CN106706769A - Separation and determination method of empagliflozin and optical isomers thereof - Google Patents
Separation and determination method of empagliflozin and optical isomers thereof Download PDFInfo
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- CN106706769A CN106706769A CN201510786991.5A CN201510786991A CN106706769A CN 106706769 A CN106706769 A CN 106706769A CN 201510786991 A CN201510786991 A CN 201510786991A CN 106706769 A CN106706769 A CN 106706769A
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- Prior art keywords
- gelie
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- net
- optical isomer
- phosphate
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- 0 CCC=C([C@@](C)*CCCC1=C(C)C=CC([C@](C)CC(*)C[C@](*)[I+][C@](*)CO)=CC1)[U][C@]1C[F+]NC1 Chemical compound CCC=C([C@@](C)*CCCC1=C(C)C=CC([C@](C)CC(*)C[C@](*)[I+][C@](*)CO)=CC1)[U][C@]1C[F+]NC1 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The invention discloses a separation and determination method of empagliflozin and optical isomers thereof. The method separates and determines the empagliflozin and the optical isomers thereof by adopting a high performance liquid chromatography and taking amylose or cellulose derivative chiral columns as chromatographic columns. The method can be used for controlling the quality of the empagliflozin and pharmaceutical compositions containing the empagliflozin.
Description
Technical field
The invention belongs to Pharmaceutical Analysis method field, and in particular to a kind of use high efficiency liquid chromatography for separating and determining antidiabetic drug En Gelie is net and its method of optical isomer.
Background technology
En Gelie is only a kind of white (SGLT) inhibitor of selective sodium glucose co-transporter 2, for treating Adult type II diabetes.En Gelie is net by the white selective inhibitory of sodium glucose co-transporter 2, limiting most of glucose reabsorption in vivo, promotes a large amount of discharges from urine of glucose to reach the purpose of control blood sugar level.
En Gelie net chemical structural formula is as follows：
Its chemistry is entitled：(1S) -1,5- is dehydrated -1-C- [the chloro- 3- of 4- [[4- [[(3S)-tetrahydrochysene -3- furyls] epoxide] phenyl] methyl] phenyl]-D-Glucose alcohol.
There are 6 chiral centres in the net structures of En Gelie, corresponding optical isomer accessory substance is also easy to produce in the position of part chiral centre in its synthetic reaction process, the purity and quality of medicine are directly affected after residual.The chemical structural formula of optical isomer A, B is as follows：
At present, relevant En Gelie is net and its optical isomer assay method has no report, to ensure net quality controllable of En Gelie, to ensure its validity and security, needs a kind of effective detection method badly, can separation determination En Gelie only and its optical isomer.The present inventor has found a kind of rapid separation and determination En Gelie only and its method for optical isomer by substantial amounts of scientific experimentation and the screening of test condition, and the method can effectively control the net optical isomer impurity of En Gelie, so as to complete the present invention.
The inventors discovered that, the net tablets of En Gelie for having listed, wherein the pharmaceutic adjuvant such as the lactose for containing, microcrystalline cellulose is in the method for the invention without interference with determining, and En Gelie is net and its measure of optical isomer.Therefore, the present disclosure applies equally to pharmaceutical composition that En Gelie is net.
The content of the invention
In a kind of method of separating and assaying of the net and its optical isomer it is an object of the invention to provide En Gelie, the method can efficiently separate En Gelie with its optical isomer only, optical isomer in the accurate detection net bulk drugs of En Gelie and its pharmaceutical composition, so as to the quality for controlling En Gelie net, it is ensured that the validity and security of the net medicines of En Gelie.
To realize the purpose of the present invention, there is provided scheme is implemented as follows.
In one embodiment, a kind of method of net and its optical isomer the invention provides use high efficiency liquid chromatography for separating and determining En Gelie, including with straight chain starch derivative chiral column as chromatographic column, using the mixture of methyl alcohol, ethanol and n-hexane as mobile phase, or, with cellulose derivative chiral post as chromatographic column, using the mixture of acetonitrile and PBS as mobile phase, eluted, detected with UV-detector.
Preferably, the method for the invention described above, the straight chain starch derivative chiral column is amylose-three（The chloro- 4- methyl phenyl carbamates of 3-）Bonded silica gel filled column, the cellulose derivative chiral post is cellulose-three（The chloro- 4- methyl phenyl carbamates of 3-）Bonded silica gel filled column；In mobile phase, the volume ratio of methyl alcohol, ethanol and n-hexane is 16: 11：73, acetonitrile is 25: 75~65: 35 with the volume ratio of PBS, more preferably acetonitrile and the volume ratio of PBS is 45: 55, the pH value of the PBS is 2~6, the phosphate is selected from one or more in sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and diammonium hydrogen phosphate, preferably sodium dihydrogen phosphate；Use phosphorus acid for adjusting pH.
