CN110836930A - Method for measuring content of dichlorobutane in levetiracetam by gas chromatography-mass spectrometry - Google Patents
Method for measuring content of dichlorobutane in levetiracetam by gas chromatography-mass spectrometry Download PDFInfo
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- CN110836930A CN110836930A CN201810938514.XA CN201810938514A CN110836930A CN 110836930 A CN110836930 A CN 110836930A CN 201810938514 A CN201810938514 A CN 201810938514A CN 110836930 A CN110836930 A CN 110836930A
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- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 title claims abstract description 7
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract 9
- SEQRDAAUNCRFIT-UHFFFAOYSA-N 1,1-dichlorobutane Chemical compound CCCC(Cl)Cl SEQRDAAUNCRFIT-UHFFFAOYSA-N 0.000 title description 2
- KJDRSWPQXHESDQ-UHFFFAOYSA-N 1,4-dichlorobutane Chemical compound ClCCCCCl KJDRSWPQXHESDQ-UHFFFAOYSA-N 0.000 claims abstract description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 239000000243 solution Substances 0.000 claims description 22
- 239000012159 carrier gas Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000001819 mass spectrum Methods 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- 230000014759 maintenance of location Effects 0.000 claims description 6
- 239000012085 test solution Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 229920001296 polysiloxane Polymers 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000010812 external standard method Methods 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims 3
- 238000010438 heat treatment Methods 0.000 claims 2
- 238000000691 measurement method Methods 0.000 claims 2
- 239000000523 sample Substances 0.000 claims 2
- 238000003556 assay Methods 0.000 claims 1
- 239000001307 helium Substances 0.000 claims 1
- 229910052734 helium Inorganic materials 0.000 claims 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims 1
- 239000013558 reference substance Substances 0.000 claims 1
- 239000012488 sample solution Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000035945 sensitivity Effects 0.000 abstract description 3
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 26
- 150000002500 ions Chemical class 0.000 description 16
- 238000010586 diagram Methods 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 3
- 206010061334 Partial seizures Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000007674 genetic toxicity Effects 0.000 description 2
- 231100000025 genetic toxicology Toxicity 0.000 description 2
- -1 polysiloxane Polymers 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 1
- 239000000064 cholinergic agonist Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention belongs to the field of analytical chemistry, and discloses a method for separating and detecting 1, 4-dichlorobutane in levetiracetam by using a gas chromatography-mass spectrometry combination method, which adopts a methylpolysiloxane type moderately polar capillary chromatographic column and can quantitatively detect the content of trace 1, 4-dichlorobutane in levetiracetam. The method has strong specificity, high sensitivity and good reproducibility, can qualitatively or quantitatively detect the 1, 4-dichlorobutane in the levetiracetam, and ensures the quality of the levetiracetam, thereby improving the safety of clinical medication.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and determining 1, 4-dichlorobutane in levetiracetam by a gas chromatography-mass spectrometry combined method.
Background
Levetiracetam belongs to the second-generation acetylcholine agonist, is clinically used for treating partial seizures or secondary full seizures of adults and children over 4 years old by adding, and also can be used for treating partial seizures or secondary full seizures of epilepsy by using a single medicine. The chemical name of levetiracetam is (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide with the molecular formula C8H14N2O2The structural formula is as follows:
1, 4-dichlorobutane is a process byproduct that may be introduced during the synthesis of levetiracetam. 1, 4-dichlorobutane is a compound with a genetic toxicity warning structure, and if the 1, 4-dichlorobutane is not completely removed in the drug synthesis process, the purity and the quality of the drug are seriously influenced, and the safety of clinical medication is caused, so a high-sensitivity method is strictly adoptedThe content of 1, 4-dichlorobutane was controlled. 1, 4-dichlorobutane having the molecular formula C4H8Cl2The structural formula is as follows:
because the 1, 4-dichlorobutane is a compound with a genetic toxicity warning structure, the separation and determination of the 1, 4-dichlorobutane in the levetiracetam are realized, the detection sensitivity of the 1, 4-dichlorobutane is improved, and the method has important practical significance in ensuring the quality of the levetiracetam and improving the safety of the levetiracetam clinical medication.
