CN106706769B - Separation and determination method of empagliflozin and optical isomer thereof - Google Patents
Separation and determination method of empagliflozin and optical isomer thereof Download PDFInfo
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- CN106706769B CN106706769B CN201510786991.5A CN201510786991A CN106706769B CN 106706769 B CN106706769 B CN 106706769B CN 201510786991 A CN201510786991 A CN 201510786991A CN 106706769 B CN106706769 B CN 106706769B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention discloses a separation and determination method of engagliflozin and an optical isomer thereof, which adopts a high performance liquid chromatography, takes an amylose or cellulose derivative chiral column as a chromatographic column, separates and determines the engagliflozin and the optical isomer thereof, and can be used for quality control of the engagliflozin and a pharmaceutical composition containing the engagliflozin.
Description
Technical Field
The invention belongs to the field of drug analysis methods, and particularly relates to a method for separating and measuring a hypoglycemic drug empagliflozin and an optical isomer thereof by adopting a high performance liquid chromatography.
Background
Engagliflozin is a selective sodium-glucose cotransporter (SGLT) inhibitor useful for treating adult type II diabetes. The engeletin limits the reabsorption of most glucose in vivo by the selective inhibition effect on the sodium-glucose cotransporter, and promotes the massive excretion of glucose from urine to achieve the aim of controlling the blood sugar level.
The chemical structural formula of the empagliflozin is as follows:
the chemical name is as follows: (1S) -1, 5-anhydro-1-C- [ 4-chloro-3- [ [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methyl ] phenyl ] -D-glucitol.
The structure of the empagliflozin has 6 chiral centers, corresponding optical isomer byproducts are easily generated at the positions of partial chiral centers in the synthetic reaction process of the empagliflozin, and the purity and the quality of the medicine are directly influenced after the residues are remained. The chemical structural formula of optical isomer A, B is as follows:
at present, no report is found about the determination method of the empagliflozin and the optical isomer thereof, and in order to ensure the quality of the empagliflozin to be controllable and ensure the effectiveness and the safety of the empagliflozin, an effective detection method capable of separating and determining the empagliflozin and the optical isomer thereof is urgently needed. The inventor discovers a method for rapidly separating and measuring the empagliflozin and the optical isomer thereof through a large amount of scientific experiments and screening of test conditions, and the method can effectively control the optical isomer impurities of the empagliflozin, thereby completing the invention.
The inventor finds that the pharmaceutical excipients contained in the marketed engagliflozin tablet, such as lactose, microcrystalline cellulose and the like, do not interfere with the determination of the engagliflozin and the optical isomer thereof in the method of the invention. Thus, the invention is equally applicable to pharmaceutical compositions of empagliflozin.
Disclosure of Invention
The invention aims to provide a separation and measurement method of engagliflozin and optical isomers thereof, which can effectively separate the engagliflozin and the optical isomers thereof and accurately detect the optical isomers in an engagliflozin raw material medicine and a medicine composition thereof, thereby controlling the quality of the engagliflozin and ensuring the effectiveness and the safety of an engagliflozin medicine.
To achieve the object of the present invention, the following embodiments are provided.
In one embodiment, the invention provides a method for separating and determining the empagliflozin and the optical isomers thereof by using a high performance liquid chromatography, which comprises the steps of taking an amylose derivative chiral column as a chromatographic column and a mixture of methanol, ethanol and n-hexane as a mobile phase, or taking a cellulose derivative chiral column as a chromatographic column and a mixture of acetonitrile and phosphate buffer solution as a mobile phase, eluting, and detecting by using an ultraviolet detector.
Preferably, in the method of the present invention, the amylose derivative chiral column is an amylose-tris (3-chloro-4-methylphenyl carbamate) bonded silica gel packed column, and the cellulose derivative chiral column is a cellulose-tris (3-chloro-4-methylphenyl carbamate) bonded silica gel packed column; in the mobile phase, the volume ratio of methanol to ethanol to n-hexane is 16:11:73, the volume ratio of acetonitrile to a phosphate buffer solution is 25: 75-65: 35, more preferably the volume ratio of acetonitrile to a phosphate buffer solution is 45: 55, the pH value of the phosphate buffer solution is 2-6, and the phosphate is selected from one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and diammonium hydrogen phosphate, preferably sodium dihydrogen phosphate; the pH was adjusted with phosphoric acid.
