CN113514563A - Method for separating and measuring lacosamide residual solvent by using gas chromatography - Google Patents
Method for separating and measuring lacosamide residual solvent by using gas chromatography Download PDFInfo
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- CN113514563A CN113514563A CN202010277579.1A CN202010277579A CN113514563A CN 113514563 A CN113514563 A CN 113514563A CN 202010277579 A CN202010277579 A CN 202010277579A CN 113514563 A CN113514563 A CN 113514563A
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- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 title claims abstract description 44
- 229960002623 lacosamide Drugs 0.000 title claims abstract description 43
- 239000013557 residual solvent Substances 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000004817 gas chromatography Methods 0.000 title claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 cyanopropyl phenyl Chemical group 0.000 claims abstract description 6
- 239000004205 dimethyl polysiloxane Substances 0.000 claims abstract description 6
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims abstract description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 54
- 239000000243 solution Substances 0.000 claims description 21
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 18
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 239000007789 gas Substances 0.000 claims description 13
- 238000000926 separation method Methods 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000012088 reference solution Substances 0.000 claims description 12
- 239000012159 carrier gas Substances 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000012085 test solution Substances 0.000 claims description 7
- 238000004587 chromatography analysis Methods 0.000 claims description 6
- 238000004458 analytical method Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000005259 measurement Methods 0.000 claims description 3
- 238000000691 measurement method Methods 0.000 claims description 3
- 238000003556 assay Methods 0.000 claims 2
- 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
- 238000003908 quality control method Methods 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 14
- 230000014759 maintenance of location Effects 0.000 description 9
- 230000008859 change Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 102100024426 Dihydropyrimidinase-related protein 2 Human genes 0.000 description 3
- 108050002467 Dihydropyrimidinase-related protein 2 Proteins 0.000 description 3
- 239000012490 blank solution Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 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
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
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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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
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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
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation detectors
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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
- G01N30/86—Signal analysis
- G01N30/8624—Detection of slopes or peaks; baseline correction
- G01N30/8631—Peaks
- G01N30/8634—Peak quality criteria
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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
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- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
- G01N2030/3084—Control of physical parameters of the fluid carrier of temperature ovens
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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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
- G01N2030/324—Control of physical parameters of the fluid carrier of pressure or speed speed, flow rate
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
Abstract
The invention belongs to the field of analytical chemistry, and discloses a method for separating and determining lacosamide residual solvent by using a gas chromatography, which adopts 6% cyanopropyl phenyl and 94% dimethyl polysiloxane weak polarity capillary chromatographic column and a hydrogen flame ionization detector, and can quantitatively determine the content of the lacosamide residual solvent, thereby achieving the effective control of the residual solvent in lacosamide and realizing the quality control of the lacosamide. The method has the advantages of strong specificity, high accuracy and simple and convenient operation.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and determining lacosamide residual solvent by using a gas chromatography.
Background
Lacosamide is a novel glycine site binding antagonist of N-methyl-D-aspartate (NMDA) receptor, belonging to a new class of functional amino acids. Thus, lacosamide is an anticonvulsant drug with a novel dual mechanism action, which can selectively promote slow inactivation of sodium channel and can regulate collapse response mediating protein 2(CRMP-2), while CRMP-2 can slow down or even regulate collapse response mediating protein 2(CRMP-2)
Arresting seizures and relieving neuropathic pain of diabetes. Lacosamide chemical name:
(2R) -2- (acetylamino) -N-benzyl-3-methoxy-propanamide with molecular formula C13H18N2O3. The structural formula is as follows:
in the process of synthesizing lacosamide, residual solvent is introduced, and because the residual solvent can directly or indirectly damage DNA at low concentration, gene mutation or cancer can occur, and if the residual solvent is not controlled properly, the safety of medication can be seriously threatened, so that strict control on the residual solvent is required in lacosamide. The lacosamide has 2 residual solvents (methyl isobutyl ketone and N-methylmorpholine, respectively) with molecular formula of C6H12O, C5H11NO。
Methyl isobutyl ketone, structural formula:
n-methylmorpholine, the structural formula is:
incomplete removal of residual solvent in lacosamide will seriously affect the safety of administration. Therefore, the scientific, reasonable and objective detection method is selected, the quality of lacosamide can be better controlled, and the method has practical value.
Disclosure of Invention
The invention aims to provide a method for separating and measuring residual solvent of lacosamide, thereby realizing strict control of the residual solvent in lacosamide within limits and ensuring the safety of lacosamide medication.
