CN113791148A - Gas chromatography for determining residual quantity of organic solvent in parecoxib sodium raw material medicine - Google Patents
Gas chromatography for determining residual quantity of organic solvent in parecoxib sodium raw material medicine Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 15
- 238000004817 gas chromatography Methods 0.000 title claims abstract description 15
- 229960003925 parecoxib sodium Drugs 0.000 title claims abstract description 14
- ICJGKYTXBRDUMV-UHFFFAOYSA-N trichloro(6-trichlorosilylhexyl)silane Chemical compound Cl[Si](Cl)(Cl)CCCCCC[Si](Cl)(Cl)Cl ICJGKYTXBRDUMV-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 239000003960 organic solvent Substances 0.000 title claims abstract description 11
- 239000002994 raw material Substances 0.000 title claims abstract description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000001514 detection method Methods 0.000 claims abstract description 12
- 238000002347 injection Methods 0.000 claims abstract description 9
- 239000007924 injection Substances 0.000 claims abstract description 9
- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 claims abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000011067 equilibration Methods 0.000 claims description 5
- 239000012159 carrier gas Substances 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229940008099 dimethicone Drugs 0.000 claims description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 2
- -1 dimethyl siloxane Chemical class 0.000 claims description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000007670 refining Methods 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 238000012795 verification Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 10
- 239000011550 stock solution Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000011084 recovery Methods 0.000 description 6
- 238000007789 sealing Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 4
- 239000012088 reference solution Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 239000013557 residual solvent Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 238000011835 investigation Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001179 sorption measurement Methods 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
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- 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)
- Sampling And Sample Adjustment (AREA)
Abstract
The invention discloses a gas chromatography for measuring the residual quantity of organic solvent in parecoxib sodium raw material medicine, which is characterized in that parecoxib sodium raw material medicine is dissolved by N, N-dimethylformamide and then is subjected to headspace sample injection, GC-FID detection is adopted, organic solvents of ethanol, dichloromethane, normal hexane, ethyl acetate and triethylamine which are possibly used in the synthesis and refining processes of the raw material medicine are quantitatively measured, and methodology verification is carried out. The method has the advantages of strong specificity, high sensitivity and good repeatability, and can accurately determine the residual quantity of the organic solvent in the parecoxib sodium bulk drug.
Description
Technical Field
The invention belongs to a residual solvent detection and analysis method, and particularly relates to a gas chromatography detection method for residual solvents in parecoxib sodium bulk drugs.
Background
Parecoxib, a specific cyclooxygenase-2 inhibitor that can be administered intravenously and intramuscularly, is chemically named N- [ [4- (5-methyl-3-phenylisoxazol-4-yl) phenyl ] sulfonyl ] propionamide. The sodium salt can be clinically used for intravenous administration and intramuscular injection administration. The traditional Chinese medicine composition is mainly used for short-term treatment of postoperative pain and treatment of moderate or severe postoperative acute pain.
In the process of synthesizing and refining the raw material medicine, 5 organic solvents such as ethanol, dichloromethane, normal hexane, ethyl acetate, triethylamine and the like are needed. These residual solvents have a detrimental effect on human health and need to be removed or allowed to remain without exceeding the regulatory limits of the 'Chinese pharmacopoeia' and ICH, 2020 edition.
Disclosure of Invention
The invention aims to provide a gas chromatography method for measuring the residual quantity of organic solvent in parecoxib sodium bulk drug by using a common capillary column gas chromatograph.
In order to achieve the above object, the gas chromatography detection method is characterized in that:
a gas chromatography for determining the residual amount of organic solvent in parecoxib sodium raw material medicine is characterized in that parecoxib sodium raw material is dissolved by N, N-dimethylformamide, headspace sample injection is carried out, gas chromatography is adopted, temperature rise separation is carried out by using a capillary column program, and a hydrogen ion flame detector (FID) is used for detection.
The chromatographic conditions in the method are as follows:
the capillary column is a 6% cyanopropylbenzene-94% dimethyl siloxane chromatographic column; the temperature programming is carried out at 60 plus or minus 2 ℃ for 4 plus or minus 1min, the temperature is raised to 200 plus or minus 5 ℃ at the speed of 10 plus or minus 1 ℃/min, and the temperature is maintained for 1-3 min; sample inlet mode: splitting, the splitting ratio is 9-11:1, the injection port temperature is: 200 plus or minus 20 ℃; the temperature of the hydrogen ion flame detector is 250 +/-20 ℃; the headspace conditions were: equilibrium temperature: 80 ℃. + -. 5 ℃ and equilibration time: 25. + -.5 min, LOOP tube temperature: 170 ℃, TRLINE temperature: at 200 ℃.