The method of the present invention further comprises the steps of:
the method of the invention further comprises the following steps:
(1) taking an engelet raw material medicine or a medicine composition thereof, adding methanol, ethanol or acetonitrile to completely dissolve the engelet, diluting to a constant volume, preparing into a solution containing 0.8-2.0 mg, preferably 1.5mg of the engelet in every 1ml of the solution, and filtering to obtain a test solution;
(2) taking an amylose or cellulose derivative chiral column as a chromatographic column, wherein the temperature of the column is 25-35 ℃, preferably 30 ℃, and the wavelength of the column is 200-250 nm, preferably 224 nm;
(3) and (3) injecting 5-20 mu l, preferably 10 mu l of the test solution into a high performance liquid chromatograph, washing at a proper flow rate, and preferably 0.8-1ml/min to separate and measure the empagliflozin and the optical isomer thereof.
In a specific embodiment, the invention relates to a method for separating and determining the empagliflozin and the optical isomer thereof by using high performance liquid chromatography, which specifically comprises the following steps:
(1) taking an engelet raw material medicine or a preparation, precisely weighing, adding a proper amount of methanol, ethanol or acetonitrile to dissolve the engelet, diluting with a solvent to prepare a solution containing 0.8-2.0 mg of the engelet in each 1ml, and filtering if necessary to serve as a test solution;
(2) the chromatographic conditions were as follows: taking an amylose-tri (3-chloro-4-methylphenyl carbamate) bonded silica gel packed column as a chromatographic column, and eluting by using a mobile phase consisting of a mixed solvent of methanol, ethanol and n-hexane, wherein the volume ratio of the methanol to the ethanol to the n-hexane is 16:11:73, or taking a cellulose-tri (3-chloro-4-methylphenyl carbamate) bonded silica gel packed column as a chromatographic column, taking a mixed solution of acetonitrile and sodium dihydrogen phosphate buffer (the pH value is adjusted to 2-6 by phosphoric acid) as a mobile phase, mixing and eluting, wherein the volume ratio of the acetonitrile to the sodium dihydrogen phosphate buffer is 45: 55, and the column temperature is as follows: 30 ℃; the detection wavelength was 224 nm.
(3) And (3) taking 10 mu l of the test solution, injecting the test solution into a high performance liquid chromatograph, and eluting at the flow rate of 0.8-1ml/min to complete the separation and determination of the empagliflozin and the optical isomer thereof.
The method has the following beneficial effects or advantages:
the method has strong specificity, other process impurities of the engagliflozin cannot interfere with the determination of the optical isomers A and B, and a quantitative result of a single optical isomer of the engagliflozin can be provided;
the sensitivity is high, and the minimum detection concentrations of the impurities of the optical isomers A and B are 0.52 mu g/ml and 0.92 mu g/ml respectively, which shows that the optical isomers A and B can ensure that a trace amount of the impurities can be detected;
the durability is good, different types of chromatographic columns mentioned in the invention are selected, or parameters such as flowing phase proportion, flow rate, column temperature and the like in chromatographic conditions are fluctuated within the range of the invention, and the detection result is not obviously influenced.
In a word, the method for separating and determining the empagliflozin and the optical isomer thereof can realize the separation and analysis of the empagliflozin and the optical isomer thereof, and has the advantages of better specificity, sensitivity, accuracy and the like.
Drawings
FIG. 1: high performance liquid chromatogram of solvent blank;
FIG. 2: a high performance liquid chromatogram of a test solution of the raw material medicine of the engagliflozin;
FIG. 3: a high performance liquid chromatogram of a reference solution of engagliflozin optical isomer A, B;
FIG. 4: a high performance liquid chromatogram of a test solution in which optical isomer A, B was added to engagliflozin;
FIG. 5: a high performance liquid chromatogram of a composition blank solution which does not contain the empagliflozin and only contains the auxiliary material component;
FIG. 6: high performance liquid chromatogram of test solution of pharmaceutical composition containing engagliflozin.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
Apparatus and conditions
High performance liquid chromatograph: agilent 1260;
a chromatographic column: amylose derivative chiral columns (CHIRALCEL IF, 4.6 × 250mm, 5 μm);
mobile phase: methanol-ethanol-n-hexane (16: 11: 73)
Sample introduction volume: 10 mu l of the mixture;
flow rate: 1 ml/min;
column temperature: 30 ℃;
detection wavelength: 224 nm.
Experimental procedure
Taking about 15mg of the raw material medicine of the empagliflozin, precisely weighing, placing the empagliflozin in a 10ml volumetric flask, adding methanol to dissolve and dilute the empagliflozin to a scale, and shaking up the empagliflozin to be used as a test solution. Taking solvent (mobile phase) and sample solution, performing high performance liquid chromatography under the above chromatographic conditions, and recording chromatogram, as shown in FIG. 1 and FIG. 2. The result shows that the solvent does not interfere with the detection of the empagliflozin, and the method has good specificity.