Disclosure of Invention
The invention aims to provide a method for analyzing the content of 1, 4-dichlorobutane in levetiracetam, so that the content of 1, 4-dichlorobutane in levetiracetam is controlled, the quality of a levetiracetam final product is effectively controlled, and the safety of clinical medication is improved.
The invention relates to a method for separating and detecting the content of 1, 4-dichlorobutane in levetiracetam by a gas chromatography-mass spectrometry combined method, which is characterized by comprising the following steps: the sample is dissolved by selecting proper solvent, the medium polarity capillary chromatographic column and the mass spectrum detector in methyl polysiloxane are selected, and the SIM scanning mode is adopted, so that the detection sensitivity can be improved to be below 0.5ppm
The solvent is one or more of acetonitrile, methanol or absolute ethyl alcohol.
The chromatographic column is selected from Agilent, OHIO VALLEY or Phenomenex.
The chromatographic column is a medium polarity polysiloxane capillary chromatographic column.
The separation and determination method of the invention can be realized according to the following steps:
1) taking a proper amount of levetiracetam, and adding acetonitrile to dissolve the levetiracetam to prepare a solution containing 20-500 mg of levetiracetam in every 1ml, wherein the solution is used as a test solution; an appropriate amount of 1, 4-dichlorobutane was dissolved in acetonitrile to give a solution containing 0.05. mu.g of 1, 4-dichlorobutane per 1ml, which was used as a control solution.
2) Setting the temperature of a sample inlet to be 220-240 ℃, the flow rate of a carrier gas to be 1.2-1.8 mL/min, and performing a temperature-raising method, wherein the temperature-raising program is an initial temperature of 70 ℃, the holding time is 2min, the temperature-raising speed is 20 ℃ per minute to 230 ℃, the holding time is 4-10 min, and the split ratio is 2: 1-10: 1;
3) the mass spectrum parameters were set as: the ionization mode is an EI source; the temperature of the quadrupole rods is 150-325 ℃; the temperature of the ion source is 200-300 ℃; the scan mode is SIM.
4) And (3) respectively taking 0.8-3 mu L of the test solution and the reference solution in the step 1), injecting the test solution and the reference solution into a gas chromatography-mass spectrometer under the conditions of the step 2) and the step 3), and calculating the content of the 1, 4-dichlorobutane by adopting an external standard method. Wherein:
the type of the gas chromatography-mass spectrometer has no special requirements, and the instrument adopted by the invention is Agilent 7890A gas chromatograph and Agilent 5975C mass spectrometer
A chromatographic column: DB-624 capillary chromatography column (30 m 0.25mm, 1.4 μm);
sample inlet temperature: 230 ℃;
scanning mode: a SIM;
scanning ions:m/e55.1
temperature of the quadrupole rods: 200 ℃;
ion source temperature: 230 ℃;
carrier gas (nitrogen) flow rate: 1.5 mL/min;
the split ratio is as follows: 2: 1;
sample introduction volume: 1 μ L
Column box temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 70 | 2 |
| 20 | 230 | 10 |
The invention adopts a gas chromatography-mass spectrometry combined method, selects a methylpolysiloxane type medium polarity capillary chromatographic column (30 m x 0.25mm, 1.4 mu m), and can effectively separate and measure the content of 1, 4-dichlorobutane in levetiracetam. The invention solves the problem of qualitative and quantitative detection of 1, 4-dichlorobutane in levetiracetam, realizes the quality control of levetiracetam and improves the safety of clinical medication.
