CN109580833B - Method for determining enantiomer impurities in sitagliptin raw material and preparation - Google Patents
Method for determining enantiomer impurities in sitagliptin raw material and preparation Download PDFInfo
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- CN109580833B CN109580833B CN201811650287.7A CN201811650287A CN109580833B CN 109580833 B CN109580833 B CN 109580833B CN 201811650287 A CN201811650287 A CN 201811650287A CN 109580833 B CN109580833 B CN 109580833B
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- 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
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- 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
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Abstract
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for determining enantiomer impurities in a sitagliptin raw material and a preparation. The determination method comprises the following steps: selecting chiral crown ether silica gel as a filling agent; taking a mixed solution of perchloric acid solution and acetonitrile as a mobile phase; the sample preparation method comprises the step of dissolving the sitagliptin raw material and the preparation by water. Compared with the prior art, the method for determining the enantiomer impurities in the sitagliptin raw material and the preparation can separate the sitagliptin or the salt thereof from the enantiomer of the sitagliptin, so that the quality of the sitagliptin raw material and the preparation thereof can be effectively controlled; the method has the advantages of strong specificity, strong accuracy, high precision, good durability and convenient operation, and can effectively control the quality of the raw material medicines and the preparation in the actual production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for determining enantiomer impurities in a sitagliptin raw material and a preparation.
Background
Sitagliptin phosphate (Sitagliptin) is a class of oral antihyperglycemic drugs known as dipeptidyl peptidase 4(DPP-4) inhibitors that can improve glycemic control in type 2 diabetic patients by increasing the levels of live gut insulinotropic hormone. Sitagliptin is able to prevent DPP-4 from hydrolyzing gut insulinotropic hormone, thereby increasing plasma concentrations of GLP-1 and GIP in active form. By increasing the active incretin level, sitagliptin is able to increase insulin release and decrease pancreatic glucagon levels in a glucose-dependent manner. For type 2 diabetic patients with hyperglycemia, the above-described changes in insulin and pancreatic glucagon levels can lower glycated hemoglobin A1c (HbA1c) and lower fasting and postprandial blood glucose levels. The glucose-dependent mechanism of action of sitagliptin differs from that of sulfonylureas, which increase insulin secretion even at low glucose levels, thereby causing hypoglycemia in type 2 diabetic patients and normal subjects. Sitagliptin is a potent and highly selective DPP-4 enzyme inhibitor that does not inhibit DPP-8 or DPP-9 closely related to DPP-4 at therapeutic concentrations.
Chiral drug (Chiral drug) refers to a pair of enantiomers which are physical and mirror images of each other and are obtained after a Chiral center is introduced into the structure of a drug molecule. The physical and chemical properties of these enantiomers are substantially similar, with only a difference in optical rotation. Enantiomers of chemical drugs containing chiral factors have significant differences in pharmacological activity, metabolic processes and toxicity in the human body. Thus, often only one of the two isomers is effective and the other is ineffective or even detrimental.
The enantiomeric impurities (form S) of sitagliptin phosphate have the following chemical structures:
USP39 contains the detection method of the enantiomer of the variety, but the practical detection still has problems, the separation degree of the enantiomer and the main peak is not good, the baseline analysis cannot be achieved, and the detection of the enantiomer can be influenced.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for measuring enantiomer impurities in a sitagliptin raw material and a preparation with high separation degree.
The invention relates to a method for measuring enantiomer impurities in sitagliptin raw materials and preparations, which comprises the following steps:
1) a chromatographic column: chiral crown ether silica gel is used as a filling agent; flow rate: 0.2-0.5 mL/min; detection wavelength: 250-280 nm; column temperature: 20-30 ℃; mobile phase: perchloric acid solution acetonitrile (90:10) - (70:30), perchloric acid solution is diluted with water to pH1.0 by 16.3g perchloric acid;
2) preparing a sample solution: preparing a sample to be detected into a 1mg/ml solution by using water; directly placing the solution at-80 deg.C for 2h, and then at 25-28 deg.C for 1h to obtain sample solution;
3) separation and analysis: and injecting 1-10 mu L of sample solution into a high performance liquid chromatograph to complete the determination of enantiomer impurities in the sitagliptin bulk drug and the preparation.
According to the method for determining the enantiomer impurities in the sitagliptin raw materials and the preparation, the enantiomer impurities exist in the form of 7- [ (3R) -3-amino-1-oxo-4- (2,4, 5-trifluorophenyl) butyl ] -5,6,7, 8-tetrahydro-3- (trifluoromethyl) -1,2, 4-triazolone [4,3-a ] pyrazine and pharmaceutically acceptable salts thereof.
The method for measuring enantiomer impurities in the sitagliptin raw material and the preparation has the advantages that the column temperature is 20-25 ℃; the detection wavelength is 260-270 nm; the mobile phase contains formic acid, acetic acid, propionic acid, glacial acetic acid, trifluoroacetic acid or perchloric acid.