Preferred chromatographic conditions are:
a chromatographic column: 6% Cyanopropylbenzene-94% Dimethicone chromatography column DB-624(30m × 0.32mm, 1.8 μm); column temperature: temperature programming, keeping the temperature at 60 ℃ for 4min, raising the temperature to 200 ℃ at the speed of 10 ℃/min, and keeping the temperature for 2 min; carrier gas: nitrogen, flow rate: 2 mL/min; sample inlet mode: splitting, splitting ratio: 10:1, injection port temperature: 200 ℃; a detector: hydrogen ion flame detector, temperature 250 ℃; the headspace conditions were: equilibrium temperature: 80 ℃, equilibration time: 25min, LOOP tube temperature: 170 ℃, TRLINE temperature: 200 ℃, headspace volume: 10 mL.
The invention has the beneficial effects that: a gas chromatography detection method for determining the residual quantity of an organic solvent in a parecoxib sodium raw material medicine is established for the first time, GC-FID detection is adopted after headspace sampling, quantitative determination is carried out on ethanol, dichloromethane, n-hexane, ethyl acetate and triethylamine, and methodology verification is carried out. In addition, the invention solves the problem of triethylamine adsorption tailing by increasing the temperature of the transmission line. Experiments prove that the method has strong specificity, high sensitivity and good repeatability, and can accurately determine the residual quantity of the organic solvent in the parecoxib sodium bulk drug.
Drawings
FIG. 1 blank solvent map
FIG. 2 Mixed control atlas
Detailed Description
The technical solutions of the present invention are further described below with reference to specific examples, which are given only for illustrating the present invention and not for limiting the scope of the present invention.
Example 1 gas chromatography analysis
1.1 Instrument and chromatographic conditions
Chromatograph: an Agilent 7890A gas chromatography system and workstation;
a chromatographic column: DB-624(30m × 0.32mm, 1.8 μm);
sample inlet temperature: 200 ℃;
the split ratio is as follows: 10: 1;
carrier gas and flow rate: 2.0mL/min of nitrogen;
a detector: hydrogen ion flame detector (FID), temperature 250 ℃;
temperature rising procedure: keeping at 60 deg.C for 4min, increasing to 200 deg.C at a speed of 10 deg.C/min, and keeping for 2 min;
headspace parameters: equilibrium temperature: 80 ℃, equilibration time: 25min, LOOP tube temperature: 170 ℃, TRLINE temperature: 200 ℃, headspace volume: 10 mL.
1.2 sample preparation
1.2.1 preparation of blank solution
3mL of N, N-dimethylformamide was accurately transferred to a 10mL headspace bottle, which was capped and sealed.
1.2.2 preparation of Mixed control solutions
Accurately weighing about 250mg, 30mg, 14, 5mg, 250mg and 250mg of ethanol, dichloromethane, N-hexane, ethyl acetate and triethylamine respectively, placing the weighed materials into a 50mL measuring flask, adding N, N-dimethylformamide to dissolve and dilute the materials to a scale, and preparing a mixed reference substance stock solution. Precisely measuring 1mL of the mixed reference stock solution, placing the mixed reference stock solution into a 10mL measuring flask, adding N, N-dimethylformamide to dilute the mixed reference stock solution to obtain a mixed solution containing 0.5mg of ethanol, 60 μ g of dichloromethane, 29 μ g of N-hexane, 0.5mg of ethyl acetate and 0.5mg of triethylamine in each 1mL of the mixed reference stock solution, precisely measuring 3mL of the mixed reference stock solution, placing the mixed reference stock solution into a 10mL headspace flask, and sealing the 10mL headspace flask to obtain a mixed reference solution.
1.2.3 preparation of test solutions
Taking about 0.3g of the product, precisely weighing, placing in a 10mL headspace bottle, precisely adding 3mL of dimethylformamide to dissolve, and sealing to obtain a test solution.
EXAMPLE 2 methodological examination of the invention
Specialization inspection
Precisely measuring blank solution and mixed reference solution 3mL respectively, placing in 10mL headspace bottle, sealing, introducing sample in headspace, detecting with gas chromatograph, and recording chromatogram, wherein the chromatogram is detailed in figures 1 and 2 of the specification. The results show that the solvent is not interfering.
Detection limit and quantitative limit investigation
And taking the mixed reference substance solution, gradually diluting until the signal-to-noise ratio S/N of each component is close to 3 as a detection limit, and gradually diluting until the signal-to-noise ratio S/N of each component is close to 10 as a quantification limit. As a result, the detection limits of ethanol, dichloromethane, n-hexane, ethyl acetate and triethylamine were 0.5028, 1.1884, 0.03148, 0.4742 and 0.3170. mu.g/mL, respectively, and the quantitation limits of ethanol, dichloromethane, n-hexane, ethyl acetate and triethylamine were 1.0056, 2.1696, 0.06296, 0.9484 and 0.6340. mu.g/mL, respectively.
