CN110873763A - Method for separating and measuring optical isomers of starting material of brivaracetam by gas chromatography - Google Patents
Method for separating and measuring optical isomers of starting material of brivaracetam by gas chromatography Download PDFInfo
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- CN110873763A CN110873763A CN201811019981.9A CN201811019981A CN110873763A CN 110873763 A CN110873763 A CN 110873763A CN 201811019981 A CN201811019981 A CN 201811019981A CN 110873763 A CN110873763 A CN 110873763A
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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
- G01N30/06—Preparation
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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
- G01N30/60—Construction of the column
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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
- G01N30/60—Construction of the column
- G01N30/6052—Construction of the column body
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- G—PHYSICS
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- G01N30/02—Column chromatography
- G01N30/60—Construction of the column
- G01N30/6052—Construction of the column body
- G01N30/6073—Construction of the column body in open tubular form
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- G—PHYSICS
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- 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
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- 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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- G01N2030/062—Preparation extracting sample from raw material
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Abstract
The invention belongs to the field of analytical chemistry, and discloses a method for rapidly separating and detecting optical purity of a starting material (R) -4-propyl-dihydrofuran-2-one of brivaracetam by using a gas chromatography. The method has the advantages of strong specificity, high accuracy, good durability and simple and quick operation.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and determining a starting material of brivaracetam and an optical isomer of the brivaracetam by using a gas chromatography.
Background
The brivaracetam is an antiepileptic drug developed by pharmaceutical companies (UCB) with better time, has wide antiepileptic activity and higher safety, can play an antiepileptic effect by combining with synaptovesicular protein SV20A, and is used for adjuvant therapy of partial epileptic seizure of epileptic patients over 16 years old. UCB submits new drug application to the United states Food and Drug Administration (FDA) for marketing, submits new drug application and approval application to the European drug administration (EMA) for marketing in 2015, and according to the clinical research data of the original research company, the anticonvulsant capacity of the Buvalracetam is 10 times stronger than that of the first-grade drug levetiracetam in the field of epilepsy drugs, and the Buvalracetam is expected to become a new leader in the market of epilepsy drugs. The chemical name of the Buvalacetam is (2S) -2- [ (4R) -2-oxo-4-n-propyl-1-pyrrolidinyl ] butanamide, and the structural formula is as follows:
in the process of drug research and development, it is particularly important to establish a chiral analysis method for bulk drugs, starting materials and key intermediates. The brivaracetam has a chiral center, is an optically active compound, and in order to better control the active ingredients of the brivaracetam, a chiral quality control analysis method is established for the starting material (R) -4-propyl-dihydrofuran-2-ketone, wherein 2 optical isomers to be controlled are (R) -4-propyl-dihydrofuran-2-ketone, and the structural formula is as follows:
and (S) -4-propyl-dihydrofuran-2-one, of the formula:
the optical impurities of the starting material of the brivaracetam are not completely removed, and the optical impurities can be introduced into the final product of the bulk drug, so that the purity and the quality of the drug are influenced. Therefore, the method realizes separation and determination of the starting material of the brivaracetam and the optical isomer thereof, can ensure the purity of reactants in the brivaracetam synthesis process, reduces the occurrence of side reactions and the generation of impurities, and has important practical significance in the aspects of brivaracetam production and quality control.
Disclosure of Invention
The invention aims to provide a method for analyzing the purity of a starting material (R) -4-propyl-dihydrofuran-2-ketone of the brivaracetam and separating an optical isomer of the brivaracetam, so that the separation and the determination of the starting material of the brivaracetam and the optical isomer of the brivaracetam are realized, the purity of the starting material of the brivaracetam is ensured, the occurrence of side reactions is reduced, and the product yield is improved.
The method for analyzing the purity of the starting material of the brivaracetam and separating the optical isomer of the brivaracetam by using the gas chromatography selects a proper solvent to dissolve a sample, and adopts a cyclodextrin capillary chromatographic column;
the solvent can be one or more of acetonitrile, methanol, dichloromethane or dimethyl sulfoxide.