Drawings
FIG. 1 is an ion flow diagram of a space-time white solvent of example 1;
FIG. 2 is an ion flow diagram of a system suitability solution in example 1;
FIG. 3 is an ion flow diagram of a space-time white solvent in example 2;
FIG. 4 is an ion flow diagram of a system suitability solution in example 2;
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 method for detecting the content of 1, 4-dichlorobutane in levetiracetam according to the present invention is further described in detail by way of examples below, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and that all technologies implemented based on the teachings of the present invention fall within the scope of the present invention.
Example 1
Apparatus and conditions
Chromatograph: agilent 7890A gas chromatograph;
mass spectrometry: agilent 5975C mass spectrometer
A chromatographic column: DB-624 capillary chromatography column (30 m 0.25mm, 1.4 μm);
sample inlet temperature: 230 ℃;
scanning mode: a SIM;
temperature of the quadrupole rods: 200 ℃;
ion source temperature: 230 ℃;
carrier gas (nitrogen) flow rate: 1.5 mL/min;
the split ratio is as follows: 2: 1;
sample introduction volume: 1 μ L
Column box temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 70 | 2 |
| 20 | 230 | 10 |
Experimental procedure
Taking a proper amount of levetiracetam samples, dissolving the samples with acetonitrile to prepare a solution containing about 100mg of levetiracetam per 1mL, taking a proper amount of 1, 4-dichlorobutane samples, dissolving the samples with acetonitrile to prepare a solution containing about 5mg of 1, 4-dichlorobutane per 1 mL; and taking appropriate amount of each levetiracetam solution and 1, 4-dichlorobutane solution to prepare system applicability solution. Acetonitrile was also taken as a blank solution. And analyzing according to the conditions of the chromatogram and the mass spectrum, and recording an ion flow diagram. The result is shown in attached figures 1-2, and figure 1 is a blank solvent ion flow diagram; the peak of the mass spectrum at retention time 4.414min in FIG. 2 is 1, 4-dichlorobutane.
Example 2
Apparatus and conditions
Chromatograph: agilent 7890A gas chromatograph;
mass spectrometry: agilent 5975C mass spectrometer
A chromatographic column: DB-624 capillary chromatography column (30 m 0.25mm, 1.4 μm);
sample inlet temperature: 230 ℃;
scanning mode: a SIM;
temperature of the quadrupole rods: 200 ℃;
ion source temperature: 230 ℃;
carrier gas (nitrogen) flow rate: 1.5 mL/min;
the split ratio is as follows: 5: 1;
sample introduction volume: 1 μ L
Column box temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 70 | 2 |
| 20 | 230 | 10 |
Experimental procedure
Taking a proper amount of levetiracetam samples, dissolving the samples by acetonitrile to prepare a solution containing about 100mg of levetiracetam per 1mL, taking another proper amount of 1, 4-dichlorobutane samples, dissolving the samples by acetonitrile to prepare a solution containing about 5mg of 1, 4-dichlorobutane per 1 mL; and taking appropriate amount of each levetiracetam solution and 1, 4-dichlorobutane solution to prepare system applicability solution. Acetonitrile was also taken as a blank solution. And analyzing according to the conditions of the chromatogram and the mass spectrum, and recording an ion flow diagram. The results are shown in the attached figures 3-4, and the figure 3 is a blank solvent ion flow diagram; the mass spectrum peak at retention time 4.416min in FIG. 4 was 1, 4-dichlorobutane.
The invention verifies the following items of the method for analyzing the content of the 1, 4-dichlorobutane:
limit of quantification
Taking a proper amount of 1, 4-dichlorobutane, precisely weighing, dissolving a sample with acetonitrile, preparing a responsive test solution, precisely weighing a proper amount of the test solution, gradually diluting, and carrying out sample injection investigation according to the conditions of the example 1. The limit of quantitation of 1, 4-dichlorobutane was 9.41 pg.