According to the method for determining enantiomer impurities in the sitagliptin raw materials and the preparation, the pharmaceutically acceptable salt is phosphate; the chromatographic column is
A CR-I (-) column; the flow rate of the mobile phase is 0.2 mL/min; the column temperature is 20 ℃; the detection wavelength is 268 nm; the mobile phase contains perchloric acid; the proportion of the perchloric acid solution to the acetonitrile is 80: 20; the sample size was 5 μ L.
The method for measuring enantiomer impurities in the sitagliptin raw material and the preparation provided by the invention is that the preparation is a common tablet, a coated tablet, a dispersible tablet, a capsule or a granule.
Compared with the prior art, the method for determining the enantiomer impurities in the sitagliptin raw material and the preparation can separate the sitagliptin or the salt thereof from the enantiomer of the sitagliptin by changing the crystal form of the enantiomer of the sitagliptin, so that the quality of the sitagliptin raw material medicine and the preparation thereof can be effectively controlled; the method has the advantages of strong specificity, strong accuracy, high precision, good durability and convenient operation, and can effectively control the quality of the raw material medicines and the preparation in the actual production.
Drawings
FIG. 1 is a chromatogram for determining the content of enantiomeric impurities in a sitagliptin mixture; FIG. 2 is a chromatogram for measuring the content of enantiomer impurities in the sitagliptin phosphate raw material.
Detailed Description
The following examples are provided to further illustrate the determination of enantiomeric impurities in sitagliptin raw materials and preparations according to the present invention, but the scope of the present invention is not limited thereto.
Example 1
Resolution experiments of enantiomeric impurities in sitagliptin: dissolving a reference substance containing sitagliptin and enantiomers thereof in a diluent and diluting to the concentration of 0.1mg/mL respectively to be used as a test solution; separating by a high performance liquid chromatography system by taking chiral crown ether silica gel as a filling agent and perchloric acid-acetonitrile mixed solution as a mobile phase; the diluent is water. The chromatographic column is
CR-I (-) chromatographic column with mobile phase of perchloric acid solution (taking 16.3g perchloric acid, diluting to 1000ml with water) -acetonitrile (80:20), flow rate of 0.2ml/min, chromatographic column temperature of 20 deg.C, detection wavelength of 268 nm. Precisely measuring 5 μ L of the sample solution, injecting into a liquid chromatograph, and recording chromatogram with elution time of 15 min. The chromatographic separation results are: the retention time of sitagliptin chromatographic peak is 8.463min, the retention time of sitagliptin isomer chromatographic peak is 7.682min, and the separation degree of the two is 1.46.
Example 2
Resolution experiments of enantiomeric impurities in sitagliptin: dissolving a reference substance containing sitagliptin and enantiomers thereof in a diluent, diluting to a solution with the concentration of 0.1mg/mL, directly placing the solution at-80 ℃ for 2h, and then placing at 25-28 ℃ for 1h to obtain a test solution; separating by a high performance liquid chromatography system by taking chiral crown ether silica gel as a filling agent and perchloric acid-acetonitrile mixed solution as a mobile phase; the diluent is water. The chromatographic column is
CR-I (-) chromatographic column with mobile phase of perchloric acid solution (taking 16.3g perchloric acid, diluting to 1000ml with water) -acetonitrile (80:20), flow rate of 0.2ml/min, chromatographic column temperature of 20 deg.C, detection wavelength of 268 nm. Precisely measuring 5 μ L of the sample solution, injecting into a liquid chromatograph, and recording chromatogram with elution time of 15 min. The chromatographic separation results are shown in FIG. 1, fromAs can be seen in the attached figure 1, the retention time of the sitagliptin chromatographic peak is 8.447min, the retention time of the sitagliptin isomer chromatographic peak is 6.346min, and the separation degree of the sitagliptin chromatographic peak and the sitagliptin isomer chromatographic peak is 3.81. The delay in the time of appearance of the sitagliptin isomer is estimated to be related to the change of the crystal form of the enantiomer of sitagliptin.
Example 3
Content determination experiment of enantiomer impurities in sitagliptin phosphate raw material: dissolving a sitagliptin phosphate raw material in a diluent, diluting to a solution with the concentration of 1mg/mL, directly placing the solution at-80 ℃ for 2 hours, and then placing at 25-28 ℃ for 1 hour to obtain a test solution; separating by a high performance liquid chromatography system by taking chiral crown ether silica gel as a filling agent and perchloric acid-acetonitrile mixed solution as a mobile phase; the diluent is water. The chromatographic column is
CR-I (-) chromatographic column with mobile phase of perchloric acid solution (taking 16.3g perchloric acid, diluting to 1000ml with water) -acetonitrile (80:20), flow rate of 0.2ml/min, chromatographic column temperature of 20 deg.C, detection wavelength of 268 nm. Precisely measuring 5 μ L of the sample solution, injecting into a liquid chromatograph, and recording chromatogram with elution time of 15 min. The chromatographic separation result is shown in figure 2, and as can be seen from figure 2, sitagliptin isomers and sitagliptin chromatographic peaks can be well separated and well detected.