The chromatographic column is capillary chromatographic column filled with CYCLOSIL-B, LIPODEX C, Rt- β DEXm, β -DEX110 or β -DEX 120.
The chromatographic column is a cyclodextrin chiral chromatographic column.
The separation and measurement method of the present invention can be realized by the following method:
1) taking a proper amount of a starting material racemate of the brivaracetam, and dissolving the starting material racemate with a solvent to prepare a system applicability solution containing the brivaracetam starting material and optical isomers of the brivaracetam starting material at a concentration of 0.5-1.0 mg/ml; taking a proper amount of a starting material of the brivaracetam, dissolving the starting material of the brivaracetam by using a solvent to prepare a test solution containing 0.5-1.0 mg/ml of the starting material of the brivaracetam, and injecting the test solution into a gas chromatograph for analysis;
2) setting the temperature of a sample inlet to be 200-250 ℃, the flow rate of a carrier gas to be 0.8-2.0 ml/min, and performing a programmed heating method, wherein the temperature raising program is an initial temperature of 60 ℃, keeping the temperature for 0-2 min, raising the temperature to 180 ℃ at a temperature raising rate of 5-10 ℃ per minute, keeping the temperature for 3-5 min, raising the temperature to 220 ℃ at a temperature raising rate of 5-10 ℃ per minute, keeping the temperature for 3-5 min, the temperature of a detector to be 250-300 ℃, and the split ratio to be 10: 1-20: 1;
3) the solvent is one or more of acetonitrile, methanol, dichloromethane or dimethyl sulfoxide;
4) and (3) respectively taking 1-3 mul of the system applicability solution and the sample solution in the step 1), and injecting the solution into a gas chromatograph according to the chromatographic conditions in the step 2) to finish the separation and determination of the starting material of the brivaracetam and the optical isomer of the starting material.
The type of the gas chromatograph has no special requirements, and the gas chromatograph adopted by the invention is an Agilent 6890N gas chromatograph
A detector: a hydrogen flame ionization detector;
a chromatographic column: CYCLOSIL-B capillary chromatography column (Agilent, 30m × 0.25mm × 0.25 μm)
Sample inlet temperature: 240 ℃;
detector temperature: 280 ℃;
carrier gas (nitrogen) flow rate: 1.0 ml/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 μ l
Column box temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 60 | 0 |
| 20 | 160 | 0 |
| 5 | 180 | 3 |
| 5 | 220 | 8 |
The method adopts a gas chromatography, selects a CYCLOSIL-B (Agilent, 30m multiplied by 0.25mm multiplied by 0.25 mu m) capillary chromatographic column, can quickly and effectively separate and measure the starting material of the brivaracetam and the optical isomer thereof, and accurately measures the purity of the brivaracetam starting material, solves the separation and measurement problems of the brivaracetam starting material and the optical isomer thereof, ensures the purity of the brivaracetam starting material, and thus ensures the controllable quality of the brivaracetam raw material medicine (the result is shown in the attached figures 1-5).
Drawings
FIG. 1 is a solvent gas chromatogram of example 1;
FIG. 2 is a gas chromatogram of the starting material of brivaracetam and its optical isomers in example 1;
FIG. 3 is a gas chromatogram of the starting material of brivaracetam in example 1;
FIG. 4 is a gas chromatogram of the starting material of brivaracetam and related substances in example 2;
FIG. 5 is a gas chromatogram of the starting material of brivaracetam and related substances in example 3;
the specific implementation mode is as follows:
the following examples are presented to further understand the present invention, but are not intended to limit the scope of the practice. The optical purity of the starting material of bwait and the method for detecting the optical isomer thereof according to the present invention are further described in detail below by way of examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and all the technologies achieved based on the above contents of the present invention are within the scope of the present invention.