Example 2
Apparatus and conditions
High performance liquid chromatograph: agilent 1260;
a chromatographic column: amylose derivative chiral columns (CHIRALCEL IF, 4.6 × 250mm, 5 μm);
mobile phase: methanol-ethanol-n-hexane (16: 11: 73)
Sample introduction volume: 10 mu l of the mixture;
flow rate: 1 ml/min;
column temperature: 30 ℃;
detection wavelength: 224 nm.
Experimental procedure
Taking appropriate amount of each Engelliflozin optical isomer A, B, precisely weighing, placing in a 10ml volumetric flask, adding methanol to dissolve and dilute to scale, shaking up, and quantitatively diluting to obtain solutions containing A, B of 7.5 μ g/ml each in 1ml, wherein the solutions are used as control solutions. Taking the control solution, performing high performance liquid chromatography under the above chromatographic conditions, and recording chromatogram, as shown in FIG. 3. The result shows that the empagliflozin optical isomer A, B can be well separated, the peak height of the optical isomer A, B is proper, the method specificity is good, and the sensitivity is good.
Example 3
Apparatus and conditions
High performance liquid chromatograph: agilent 1260;
a chromatographic column: amylose derivative chiral columns (CHIRALCEL IF, 4.6 × 250mm, 5 μm);
mobile phase: methanol-ethanol-n-hexane (16: 11: 73)
Sample introduction volume: 10 mu l of the mixture;
flow rate: 1 ml/min;
column temperature: 30 ℃;
detection wavelength: 224 nm.
Experimental procedure
Taking about 15mg of the raw material medicine of the engelet, precisely weighing, placing in a 10ml volumetric flask, adding methanol for dissolving, adding an appropriate amount of each of the optical isomers A, B of the engelet, diluting to a scale with the methanol, shaking up, and preparing into a solution containing 1.5mg of the engelet and 7.5 mu g/ml of each of the optical isomers A, B in 1ml as a mixed solution. Taking the mixed solution, performing high performance liquid chromatography under the above chromatographic conditions, and recording chromatogram as shown in FIG. 4. The results show that both engagliflozin and its optical isomer A, B are well separated.
Example 4
Apparatus and conditions
A chromatographic column: a cellulose derivative chiral column (CHIRALCEL OZ-RH, 4.6 × 150mm, 5 μm);
mobile phase: acetonitrile-0.01 mol/L sodium dihydrogen phosphate solution (pH adjusted to 4 with phosphoric acid) (45: 55)
Sample introduction volume: 10 mu l of the mixture;
flow rate: 0.8 ml/min;
column temperature: 30 ℃;
detection wavelength: 224 nm.
Experimental procedure
Taking about 10mg of the raw material medicine of the engeletrin, precisely weighing, placing the raw material medicine of the engeletrin in a 10ml volumetric flask, adding acetonitrile for dissolving, then adding a proper amount of each of the optical isomers A, B of the engeletrin, diluting the mixture to a scale by using the acetonitrile, shaking up, and preparing a solution containing 1mg of the engeletrin and 5 mu g/ml of each of the optical isomers A, B in each 1ml as a mixed solution. Taking the mixed solution, carrying out high performance liquid chromatography analysis under the chromatographic conditions, and recording a chromatogram. The result shows that the chiral column of the cellulose derivative and the chiral column of the amylose derivative can achieve similar separation effect.
Example 5
Apparatus and conditions
A chromatographic column: amylose derivative chiral columns (CHIRALCEL IF, 4.6 × 250mm, 5 μm);
mobile phase: methanol-ethanol-n-hexane (16: 11: 73)
Sample introduction volume: 10 mu l of the mixture;
flow rate: 1 ml/min;
column temperature: 30 ℃;
detection wavelength: 224 nm.
Experimental procedure
Taking about 15mg of the crude drug of the empagliflozin, precisely weighing, placing the empagliflozin in a 10ml volumetric flask, adding methanol to dissolve and dilute the empagliflozin to a scale, and shaking up the empagliflozin to be used as a test solution. Taking the sample solution, performing high performance liquid chromatography under the chromatographic conditions, and recording the chromatogram. As a result, the determination of the optical isomer A, B of Empagliflozin is not interfered by each impurity peak in the crude product, and the method has good specificity.
Example 6
Apparatus and conditions
High performance liquid chromatograph: agilent 1260;
a chromatographic column: amylose derivative chiral columns (CHIRALCEL IF, 4.6 × 250mm, 5 μm);
mobile phase: methanol-ethanol-n-hexane (16: 11: 73)
Sample introduction volume: 10 mu l of the mixture;
flow rate: 1 ml/min;
column temperature: 30 ℃;
detection wavelength: 224 nm.
