten
Liquid；
C) need testing solution is diluted 1000 times as contrast solution by the use of absolute ethyl alcohol；
D) each 10 μ l of solution of step a), step b), step c) are taken respectively, are injected separately into high performance liquid chromatograph and are carried out
Determine, record chromatogram, the measure 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 in n-hexane, pentane, hexamethylene and normal heptane to state lower paraffin hydrocarbon, and the lower alcohol is isopropanol, methyl alcohol
With at least one in ethanol, lower paraffin hydrocarbon is with the volume ratio of lower alcohol 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
The mixed solution that mobile phase A is n-hexane-isopropanol-methanol is stated, 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
Eluted according to the 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 material shown in listed in Table seven kind structure：
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, and Detection wavelength is 300nm, and chiral chromatographic column isIC, chromatographic column column temperature
For 22 DEG C, 25 DEG C or 28 DEG C.
The present invention to ticagrelor chiral isomer is separated using high performance liquid chromatography and using chiral chromatographic column,
The compound chromatogram peak energy of ticagrelor is effectively and its seven kinds of chiral isomers are realized separating in formula 1, 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, the degree of accuracy, stability and durability, are a kind of effective detection methods for controlling ticagrelor isomers, so as to protect
Ticagrelor product quality and patient medication safety are demonstrate,proved.
Description of the drawings
Fig. 1 shows the HPLC figures obtained to the detection of system suitability solution using the detection method of the present invention in embodiment 1.
Fig. 2 shows the HPLC figures obtained to need testing solution detection using the detection method of the present invention in embodiment 1.
Fig. 3 shows the HPLC figures that detection method is obtained to the detection of system suitability solution in comparative example 1.
Fig. 4 shows the HPLC figures that detection method is obtained to the detection of system suitability solution in comparative example 2.
Fig. 5 shows the HPLC figures that detection method is obtained to the detection of system suitability solution in comparative example 3.
Fig. 6 shows the HPLC figures that detection method is obtained to the detection of system suitability solution in comparative example 4.
Specific embodiment
All features disclosed in this specification, or disclosed all methods or during the step of, except mutually exclusive
Feature and/or step beyond, can combine by any way.
Any feature disclosed in this specification, unless specifically stated otherwise, can be by other equivalent or replacing with similar purpose
Replaced for feature.I.e., unless specifically stated otherwise, 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 described in detail below.
Exemplary embodiment of the invention, the present invention is adopted with Silica Surface binding fibers-three (3,5- dichloro-benzenes of element
Carbamate) for filler chiral chromatographic column, the mixed solution with 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 Silica Surface binding fibers-three (3,5- diChloroanilines of element
Carbamate) for filler chiral chromatographic column, solve silica gel show coated fiber element class (or polysaccharide derivates) the chromatographic column longevity
Life is short, easily damages (class requirement of reagent is higher) 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 fixing phase has differences, but its selectivity presence to compound is significantly poor
It is different, thus belong to diverse chromatographic column.Contain 6 asymmetric carbon atoms in ticagrelor molecular structure, actually synthesizing
In journey and impurity can be produced in storage, wherein chiral isomer impurity is one of its major impurity, and the analysis of routine is examined
Survey method is difficult to separate numerous chiral isomer impurity.And chiral separation chromatographic column is numerous, mainly cellulose family, protide,
Polysaccharide, crown ether-like.Cellulose chromatography post is broadly divided into coating-type and bonding type chromatographic column, and main for Ge Ruiluo Chirality Methods at present
For coating-type chromatographic column, such chromatographic column solvent compatibility is narrow, has larger restriction to solvent and diluent；To the equal levels that flow
Requirement is higher, and part domestic manufacturer reagent cannot meet analysis and require；Life-span is shorter, so as to cause chromatographic column change durability compared with
Difference.Bonding type chromatographic column gives Bonded Phase special selective power relative to coating-type chromatographic column, the solvent species for newly increasing.Therefore
Our company develops Bonded Phase for Ge Ruiluo chirality development approaches, has expanded solvent species, can be with compatible dichloromethane and/or chloroform
Etc. most of organic solvents, therefore the dissolubility of compound is not only improved, while also increasing the selectivity unique to compound, institute
The isomer impurities numerous so that ticagrelor can be efficiently separated.And the intrinsic stability of bonded-phase chromatography post and and durability,
The stability and reappearance of detection method are further increased, so that the present invention is much better than to adopt coating-type chromatogram column method at present.