The method for determining residual solvent of lacosamide comprises the steps of selecting a proper solvent to dissolve a sample, and adopting 6% cyanopropyl phenyl and 94% dimethylpolysiloxane capillary chromatographic column;
the solvent may be N, N-dimethylformamide.
The chromatographic column is selected from Agilent, Ohio Valley or SGE chromatographic column.
The chromatographic column is a weak polarity capillary chromatographic column of 6% cyanopropylphenyl and 94% dimethylpolysiloxane.
The separation and measurement method of the present invention can be realized by the following method:
1) dissolving lacosamide 100-200 mg by using a solvent to prepare a test solution containing lacosamide 100-200 mg per 1 mL; dissolving appropriate amount of residual solvent with solvent to obtain control solution containing methyl isobutyl ketone 500-1000 μ g and N-methylmorpholine 495-990 μ g per 1 mL; taking 100 mg-200 mg lacosamide, adding 1.0mL of reference solution, shaking up to prepare a system applicability solution containing 500-1000 mug of methyl isobutyl ketone and 495-990 mug of N-methylmorpholine in each 1 mL;
2) setting the temperature of a sample inlet to be 200-300 ℃, the flow rate of a carrier gas to be 0.5-2.0 mL/min, and performing a programmed heating method, wherein the temperature raising program is an initial temperature of 50 ℃, keeping the temperature for 0-10 min, raising the temperature to 70 ℃ at a rate of 1-10 ℃ per minute, keeping the temperature for 1-10 min, raising the temperature to 110 ℃ at a rate of 1-10 ℃ per minute, keeping the temperature for 0-10 min, raising the temperature to 180 ℃ at a rate of 1-10 ℃ per minute, keeping the temperature for 1-10 min, keeping the temperature for 220-320 ℃, and controlling the flow ratio of 20: 1-80: 1;
3) and (3) respectively taking 1-3 mu L of the test solution and the system applicability 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 measurement of the residual solvent of lacosamide.
Wherein:
the type of the gas chromatograph has no special requirements, and the chromatograph adopted by the invention is an Shimadzu 2010 plus gas chromatograph
Hydrogen flame ionization detector
A chromatographic column: DB-624UI capillary chromatography column (Agilent, 30 m' 0.32mm, 1.8 μm);
sample inlet temperature: 230 ℃;
detector temperature: 260 ℃;
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:
the present invention solves the problem of separation and measurement of lacosamide residual solvent by gas chromatography using 6% cyanopropylphenyl and 94% dimethylpolysiloxane-based capillary chromatography columns (30 m' 0.32mm, 1.8 μm) and can thus strictly control the amount of residual solvent within limits to ensure the safety of lacosamide, the results of which are shown in fig. 1 to 6.
Drawings
FIG. 1 is a gas chromatogram of a solvent (N, N-dimethylformamide) in example 1;
FIG. 2 is a solution gas chromatogram for suitability of the system in example 1;
FIG. 3 is a gas chromatogram of the sample solution in example 1;
FIG. 4 is a gas chromatogram of a control solution in example 1;
FIG. 5 is a gas chromatogram of a system suitability solution from time to time in example 2;
FIG. 6 is the gas chromatogram of the system suitability solution 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 method for measuring residual solvent content of lacosamide according to the present invention is described in further 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 that the technologies realized based on the above contents of the present invention are within the scope of the present invention.
Example 1
Apparatus and conditions
Chromatograph: shimadzu 2010 plus gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: DB-624UI capillary chromatography column (Agilent, 30 m' 0.32mm, 1.8 μm);
column temperature: the initial temperature is 50 ℃, the temperature is raised to 70 ℃ at the temperature rising rate of 5 ℃ per minute, and the temperature is kept for 5 min; heating to 110 ℃ at a heating rate of 5 ℃ per minute, heating to 180 ℃ at a heating rate of 10 ℃ per minute, and keeping the temperature for 5 min.