Example 1
Apparatus and conditions
Chromatograph: agilent 6890N gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: CYCLOSIL-B capillary chromatography column (Agilent, 30m × 0.25mm × 0.25 μm)
Sample inlet temperature: 240 ℃;
detector temperature: 280 ℃;
carrier gas (nitrogen) flow rate: 1.0 ml/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 μ l
Column box temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 60 | 0 |
| 20 | 160 | 0 |
| 5 | 180 | 3 |
| 5 | 220 | 8 |
Experimental procedure
Taking a proper amount of the racemate of the starting material of the brivaracetam, and dissolving the racemate by using a solvent to prepare a system applicability solution containing the brivaracetam starting material and optical isomers of the brivaracetam starting material of 1.0 mg/ml; taking a proper amount of the starting material of the bravaracetam, dissolving the starting material of the bravaracetam by using a solvent to prepare a test solution containing 1.0mg of the starting material of the bravaracetam per 1ml, injecting the test solution into a gas chromatograph, analyzing according to the chromatographic conditions, and recording a chromatogram. The result is shown in the attached figures 1-3, and the figure 1 is a blank solution chromatogram; in FIG. 2, the chromatographic peak with the retention time of 8.167min is the starting material of the brivaracetam, and the chromatographic peak with the retention time of 10.607min is the chromatographic peak of the optical isomer of the starting material of the brivaracetam; the chromatographic peak with retention time of 8.107min in FIG. 3 is the starting material of the brivaracetam; FIGS. 1 to 3 show that: the method provided by the invention can quickly and effectively separate and measure the starting material of the brivaracetam and the optical isomer of the brivaracetam, and can accurately carry out quantitative detection, thereby achieving the effective control of the purity and quality of the brivaracetam starting material.
Example 2
Chromatograph: agilent 6890N gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: CYCLOSIL-B capillary chromatography column (Agilent, 30m × 0.25mm × 0.25 μm)
Sample inlet temperature: 240 ℃;
detector temperature: 280 ℃;
carrier gas (nitrogen) flow rate: 0.8 ml/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 μ l
Column box temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 60 | 0 |
| 20 | 160 | 0 |
| 5 | 180 | 3 |
| 5 | 220 | 8 |
Experimental procedure
Taking a proper amount of the starting material racemate of the bravaracetam, dissolving the starting material racemate with a solvent to prepare a system applicability solution containing the starting material of the bravaracetam and optical isomers of the starting material of the bravaracetam 1.0mg/ml, injecting the system applicability solution into a gas chromatograph, analyzing according to the chromatographic conditions, and recording a chromatogram map. The result is shown in figure 4, the chromatographic peak with the retention time of 8.968min in figure 4 is the starting material of the brivaracetam, and the chromatographic peak with the retention time of 11.207min is the chromatographic peak of the optical isomer of the starting material of the brivaracetam. As can be seen from the figure, the intermediate of the brivaracetam and the optical isomer thereof can achieve baseline separation and meet the requirements of Chinese pharmacopoeia.
Example 3
Chromatograph: agilent 6890N gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: CYCLOSIL-B capillary chromatography column (Agilent, 30m × 0.25mm × 0.25 μm)
Sample inlet temperature: 230 ℃;
detector temperature: 250 ℃;
carrier gas (nitrogen) flow rate: 1.0 ml/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 μ l
Column box temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 60 | 0 |
| 20 | 160 | 0 |
| 5 | 180 | 3 |
| 5 | 220 | 8 |
Experimental procedure
Taking a proper amount of the starting material racemate of the bravaracetam, dissolving the starting material racemate with a solvent to prepare a system applicability solution containing the starting material of the bravaracetam and optical isomers of the starting material of the bravaracetam 1.0mg/ml, injecting the system applicability solution into a gas chromatograph, analyzing according to the chromatographic conditions, and recording a chromatogram map. The result is shown in figure 5, the chromatographic peak with the retention time of 8.149min in figure 5 is the starting material of the brivaracetam, and the chromatographic peak with the retention time of 10.612min is the chromatographic peak of the optical isomer of the starting material of the brivaracetam. As can be seen from the figure, the intermediate of the brivaracetam and the optical isomer thereof can achieve baseline separation and meet the requirements of Chinese pharmacopoeia.