Wherein, the chemical structural formula of ticagrelor is as shown in following formula 1：
Also, material shown in seven kinds of structures of the chiral isomer of ticagrelor listed by table 1 below：
Seven kinds of chiral isomer structures of the ticagrelor of table 1
Lower paraffin hydrocarbon can be at least one in n-hexane, pentane, hexamethylene and normal heptane, and lower alcohol can be different
At least one in propyl alcohol, methyl alcohol and ethanol, the volume of lower paraffin hydrocarbon and lower alcohol in the mixed solution of lower paraffin hydrocarbon-lower alcohol
Than for 100:10～120:10.According to a preferred embodiment of the invention, the mobile phase A for adopting 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 adopts Silica Surface binding fibers-three (3,5- diChloroaniline carbamates) of element for the chiral color of filler
Spectrum post is (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, using anhydrous alcohol solution simultaneously
Dilution is made in every 1ml containing about ticagrelor 1mg, the system suitability solution of the μ g of each chiral isomer 2；
B) ticagrelor sample is weighed, the test sample for being configured in every 1ml contain 1mg ticagrelors using absolute ethyl alcohol is molten
Liquid；
C) need testing solution is diluted 1000 times as contrast solution by the use of absolute ethyl alcohol；
D) each 10 μ l of solution of step a), step b), step c) are taken respectively, are injected separately into high performance liquid chromatograph and are carried out
Determine, record chromatogram, the measure 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 be 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, and Detection wavelength is 300nm, and chiral chromatographic column isIC, chromatographic column column temperature is 25 DEG C.
During wash-out, eluted preferably by the gradient shown in table 2 below.
The elution program of table 2
According to the existing stability feature for wanting ticagrelor production line and compound, 7 kinds of chiral isomers of major control
Impurity, the present invention is using high performance liquid chromatography and is separated with reference to particular chiral chromatographic column, the chemical combination of ticagrelor in formula 1
Look for spectral peak effectively can realize separating with its 7 kinds of chiral isomers, and, impurity is carried out using Self-control method and is quantitatively surveyed
Fixed, easy to operate, testing cost is low and with good sensitivity and specificity, is auxiliary control ticagrelor chiral isomer
The effective detection method of content, so as to ensure that the product quality and patient medication safety of ticagrelor.
Below in conjunction with the efficient liquid phase of specific embodiment and test example to 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 chromatograph.
Chromatographic condition：Chromatographic column isIC posts (250 × 4.6mm, 5 μm), chromatographic column column temperature is 25
℃；Using UV-detector, Detection wavelength is set to 300nm；Flow rate of mobile phase is 1.0ml/min；With n-hexane-isopropanol-
Methyl alcohol (330:15:15) it is mobile phase A, with dichloromethane as Mobile phase B, elution requirement is as shown in table 3 below：
The elution requirement of the embodiment 1 of table 3
Experimental procedure：
Take ticagrelor sample appropriate, plus anhydrous alcohol solution and diluting make it is molten containing about 1mg ticagrelors in every 1ml
Liquid, as need testing solution；Measure need testing solution appropriate, made in every 1ml containing about 1 μ g ticagrelors with absolute ethyl alcohol dilution
Solution as contrast solution；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 anhydrous alcohol solution and dilution make it is certain density
Stock solution, separately weighs ticagrelor reference substance in right amount, and precision adds the stock solution of above-mentioned each impurity reference substance appropriate, uses anhydrous second
Alcohol dissolves and dilutes to be made containing about ticagrelor 1mg, the solution of the μ g of Isomers 2 in every 1ml, as system suitability solution.
The μ l of each solution 10 are taken respectively and liquid chromatograph is injected, is detected using above-mentioned chromatographic test strip part, record chromatogram.