The method of the invention described above, it is further comprising the steps：
The method of the present invention, it is further comprising the steps：
（1）The net bulk drugs of En Gelie or its pharmaceutical composition are taken, plus methyl alcohol, ethanol or acetonitrile make En Gelie be completely dissolved only and dilute constant volume, are configured to net 0.8~2.0mg containing En Gelie in every 1ml solution, preferably 1.5mg, filtration, as need testing solution；
（2）With amylose or cellulose derivative class chiral column as chromatographic column, column temperature is 25~35 DEG C, and preferably 30 DEG C, wavelength is 200~250nm, preferably 224 nm；
（3）The μ l of need testing solution 5~20, preferably 10 μ l are taken, high performance liquid chromatograph is injected, is washed with appropriate flow velocity, preferably 0.8-1ml/min takes off and completes En Gelie only and its separation determination of optical isomer.
In one embodiment, a kind of high performance liquid chromatography separation of the invention determines En Gelie only and its method for optical isomer, and it specifically includes following steps：
（1）The net bulk drugs of En Gelie or preparation are taken, it is accurately weighed, plus methyl alcohol, ethanol or acetonitrile make En Gelie dissolve only in right amount, then diluted with solvent and be made the solution containing the net 0.8~2.0mg of En Gelie in every 1ml, filter if necessary, as need testing solution；
（2）Chromatographic condition is as follows：With amylose-three（The chloro- 4- methyl phenyl carbamates of 3-）Bonded silica gel filled column is chromatographic column, is eluted with the mixed solvent composition mobile phase of methyl alcohol, ethanol and n-hexane, wherein, the volume ratio of methyl alcohol, ethanol and n-hexane is 16: 11：73, or with cellulose-three（The chloro- 4- methyl phenyl carbamates of 3-）Bonded silica gel filled column is chromatographic column, and used as mobile phase, mixing is eluted the mixed liquor using acetonitrile and phosphate sodium dihydrogen buffer solution (adjusting pH value to 2~6 with phosphoric acid), wherein, the volume ratio of acetonitrile and phosphate sodium dihydrogen buffer solution is 45: 55, and column temperature is：30℃；Detection wavelength is 224nm.
（3）The μ l of need testing solution 10 are taken, high performance liquid chromatograph is injected, En Gelie is completed only with 0.8-1ml/min flow velocitys wash-out and its separation determination of optical isomer.
The method of the present invention, beneficial effect or advantage are：
1. specificity is strong, measure of net other process contaminants of En Gelie without interference with optical isomer A and B, it is possible to provide the quantitative result of the net single optical isomers of En Gelie；
2. sensitivity is high, and the minimal detectable concentration of optical isomer A and B impurity is respectively 0.52 μ g/ml and 0.92 μ g/ml in the present invention, shows that it ensure that the micro above-mentioned impurity of detection；
3. durability is good, from the different type chromatographic column mentioned in the present invention, or the parameter such as mobile phase ratio, flow velocity, column temperature in chromatographic condition is fluctuated in scope of the present invention, and testing result will not be made a significant impact.
In a word, separation determination En Gelie of the invention is net and its method of optical isomer, it is possible to achieve En Gelie separates analysis with its optical isomer only, and method possesses preferable specificity, sensitivity and accuracy advantage.
Brief description of the drawings
Fig. 1：The high-efficient liquid phase chromatogram of solvent blank；
Fig. 2：The high-efficient liquid phase chromatogram of the net bulk drug need testing solutions of En Gelie；
Fig. 3：The high-efficient liquid phase chromatogram of net optical isomer A, B reference substance solutions of En Gelie；
Fig. 4：The high-efficient liquid phase chromatogram of the need testing solution of optical isomer A, B is added in net to En Gelie；
Fig. 5：Only contain the high-efficient liquid phase chromatogram of the composition blank solution of adjunct ingredient only without En Gelie；
Fig. 6：High-efficient liquid phase chromatogram containing En Gelie net pharmaceutical composition need testing solution.
Specific embodiment
With reference to embodiment, the present invention will be further described.
Embodiment 1
Instrument and condition
High performance liquid chromatograph：Agilent 1260；
Chromatographic column：Straight chain starch derivative class chiral column（CHIRALCEL IF, 4.6 × 250mm, 5 μm）；
Mobile phase：Methanol/ethanol-n-hexane（16∶11∶73）
Sampling volume：10μl；
Flow velocity：1ml/min；
Column temperature：30℃；
Detection wavelength：224nm.