The invention verifies the following items of the starting material of the brivaracetam and the optical isomer analysis method thereof:
experiment of system applicability
Taking a proper amount of the racemate of the starting material of the brivaracetam, and dissolving the racemate by using a solvent to prepare a system applicability solution containing 1.0mg/ml of the starting material of the brivaracetam and optical isomers of the starting material of the brivaracetam. Gas chromatography was carried out according to the chromatographic conditions of example 1 and chromatograms were recorded. It can be seen from FIG. 2 that under these conditions, the separation between the relevant substance and the main peak is satisfactory.
Sample introduction repeatability test
Taking a sample solution of a starting material of the brivaracetam, repeatedly injecting samples for 6 times according to the chromatographic conditions of the example 1, and inspecting the repeatability of the method. As can be seen from the results, the method had good reproducibility
| Number of samples taken | 1 | 2 | 3 | 4 | 5 | 6 | Mean value of | RSD% |
| Starting material of Buvalsartan | 55150.2 | 54892.3 | 55105.7 | 55124.5 | 55821.4 | 55311.6 | 55234.3 | 0.57 |
Claims (7)
1. A method for separating and detecting optical isomers of a starting material of brivaracetam by using a gas chromatography is characterized by comprising the following steps: and (3) selecting a proper solvent to dissolve a sample, and selecting a cyclodextrin chiral capillary chromatographic column and a hydrogen flame ionization detector according to the structure and the physicochemical property of a substance to be analyzed.
2. The separation and determination method according to claim 1, wherein the solvent is one or more selected from acetonitrile, methanol, dichloromethane or dimethyl sulfoxide.
3. The separation assay of claim 1, wherein the chiral chromatographic column is CYCLOSIL-B, LIPODEX C, Rt- β DEX, β -DEX110 or β -DEX 120.
4. The separation assay method of claim 1, comprising the steps of:
1) taking a proper amount of a starting material racemate of the brivaracetam, and dissolving the starting material racemate with a solvent to prepare a system applicability solution containing the brivaracetam starting material and optical isomers of the brivaracetam starting material at a concentration of 0.5-1.0 mg/ml; taking a proper amount of a starting material of the brivaracetam, and dissolving the starting material of the brivaracetam by using a solvent to prepare a test solution containing 0.5-1.0 mg/ml of the starting material of the brivaracetam;
2) setting the temperature of a sample inlet to be 200-250 ℃, the flow rate of a carrier gas to be 0.8-2.0 ml/min, and performing a programmed heating method, wherein the temperature raising program is an initial temperature of 60 ℃, keeping the temperature for 0-2 min, raising the temperature to 180 ℃ at a temperature raising rate of 5-10 ℃ per minute, keeping the temperature for 3-5 min, raising the temperature to 220 ℃ at a temperature raising rate of 5-10 ℃ per minute, keeping the temperature for 3-5 min, the temperature of a detector to be 250-300 ℃, and the split ratio to be 10: 1-20: 1;
3) and (3) respectively taking 1-3 mul of the system applicability solution and the sample solution in the step 1), and injecting the solution into a gas chromatograph according to the chromatographic conditions in the step 2) to finish the separation and determination of the starting material of the brivaracetam and the optical isomer of the starting material.
5. The separation analysis method according to claim 4, wherein said carrier gas of step 2) is nitrogen or helium.
6. The separation analysis method according to claim 4, wherein the flow rate of said carrier gas in step 2) is preferably 1 ml/min.
7. The separation and analysis method according to claim 4, wherein the programmed temperature raising method in step 2) is preferably performed by the following temperature raising program:
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Cited By (1)
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|---|---|---|---|---|
| CN115128194A (en) * | 2022-08-31 | 2022-09-30 | 天津辰欣药物研究有限公司 | Method for determining impurities in brivaracetam starting material by using gas chromatography |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115128194A (en) * | 2022-08-31 | 2022-09-30 | 天津辰欣药物研究有限公司 | Method for determining impurities in brivaracetam starting material by using gas chromatography |
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