Sample inlet temperature: 230 ℃;
detector temperature: 260 ℃;
carrier gas (nitrogen) flow rate: 1.0 mL/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 μ L
Experimental procedure
Dissolving lacosamide 100-200 mg by using a solvent to prepare a test solution containing lacosamide 100-200 mg per 1 mL; taking a proper amount of residual solvent, dissolving the residual solvent by using the solvent to prepare a reference solution containing 500 mu g-1000 mu g of methyl isobutyl ketone and 495 mu g-990 mu g of N-methylmorpholine in each 1 mL; and adding 100 mg-200 mg lacosamide into 1.0mL of reference solution, shaking uniformly, and preparing a system applicability solution containing 500-1000 mug of methyl isobutyl ketone and 495-990 mug of N-methylmorpholine in each 1 mL. And taking N, N-dimethylformamide as a blank solution. And analyzing according to the chromatographic conditions, and recording a chromatogram. The result is shown in the attached figures 1-4, and the figure 1 is a blank solution chromatogram; FIG. 2 is a system suitability solution chromatogram showing that the chromatographic peak with retention time of 13.435min is methyl isobutyl ketone and the chromatographic peak with retention time of 15.225min is N-methylmorpholine. FIG. 3 is a chromatogram of a test solution, FIG. 4 is a chromatogram of a reference solution, a chromatographic peak with a retention time of 13.436 min is methyl isobutyl ketone, and a chromatographic peak with a retention time of 15.234min is N-methylmorpholine; FIGS. 1 to 4 show that: the method can accurately carry out quantitative detection on the residual solvent in the lacosamide so as to calculate the content of the residual solvent in the sample.
Example 2
Apparatus and conditions
Chromatograph: shimadzu 2010 plus gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: DB-624UI capillary chromatography column (Agilent, 30 m' 0.32mm, 1.8 μm);
column temperature: the initial temperature is 50 ℃, the temperature is raised to 70 ℃ at the temperature rising rate of 5 ℃ per minute, and the temperature is kept for 5 min; heating to 110 ℃ at a heating rate of 5 ℃ per minute, heating to 200 ℃ at a heating rate of 10 ℃ per minute, and keeping the temperature for 5 min.
Sample inlet temperature: 230 ℃;
detector temperature: 260 ℃;
carrier gas (nitrogen) flow rate: 1.0 mL/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 μ L
Experimental procedure
Taking a proper amount of residual solvent, dissolving the residual solvent by using the solvent to prepare a reference solution containing 500 mu g-1000 mu g of methyl isobutyl ketone and 495 mu g-990 mu g of N-methylmorpholine in each 1mL, taking 100 mg-200 mg of lacosamide, adding 1.0mL of the reference solution, shaking up to prepare a system applicability solution containing 500 mu g-1000 mu g of methyl isobutyl ketone and 495 mu g-990 mu g of N-methylmorpholine in each 1 mL. And analyzing according to the chromatographic conditions, and recording a chromatogram. The result is shown in figure 5, wherein the chromatographic peak with the retention time of 13.444min is methyl isobutyl ketone, and the chromatographic peak with the retention time of 15.234min is N-methylmorpholine.
Example 3
Apparatus and conditions
Chromatograph: shimadzu 2010 plus gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: DB-624UI capillary chromatography column (Agilent, 30 m' 0.32mm, 1.8 μm);
column temperature: the initial temperature is 50 ℃, the temperature is increased to 110 ℃ at the temperature rising rate of 5 ℃ per minute, and the temperature is kept for 3 min; heating to 200 ℃ at a heating rate of 10 ℃ per minute, and keeping the temperature for 5 min.
Sample inlet temperature: 230 ℃;
detector temperature: 260 ℃;
carrier gas (nitrogen) flow rate: 1.0 mL/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 μ L
Experimental procedure
Taking a proper amount of residual solvent, dissolving the residual solvent by using the solvent to prepare a reference solution containing 500 mu g-1000 mu g of methyl isobutyl ketone and 495 mu g-990 mu g of N-methylmorpholine in each 1 mL; and adding 100 mg-200 mg lacosamide into 1.0mL of reference solution, shaking uniformly, and preparing a system applicability solution containing 500-1000 μ g of methyl isobutyl ketone and 495-990 μ g of N-methylmorpholine in each 1 mL. And (4) taking the system applicability solution, analyzing according to the chromatographic conditions, and recording a chromatogram. The result is shown in figure 6, wherein the chromatographic peak with retention time of 11.055min is methyl isobutyl ketone, and the chromatographic peak with retention time of 12.401min is N-methylmorpholine.