Durability
By fine-tuning the conditions of the sample inlet temperature, carrier gas flow rate, quadrupole rod temperature, ion source temperature, chromatography column brand and other chromatography and mass spectrometry, we further investigated the durability of the method. As a result, the method is found to have good durability under the conditions of chromatographic columns of different brands, the variation of the temperature of a sample inlet is +/-10 ℃, the variation of the flow rate of carrier gas is +/-0.3 mL/min, the variation of the temperature of a quadrupole rod is +/-15 ℃, the temperature of an ion source is +/-30 ℃, and the like. Under the conditions of chromatographic columns of different brands, different injection port temperatures, carrier gas flow rates, different quadrupole rod temperatures and ion source temperatures, the detection of the 1, 4-dichlorobutane is not influenced.
Claims (9)
1. A method for separating and detecting the content of 1, 4-dichlorobutane in levetiracetam by a gas chromatography-mass spectrometry combined method is characterized by comprising the following steps: and (3) selecting a proper solvent to dissolve a sample, selecting a methylpolysiloxane type medium polarity capillary chromatographic column and a mass spectrum detector, and adopting an SIM scanning mode.
2. The method according to claim 1, wherein the solvent is one or more selected from acetonitrile, methanol and absolute ethanol.
3. The separation and measurement method according to claim 1, wherein the column is selected from Agilent, OHIO VALLEY, Phenomenex brand.
4. The separation and measurement method according to claim 1, wherein the column is a medium-polarity silicone capillary column.
5. The separation assay method of claim 1, comprising the steps of:
1) taking a proper amount of levetiracetam, and adding acetonitrile to dissolve the levetiracetam to prepare a solution containing 20-500 mg of levetiracetam in every 1ml, wherein the solution is used as a test solution; an appropriate amount of 1, 4-dichlorobutane was dissolved in acetonitrile to give a solution containing 0.05. mu.g of 1, 4-dichlorobutane per 1ml, which was used as a control solution.
6.2) setting the temperature of a sample inlet to be 220-240 ℃, the flow rate of carrier gas to be 1.2-1.8 mL/min, and adopting a programmed heating method, wherein the heating program is that the initial temperature is 70 ℃, the holding time is 2min, the heating speed is increased to 230 ℃ at 20 ℃ per minute, the holding time is 4-10 min, and the split ratio is 2: 1-10: 1;
3) the mass spectrum parameters were set as: the ionization mode is an EI source; the temperature of the quadrupole rods is 150-325 ℃; the temperature of the ion source is 200-300 ℃; the scan mode is SIM.
7.4) taking 0.8-3 mu L of each of the sample solution and the reference substance solution in the step 1), injecting the solution into a gas chromatography-mass spectrometer under the conditions of the step 2) and the step 3), and calculating the content of the 1, 4-dichlorobutane by adopting an external standard method.
8. The separation analysis method according to claim 5, wherein said carrier gas of step 2) is nitrogen or helium.
9. The separation and analysis method according to claim 5, wherein the programmed temperature raising method in step 2) is preferably a temperature raising program comprising:
The separation and analysis method according to claim 5, wherein the temperature of the injection port in step 2) is preferably 230 ℃; the temperature of the quadrupole rods is preferably 200 ℃; the ion source temperature is preferably 230 ℃; the split ratio is preferably 2: 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112326860A (en) * | 2020-10-30 | 2021-02-05 | 淄博高新技术产业开发区生物医药研究院 | Method for simultaneously detecting genotoxic impurities of 1, 4-dichlorobutane and 1-chloro-4-hydroxybutane in bulk drug or preparation |
| CN112630354A (en) * | 2021-01-22 | 2021-04-09 | 烟台东诚药业集团股份有限公司 | Method for determining two kinds of chloralkane gene toxic impurities in amino acid medicine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112326860A (en) * | 2020-10-30 | 2021-02-05 | 淄博高新技术产业开发区生物医药研究院 | Method for simultaneously detecting genotoxic impurities of 1, 4-dichlorobutane and 1-chloro-4-hydroxybutane in bulk drug or preparation |
| CN112630354A (en) * | 2021-01-22 | 2021-04-09 | 烟台东诚药业集团股份有限公司 | Method for determining two kinds of chloralkane gene toxic impurities in amino acid medicine |
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