Experimental procedure
The net bulk drugs of En Gelie about 15mg is taken, accurately weighed, in putting 10ml volumetric flasks, plus methyl alcohol dissolves and is diluted to scale, shakes up, as need testing solution.Take solvent（Mobile phase）And need testing solution, efficient liquid phase chromatographic analysis are carried out under above-mentioned chromatographic condition, chromatogram is recorded, see Fig. 1, Fig. 2.Result shows that solvent does not disturb the net detections of En Gelie, and method specificity is good.
Embodiment 2
Instrument and condition
High performance liquid chromatograph：Agilent 1260；
Chromatographic column：Straight chain starch derivative class chiral column（CHIRALCEL IF, 4.6 × 250mm, 5 μm）；
Mobile phase：Methanol/ethanol-n-hexane（16∶11∶73）
Sampling volume：10μl；
Flow velocity：1ml/min；
Column temperature：30℃；
Detection wavelength：224nm.
Experimental procedure
Take En Gelie net optical isomer A, B each appropriate, accurately weighed, in putting 10ml volumetric flasks, plus methyl alcohol dissolves and is diluted to scale, shakes up, then quantitative dilution is made the solution containing each 7.5 μ g/ml of A, B in every 1ml, used as reference substance solution.Reference substance solution is taken, efficient liquid phase chromatographic analysis are carried out under above-mentioned chromatographic condition, record chromatogram, see Fig. 3.Result shows energy good separation between En Gelie net optical isomer A, B, and the peak height of optical isomer A, B is suitable, and method specificity is good, and sensitivity is good.
Embodiment 3
Instrument and condition
High performance liquid chromatograph：Agilent 1260；
Chromatographic column：Straight chain starch derivative class chiral column（CHIRALCEL IF, 4.6 × 250mm, 5 μm）；
Mobile phase：Methanol/ethanol-n-hexane（16∶11∶73）
Sampling volume：10μl；
Flow velocity：1ml/min；
Column temperature：30℃；
Detection wavelength：224nm.
Experimental procedure
Take the net bulk drugs of En Gelie about 15mg, it is accurately weighed, in putting 10ml volumetric flasks, plus methyl alcohol dissolving, it is each appropriate to add En Gelie net optical isomer A, B, with methanol dilution to scale, shake up, it is made the net 1.5mg containing En Gelie in every 1ml, the solution of each 7.5 μ g/ml of A containing optical isomer, B, as mixed solution.Mixed solution is taken, efficient liquid phase chromatographic analysis are carried out under above-mentioned chromatographic condition, record chromatogram, see Fig. 4.Result shows that En Gelie only can good separation with its optical isomer A, B.
Embodiment 4
Instrument and condition
Chromatographic column：Cellulose derivative class chiral column（CHIRALCEL OZ-RH, 4.6 × 150mm, 5 μm）；
Mobile phase：Acetonitrile -0.01mol/L sodium dihydrogen phosphates（PH value to 4 is adjusted with phosphoric acid）（45∶55）
Sampling volume：10μl；
Flow velocity：0.8ml/min；
Column temperature：30℃；
Detection wavelength：224nm.
Experimental procedure
Take the net bulk drugs of En Gelie about 10mg, it is accurately weighed, in putting 10ml volumetric flasks, plus acetonitrile dissolving, it is each appropriate to add En Gelie net optical isomer A, B, with dilution in acetonitrile to scale, shake up, it is made the net 1mg containing En Gelie in every 1ml, the solution of each 5 μ g/ml of A containing optical isomer, B, as mixed solution.Mixed solution is taken, efficient liquid phase chromatographic analysis are carried out under above-mentioned chromatographic condition, record chromatogram.As a result En Gelie only with its optical isomer A, B can good separation, as a result show that the cellulose derivative class chiral column can reach similar separating effect with above-mentioned straight chain starch derivative class chiral column.
Embodiment 5
Instrument and condition
Chromatographic column：Straight chain starch derivative chiral column（CHIRALCEL IF, 4.6 × 250mm, 5 μm）；
Mobile phase：Methanol/ethanol-n-hexane（16∶11∶73）
Sampling volume：10μl；
Flow velocity：1ml/min；
Column temperature：30℃；
Detection wavelength：224nm.
Experimental procedure
The net bulk drug crude product about 15mg of En Gelie are taken, accurately weighed, in putting 10ml volumetric flasks, plus methyl alcohol dissolves and is diluted to scale, shakes up, as need testing solution.Need testing solution is taken, efficient liquid phase chromatographic analysis are carried out under above-mentioned chromatographic condition, record chromatogram.As a result each impurity peaks do not disturb the measure of En Gelie net optical isomer A, B in crude product, and method specificity is good.