Claims (4)
1. A method for measuring enantiomer impurities in sitagliptin raw materials and preparations is characterized by comprising the following specific steps:
1) a chromatographic column: chiral crown ether silica gel is used as a filling agent; flow rate: 0.2-0.5 mL/min; detection wavelength: 250-280 nm; column temperature: 20-30 ℃; mobile phase: perchloric acid solution and acetonitrile in a volume ratio of 90: 10-70: 30; the perchloric acid solution is prepared by diluting 16.3g of perchloric acid with water to pH1.0;
2) preparing a sample solution: preparing a sample to be detected into a 1mg/mL solution by using water; placing the solution at-80 deg.C for 2h, and then at 25-28 deg.C for 1h to obtain sample solution;
3) separation and analysis: injecting 1-10 mu L of sample solution into a high performance liquid chromatograph to complete the determination of enantiomer impurities in the sitagliptin bulk drug and the preparation;
the enantiomeric impurity is present in the form of 7- [ (3R) -3-amino-1-oxo-4- (2,4, 5-trifluorophenyl) butyl ] -5,6,7, 8-tetrahydro-3- (trifluoromethyl) -1,2, 4-triazolone [4,3-a ] pyrazine and pharmaceutically acceptable salts thereof.
2. The method for determining enantiomer impurities in sitagliptin raw materials and preparations according to claim 1, characterized in that the column temperature is 20-25 ℃; the detection wavelength is 260-270 nm.
3. The method for the determination of enantiomeric impurities in sitagliptin raw materials and preparations according to claim 1, wherein the pharmaceutically acceptable salt is phosphate; the chromatographic column is a CROWNPAK CR-I (-) chromatographic column; the flow rate of the mobile phase is 0.2 mL/min; the column temperature is 20 ℃; the detection wavelength is 268 nm; the mobile phase contains perchloric acid; the volume ratio of the perchloric acid solution to the acetonitrile is 80: 20; the amount of sample was 5. mu.L.
4. The method for determining enantiomer impurities in sitagliptin raw materials and preparations according to claim 1, characterized in that the preparations are ordinary tablets, coated tablets, dispersible tablets, capsules or granules.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104458945A (en) * | 2014-01-24 | 2015-03-25 | 广东东阳光药业有限公司 | Separation and measurement method of besifloxacin hydrochloride and isomer of besifloxacin hydrochloride |
| CN104749269A (en) * | 2013-12-31 | 2015-07-01 | 中美华世通生物医药科技（武汉）有限公司 | Method for determining enantiomer impurity in alogliptin crude drug and preparation by virtue of HPLC |
| CN106124667A (en) * | 2016-08-29 | 2016-11-16 | 上海应用技术学院 | A kind of method that separation determination sitagliptin has related substance |
| CN107543872A (en) * | 2016-06-29 | 2018-01-05 | 南京长澳医药科技有限公司 | Pass through chiral hplc separation determination toluenesulfonic acid Yi Dushaban hydrates and the method for its isomer impurities |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153559B (en) * | 2011-02-28 | 2013-04-24 | 南京工业大学 | Novel method for synthesizing sitagliptin phosphate and derivative thereof |
| EP2508506A1 (en) * | 2011-04-08 | 2012-10-10 | LEK Pharmaceuticals d.d. | Preparation of sitagliptin intermediates |
| CN103760264A (en) * | 2014-01-15 | 2014-04-30 | 浙江理工大学 | Chiral separation method for phenylalanine derivative enantiomers |
| IN2014MU00212A (en) * | 2014-01-21 | 2015-08-28 | Cadila Healthcare Ltd | |
| TWI532993B (en) * | 2015-06-18 | 2016-05-11 | 高雄醫學大學 | A method for detecting sitagliptin |
| CN106478637B (en) * | 2016-08-30 | 2018-08-21 | 南京正大天晴制药有限公司 | A kind of impurity and its preparation, detection method of Xi Gelieting |
| CN108918692A (en) * | 2018-04-27 | 2018-11-30 | 丽珠集团新北江制药股份有限公司 | A kind of method of separating and assaying of L-2- amino-butanamide hydrochloride and its isomers |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104749269A (en) * | 2013-12-31 | 2015-07-01 | 中美华世通生物医药科技（武汉）有限公司 | Method for determining enantiomer impurity in alogliptin crude drug and preparation by virtue of HPLC |
| CN104458945A (en) * | 2014-01-24 | 2015-03-25 | 广东东阳光药业有限公司 | Separation and measurement method of besifloxacin hydrochloride and isomer of besifloxacin hydrochloride |
| CN107543872A (en) * | 2016-06-29 | 2018-01-05 | 南京长澳医药科技有限公司 | Pass through chiral hplc separation determination toluenesulfonic acid Yi Dushaban hydrates and the method for its isomer impurities |
| CN106124667A (en) * | 2016-08-29 | 2016-11-16 | 上海应用技术学院 | A kind of method that separation determination sitagliptin has related substance |
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