Fig. 1 shows the HPLC figures obtained to the detection of system suitability solution using the detection method of the present invention in embodiment 1, and Fig. 2 shows
The HPLC figures obtained to need testing solution detection using the detection method of the present invention in embodiment 1 are gone out.As depicted in figs. 1 and 2,
Ticagrelor and each chiral photo-isomerisation physical efficiency are efficiently separated and the minimum of adjacent chiral isomers is divided under the chromatographic condition of the present invention
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 chromatograph.
Chromatographic condition：Chromatographic column isAD-H posts (250 × 4.6mm, 5 μm)；With n-hexane-anhydrous
Ethanol (80:20) it is mobile phase；Chromatographic column column temperature is 30 DEG C；Using UV-detector；Detection wavelength is set to 300nm；Flowing
Phase flow velocity is 1.0ml/min.
Experimental procedure：By the method compounding system applicability solution of implementation steps 1.
The μ l of system suitability solution 10 are taken, liquid chromatograph is injected, chromatogram Fig. 3 is recorded.Can be seen that by chromatogram Fig. 3
Ticagrelor and adjacent chiral isomer separating degree only have 1.15 under the chromatographic condition, and have isomers and peak position weight
Fold and equilibration time is longer.
Comparative example 2：
Detecting instrument：Shimadzu LC-2030 high performance liquid chromatograph.
Chromatographic condition：Chromatographic column isIC posts (250 × 4.6mm, 5 μm), chromatographic column column temperature is 21
℃；Using UV-detector, Detection wavelength is set to 300nm；Flow rate of mobile phase is 1.0ml/min；With n-hexane-anhydrous second
Alcohol-isopropanol (85:10:5) it is mobile phase；
Experimental procedure：By the method compounding system applicability solution of implementation steps 1.
The μ l of system suitability solution 10 are taken, liquid chromatograph is injected, chromatogram Fig. 4 is recorded.Can be seen that by chromatogram Fig. 4
There is isomers not separated under the chromatographic condition at ticagrelor appearance, adjacent isomers separating degree only has 1.18.
Comparative example 3：
Detecting instrument：Shimadzu LC-2030 high performance liquid chromatograph.
Chromatographic condition：Chromatographic column isIC posts (250 × 4.6mm, 5 μm), chromatographic column column temperature is 30
℃；Using UV-detector, Detection wavelength is set to 300nm；Flow rate of mobile phase is 1.0ml/min；With n-hexane-isopropanol-
Methyl alcohol (330:15:15) it is mobile phase A, with dichloromethane as Mobile phase B, elution requirement is as shown in table 4 below：
The elution requirement of the comparative example 3 of table 4
Experimental procedure：By the method compounding system applicability solution of implementation steps 1.
The μ l of system suitability solution 10 are taken, liquid chromatograph is injected, chromatogram Fig. 5 is recorded, be can be seen that by chromatogram Fig. 5
Ticagrelor peak type is deteriorated, responds step-down under the chromatographic condition, and it only has with the separating degree of adjacent chiral isomers
1.157, not up to 1.5 separating degree.
Comparative example 4：
Detecting instrument：Shimadzu LC-2030 high performance liquid chromatograph.
Chromatographic condition：Chromatographic column isIC posts (250 × 4.6mm, 5 μm), chromatographic column column temperature is 30
℃；Using UV-detector, Detection wavelength is set to 300nm；Flow rate of mobile phase is 1.0ml/min；With absolute ethyl alcohol as flowing
Phase A, with dichloromethane as Mobile phase B, elution requirement is as shown in table 5 below：
The elution requirement of the comparative example 4 of table 5
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 60 | 80 | 20 |
Experimental procedure：By the method compounding system applicability solution of implementation steps 1.
The μ l of system suitability solution 10 are taken, liquid chromatograph is injected, chromatogram Fig. 6 is recorded, be can be seen that at this from chromatogram Fig. 6
Under chromatographic condition, the retention time of ticagrelor is too short and only 3.818, and it can not have been realized with chiral isomer impurity
Effect is separated.
In order to further illustrate beneficial effects of the present invention, the present invention provides tests below example.