The invention verifies the following items of the analysis method of lacosamide residual solvent:
specificity
Dissolving lacosamide 100-200 mg by using a solvent to prepare a test solution containing lacosamide 100-200 mg per 1 mL; taking a proper amount of residual solvent, dissolving the residual solvent by using the solvent to prepare a reference solution containing 500 mu g-1000 mu g of methyl isobutyl ketone and 495 mu g-990 mu g of N-methylmorpholine in each 1 mL; and adding 100 mg-200 mg lacosamide into 1.0mL of reference solution, shaking uniformly, and preparing a system applicability solution containing 500-1000 mug of methyl isobutyl ketone and 495-990 mug of N-methylmorpholine in each 1 mL. And taking N, N-dimethylformamide as a blank solution. Gas chromatography was carried out according to the chromatographic conditions of example 1 and chromatograms were recorded. The result is shown in attached figures 1-4, under the chromatographic condition, the separation degree between related substances and a main peak meets the requirement, the detection is not interfered by solvents and other impurities in samples, the number of theoretical plates meets the detection requirement, and the method has good specificity.
Sample introduction repeatability test
Taking a reference substance solution, repeating sample injection for 6 times according to the chromatographic conditions of the example 1, and inspecting the repeatability of the method. The results are given in the following table:
stability of solution
Taking a reference solution, injecting samples at 0, 2, 4, 6 and 8 hours respectively according to the chromatographic conditions of the example 1, and inspecting the stability of the solution at room temperature when the product is measured quantitatively, wherein the results are shown in the following table:
durability
We further investigated the durability of the method by fine tuning the injection port temperature, carrier gas flow rate, detector temperature and chromatographic conditions for different chromatographic columns. As a result, the method has good durability under the conditions of chromatographic columns of different brands, the temperature change of a sample inlet +/-5 ℃, the flow rate change of carrier gas +/-0.1 mL/min, the temperature change of a detector +/-5 ℃ and the like. The retention time of each residual solvent of lacosamide under the conditions of different injection port temperatures, carrier gas flow rates and detector temperatures has no obvious change, and the lacosamide can be effectively separated.
Claims (9)
1. A method for separating and measuring lacosamide residual solvent by gas chromatography is characterized in that: the sample was dissolved in a suitable solvent and tested using a capillary chromatography column of 6% cyanopropylphenyl and 94% dimethylpolysiloxane, hydrogen flame ionization detector.
2. The separation assay method of claim 1, wherein the solvent is N, N-dimethylformamide.
3. The separation and measurement method according to claim 1, wherein the column is selected from columns sold under the brand name Agilent, OHIO VALLEY or SGE.
4. The separation and measurement method according to claim 1, wherein the column is a capillary column of 6% cyanopropylphenyl and 94% dimethylpolysiloxane.
5. The separation assay method of claim 1, comprising the steps of:
1) dissolving 100-200 mg of lacosamide by using a solvent to prepare a test solution containing 100-200 mg of lacosamide per 1 mL; dissolving appropriate amount of residual solvent with solvent to obtain control solution containing methyl isobutyl ketone 500-1000 μ g and N-methylmorpholine 495-990 μ g per 1 mL; taking 100 mg-200 mg lacosamide, adding 1.0mL of reference solution, shaking up to prepare a system applicability solution containing 500-1000 mug of methyl isobutyl ketone and 495-990 mug of N-methylmorpholine in each 1 mL;
2) setting the temperature of a sample inlet to be 200-300 ℃, the flow rate of a carrier gas to be 0.5-2.0 mL/min, and performing a programmed heating method, wherein the temperature raising program is an initial temperature of 50 ℃, keeping the temperature for 0-10 min, raising the temperature to 70 ℃ at a rate of 1-10 ℃ per minute, keeping the temperature for 1-10 min, raising the temperature to 110 ℃ at a rate of 1-10 ℃ per minute, keeping the temperature for 0-10 min, raising the temperature to 180 ℃ at a rate of 1-10 ℃ per minute, keeping the temperature for 1-10 min, keeping the temperature for 220-320 ℃, and controlling the flow ratio of 20: 1-80: 1;
3) and (3) respectively taking 1-3 mu L of the test solution and the system applicability 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 measurement of the residual solvent of lacosamide.
6. The separation analysis method according to claim 5, wherein said carrier gas of step 2) is nitrogen or helium.
7. The separation and analysis method according to claim 5, wherein the flow rate of said carrier gas in step 2) is preferably 1 mL/min.
8. The separation analysis method according to claim 5, wherein the temperature of said detector in step 2) is preferably 260 ℃.
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:
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010277579.1A CN113514563A (en) | 2020-04-10 | 2020-04-10 | Method for separating and measuring lacosamide residual solvent by using gas chromatography |
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| CN202010277579.1A CN113514563A (en) | 2020-04-10 | 2020-04-10 | Method for separating and measuring lacosamide residual solvent by using gas chromatography |
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