Embodiment 6
Instrument and condition
High performance liquid chromatograph：Agilent 1260；
Chromatographic column：Straight chain starch derivative class chiral column（CHIRALCEL IF, 4.6 × 250mm, 5 μm）；
Mobile phase：Methanol/ethanol-n-hexane（16∶11∶73）
Sampling volume：10μl；
Flow velocity：1ml/min；
Column temperature：30℃；
Detection wavelength：224nm.
Experimental procedure
Take the net pharmaceutical compositions of En Gelie appropriate, it is accurately weighed containing the net 15mg of En Gelie, in putting 10ml volumetric flasks, plus appropriate methyl alcohol, it is ultrasonic 10 minutes, En Gelie is completely dissolved only, then scale is diluted to, shake up, as need testing solution.It is another take equivalent without the net compositions containing only auxiliary material of En Gelie, it is accurately weighed, in putting 10ml volumetric flasks, plus methyl alcohol ultrasound 10 minutes, then be diluted to scale, shake up, as blank solution.Blank solution and need testing solution are taken, efficient liquid phase chromatographic analysis are carried out under above-mentioned chromatographic condition, record chromatogram, see Fig. 5, Fig. 6.Result shows that adjuvant composition does not disturb En Gelie net and its optical isomer detection.
Embodiment described above is only that the preferred embodiment of the present invention is described; not the scope of the present invention is defined; on the premise of design spirit of the present invention is not departed from; various modifications and improvement that those of ordinary skill in the art make to technical scheme, all should fall into the protection domain of claims of the present invention determination.
Claims (10)
1. a kind of use high efficiency liquid chromatography for separating and determining En Gelie is net and its method of optical isomer, including with straight chain starch derivative chiral column as chromatographic column, using the mixture of methyl alcohol, ethanol and n-hexane as mobile phase, or, with cellulose derivative chiral post as chromatographic column, mixture using acetonitrile and PBS is eluted as mobile phase, is detected with UV-detector.
2. method according to claim 1, the straight chain starch derivative chiral column is amylose-three（The chloro- 4- methyl phenyl carbamates of 3-）Bonded silica gel filled column.
3. method according to claim 1, the cellulose derivative chiral post is cellulose-three（The chloro- 4- methyl phenyl carbamates of 3-）Bonded silica gel filled column.
4. method according to claim 1, the volume ratio of methyl alcohol, ethanol and n-hexane is 16:11:73.
5. method according to claim 1, acetonitrile is 25: 75~65: 35 with the volume ratio of PBS.
6. method according to claim 5, acetonitrile is 45 with the volume ratio of PBS：55.
7. method according to claim 1 or 5, the pH value of PBS is 2~6 in mobile phase.
8. method according to claim 1, the phosphate is selected from one or more in sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and diammonium hydrogen phosphate.
9. method according to claim 1, the phosphate is sodium dihydrogen phosphate.
10. method according to claim 1, further comprising the steps：
（1）The net bulk drugs of En Gelie or its pharmaceutical composition are taken, plus methyl alcohol, ethanol or acetonitrile make En Gelie be completely dissolved only and dilute constant volume, are configured to net 0.8~2.0mg containing En Gelie in every 1ml solution, filtration, as need testing solution；
（2）With amylose or cellulose derivative class chiral column as chromatographic column, column temperature is 25~35 DEG C, and wavelength is 200~250nm；
（3）The μ l of need testing solution 5~20 are taken, high performance liquid chromatograph is injected, with 0.8-1
Ml/min flow velocitys wash-out completes En Gelie only and its separation determination of optical isomer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112557533A (en) * | 2020-11-29 | 2021-03-26 | 北京康立生医药技术开发有限公司 | Analysis method of engletzin |
| CN112986456A (en) * | 2021-02-22 | 2021-06-18 | 扬子江药业集团北京海燕药业有限公司 | HPLC analysis detection method of empagliflozin intermediate |
| CN114591310A (en) * | 2020-12-04 | 2022-06-07 | 浙江医药股份有限公司新昌制药厂 | Preparation method and application of empagliflozin isomer |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112557533A (en) * | 2020-11-29 | 2021-03-26 | 北京康立生医药技术开发有限公司 | Analysis method of engletzin |
| CN114591310A (en) * | 2020-12-04 | 2022-06-07 | 浙江医药股份有限公司新昌制药厂 | Preparation method and application of empagliflozin isomer |
| CN112986456A (en) * | 2021-02-22 | 2021-06-18 | 扬子江药业集团北京海燕药业有限公司 | HPLC analysis detection method of empagliflozin intermediate |
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