Test example is mainly used in carrying out the methodological study of detection method, wherein, various tests in this test example
Adopt following condition：
Chromatographic column：IC, 250 × 4.6mm, 5 μm；Chromatographic column column temperature is 30 DEG C；Using ultraviolet detection
Device, Detection wavelength is set to 300nm；Flow rate of mobile phase is 1.0ml/min；With absolute ethyl alcohol as mobile phase A, it is with dichloromethane
Mobile phase B, elution requirement is as shown in table 6 below：
The elution requirement of the test example of table 6
| 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
Take carries out sour (0.1mol/L 2 days), alkali (0.1mol/L 2 days), oxidation (3% hydrogen peroxide 2 for Luo Ruiluo samples
My god), high light (5000LX 30 days), ultraviolet light (30 days), high temperature (at 60 DEG C 30 days), high humidity (92.5% lower 30 days) etc. force
The need testing 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 see the table below shown in 7：
Specificity result of the test in the test example of table 7
The result of the test of table 7 shows that the impurity that interference chiral isomer detection is not produced after sample broke occurs, after destruction
The isomery physical efficiency of generation is effectively detected under the testing conditions of the present invention.
In sum, the present invention is using high performance liquid chromatography and utilizes chiral chromatographic column to ticagrelor chiral isomer
Separated, the compound chromatogram peak energy of ticagrelor is effectively and its seven kinds of chiral isomers are realized separating in formula 1, 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, the degree of accuracy, stability and durability, are a kind of effective detection sides for controlling ticagrelor isomers
Method, so as to ensure that ticagrelor product quality and patient medication safety.
The invention is not limited in aforesaid specific embodiment.The present invention is expanded to and any in this manual disclosed
New feature or any new combination, and the arbitrary new method that discloses or the step of process or any new combination.
Claims (9)
1. a kind of high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content, it is characterised in that adopt 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, with dichloromethane and/or chloroform as Mobile phase B.
2. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 1, its feature exists
In the detection method specifically includes following steps：
A) ticagrelor reference substance and ticagrelor chiral isomer reference substance are weighed respectively, using anhydrous alcohol solution and are diluted
Make in every 1ml containing about ticagrelor 1mg, the system suitability solution of the μ g of each chiral isomer 2；
B) ticagrelor sample is weighed, using absolute ethyl alcohol the need testing solution containing 1mg ticagrelors is configured in every 1ml；
C) need testing solution is diluted 1000 times as contrast solution by the use of absolute ethyl alcohol；
D) each 10 μ l of solution of step a), step b), step c) are taken respectively, are injected separately into high performance liquid chromatograph and are surveyed
It is fixed, chromatogram is recorded, the measure of ticagrelor chiral isomer is completed, it is chiral to ticagrelor using main composition Self-control method
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, its feature
It is that 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, its feature
It is that the lower paraffin hydrocarbon is at least one in n-hexane, pentane, hexamethylene and normal heptane, the lower alcohol is isopropyl
At least one in alcohol, methyl alcohol and ethanol, the body of lower paraffin hydrocarbon and lower alcohol in the mixed solution of the lower paraffin hydrocarbon-lower alcohol
Product is than being 100:10～120:10.
5. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 4, its feature exists
In, the mobile phase A is the mixed solution of n-hexane-isopropanol-methanol, wherein, the volume ratio of n-hexane-isopropanol-methanol
For (300～330):(17～12):(17～12).
6. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 1 or claim 2, its feature
It is that the chiral chromatographic column isIC、IA andIB hands
One kind in property chromatographic column.
7. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 1 or claim 2, its feature
It is to be eluted according to the gradient shown in following table：
8. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 1 or claim 2, its feature
It is that the chiral isomer of ticagrelor is material shown in listed in Table seven kind structure：
9. the high-efficiency liquid chromatography method for detecting of ticagrelor chiral isomer content according to claim 1 or claim 2, its feature
It is that the flow velocity of mobile phase is 1ml/min, and Detection wavelength is 300nm, and chiral chromatographic column isIC, chromatogram
Post column temperature is 25 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN112666269A (en) * | 2019-10-16 | 2021-04-16 | 北京科莱博医药开发有限责任公司 | Method for detecting isomer in SAR107375 by using high performance liquid chromatography |
| CN115327006A (en) * | 2022-08-12 | 2022-11-11 | 成都施贝康生物医药科技有限公司 | Detection method of clopidogrel oxide isomer |
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