Experimental procedure
Taking a proper amount of the engelet pharmaceutical composition containing 15mg of engelet, precisely weighing, placing in a 10ml volumetric flask, adding a proper amount of methanol, performing ultrasonic treatment for 10 minutes to completely dissolve the engelet, diluting to a scale, and shaking up to be used as a test solution. And precisely weighing an equal amount of composition which does not contain the empagliflozin and only contains the auxiliary materials, placing the composition into a 10ml volumetric flask, adding methanol for ultrasonic treatment for 10 minutes, diluting to a scale, and shaking up to obtain a blank solution. Taking blank solution and sample solution, performing high performance liquid chromatography under the above chromatographic conditions, and recording chromatogram, as shown in FIG. 5 and FIG. 6. The result shows that the auxiliary material composition does not interfere the detection of the empagliflozin and the optical isomer thereof.
The above-mentioned embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solution of the present invention by those skilled in the art should fall within the protection scope defined by the claims of the present invention without departing from the spirit of the present invention.
Claims (8)
1. A method for separating and measuring empagliflozin and optical isomers thereof by using a high performance liquid chromatography is characterized in that: taking an amylose-tri (3-chloro-4-methylphenyl carbamate) bonded silica gel packed column as a chromatographic column, and taking a mixture of methanol, ethanol and n-hexane as a mobile phase; or taking a cellulose-tri (3-chloro-4-methylphenyl carbamate) bonded silica gel packed column as a chromatographic column, and taking a mixture of acetonitrile and a phosphate buffer solution as a mobile phase; detecting by an ultraviolet detector; wherein the detection wavelength is 224nm, the column temperature is 25-35 ℃, and the preparation of the test solution: taking the raw material medicines of the engelet or the medicine combination thereof, adding methanol, ethanol or acetonitrile to completely dissolve the engelet, diluting and fixing the volume, and preparing a test solution with the concentration of 0.8-2.0 mg/ml.
2. The method of claim 1, wherein the volume ratio of methanol, ethanol, and n-hexane is 16:11: 73.
3. The method of claim 1, wherein the volume ratio of acetonitrile to phosphate buffer solution is 25: 75 to 65: 35.
4. The method of claim 3, wherein the volume ratio of acetonitrile to phosphate buffer solution is 45: 55.
5. the method according to claim 1 or 3, wherein the pH value of the phosphate buffer solution in the mobile phase is 2-6.
6. The method of claim 1, wherein the phosphate is selected from one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and diammonium hydrogen phosphate.
7. The method of claim 1, wherein the phosphate salt is sodium dihydrogen phosphate.
8. The method of claim 1, further comprising the steps of:
(1) taking an engelet raw material medicine or a medicine composition thereof, adding methanol, ethanol or acetonitrile to completely dissolve the engelet, diluting to a constant volume, preparing into a solution containing 0.8-2.0 mg of the engelet in each 1ml of the solution, and filtering to obtain a test solution;
(2) taking an amylose or cellulose derivative chiral column as a chromatographic column, wherein the temperature of the column is 30 ℃, and the wavelength is 224 nm;
(3) and (3) injecting 5-20 mu l of the test solution into a high performance liquid chromatograph, and eluting at the flow rate of 0.8-1ml/min to complete the separation and determination of the empagliflozin and the optical isomer thereof.
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| 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 |
Citations (2)
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| WO2004100895A2 (en) * | 2003-05-13 | 2004-11-25 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a peroxisome proliferator activated receptor agonist for the treatment of ischemic mediated central nervous system disorders |
| WO2006117654A1 (en) * | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Processes for the preparation of pioglitazone or salts thereof |
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| WO2004103283A2 (en) * | 2003-05-14 | 2004-12-02 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a central nervous system stimulant for the treatment of central nervous system damage |
| US7435741B2 (en) * | 2006-05-09 | 2008-10-14 | Teva Pharmaceutical Industries, Ltd. | 2-N{5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]methyl]-2,4-thiazolidinedione} butanedioic acid, methods of preparation and compositions with rosiglitazone maleate |
| US20120093878A1 (en) * | 2010-07-30 | 2012-04-19 | Ranbaxy Laboratories Limited | Pharmaceutical compositions containing a biguanide and a thiazolidinedione |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004100895A2 (en) * | 2003-05-13 | 2004-11-25 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a peroxisome proliferator activated receptor agonist for the treatment of ischemic mediated central nervous system disorders |
| WO2006117654A1 (en) * | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Processes for the preparation of pioglitazone or salts thereof |
Non-Patent Citations (2)
| Title |
|---|
| A quantitative LC–MS/MS method for determining ipragliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, and its application to a pharmacokinetic study in rats;Shinji Kobuchi等;《Journal of Chromatography B》;20150714;第1000卷;全文 * |
| The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study;Arne Ring等;《Cardiovascular Diabetology》;20131231;第12卷;全文 * |
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