Investigation of linear relationships
And (4) taking the stock solution of the mixed reference substance for dilution step by step to prepare a linear investigation sample solution. 3mL of the sample was precisely measured, placed in a 10mL headspace bottle, and sealed to obtain a linear test sample. And (4) performing linear regression by taking the peak area A as a vertical coordinate and the concentration C as a horizontal coordinate to respectively obtain a regression equation. The linear test result shows that the ethanol has a good linear relation with the peak area within the range of 1.0176 mu g/mL-814.08 mu g/mL; the dichloromethane has good linear relation with the peak area within the range of 2.2176 mu g/ml-88.704 mu g/ml; n-hexane has good linear relation with the peak area within the range of 0.06456 mu g/ml-51.648 mu g/ml; the ethyl acetate has good linear relation with the peak area within the range of 0.9968 mu g/ml-797.44 mu g/ml; the triethylamine is in good linear relation with the peak area within the range of 3.37 mu g/ml to 674 mu g/ml.
Repeatability survey
Taking about 0.3g of the product, precisely weighing, placing in a 10mL headspace bottle, precisely adding 3mL of mixed reference solution to dissolve, sealing, and using as a repeatability inspection sample solution. 6 parts are prepared by the same method, and are respectively subjected to sample injection and measurement, the content of each component is calculated by an external standard method, and the RSD is calculated. The RSD contents of ethanol, dichloromethane, normal hexane, ethyl acetate and triethylamine are respectively 1.09%, 1.89%, 2.19%, 1.48% and 0.93%, and the test results are shown in Table 1. From the results, the method was found to have good reproducibility.
TABLE 1 results of the repeatability tests
| 1 | 2 | 3 | 4 | 5 | 6 | RSD％ | |
| Ethanol | 0.510％ | 0.503％ | 0.501％ | 0.507％ | 0.511％ | 0.516％ | 1.09％ |
| Methylene dichloride | 0.0584％ | 0.0558％ | 0.0555％ | 0.0565％ | 0.0570％ | 0.0574％ | 1.89％ |
| N-hexane | 0.0322％ | 0.0312％ | 0.0302％ | 0.0310％ | 0.0308％ | 0.0312％ | 2.19％ |
| Ethyl acetate | 0.526％ | 0.507％ | 0.514％ | 0.522％ | 0.527％ | 0.524％ | 1.48％ |
| Triethylamine | 0.520％ | 0.530％ | 0.521％ | 0.525％ | 0.526％ | 0.532％ | 0.93％ |
Accuracy survey
Precisely measuring about 4mL, 5mL and 6mL of the mixed reference stock solution, respectively placing the mixed reference stock solution into a 50mL measuring flask, and performing constant volume by using N, N-dimethylformamide to obtain low, medium and high concentration reference solutions. Precisely weighing 0.3mg of the product, placing the product in a 10mL headspace bottle, precisely adding 3mL of each of the low, medium and high concentration reference substance solutions, respectively, 3 parts, sealing, and shaking for dissolution. And respectively carrying out sample injection measurement and calculating the recovery rate. The test results are shown in tables 2 to 6, and the results show that the method has good accuracy.
TABLE 2 ethanol recovery test results
TABLE 3 methylene chloride recovery test results
TABLE 4 n-Hexane recovery test results
TABLE 5 test results for ethyl acetate recovery
TABLE 6 Triethylamine recovery test results
In conclusion, the content of residual solvents of ethanol, dichloromethane, n-hexane, ethyl acetate and triethylamine in parecoxib sodium can be accurately measured, and the method is high in specificity and precision.
Claims (4)
1. A gas chromatography for determining the residual amount of organic solvent in parecoxib sodium raw material medicine is characterized in that parecoxib sodium raw material medicine is dissolved by N, N-dimethylformamide, headspace sample injection is carried out, GC-FID detection is adopted, and ethanol, dichloromethane, N-hexane, ethyl acetate and triethylamine are quantitatively determined;
the chromatographic column used in the GC-FID detection method is a 6% cyanopropylbenzene-94% dimethyl siloxane chromatographic column;
column temperature: temperature programming, keeping at 60 + -2 deg.C for 4 + -1 min, raising to 200 + -5 deg.C at a speed of 10 + -1 deg.C/min, and keeping for 1-3 min;
sample inlet mode: splitting, the splitting ratio is 9-11:1, the injection port temperature is: 200 plus or minus 20 ℃.
2. The gas chromatography method of claim 1, wherein a hydrogen ion flame detector FID is used, with a detector temperature of 250 ± 20 ℃.
3. The gas chromatography method of claim 1, wherein the headspace equilibrium temperature: 80. + -.5 ℃ headspace equilibration time: 25 +/-5 min.
4. The gas chromatography method of any one of claims 1-3, the chromatography conditions being:
a chromatographic column: 6% Cyanopropylbenzene-94% Dimethicone chromatography column DB-624(30m × 0.32mm, 1.8 μm);
column temperature: temperature programming, keeping the temperature at 60 ℃ for 4min, raising the temperature to 200 ℃ at the speed of 10 ℃/min, and keeping the temperature for 2 min;
carrier gas: nitrogen, flow rate: 2 mL/min;
sample inlet mode: splitting, splitting ratio: 10:1, injection port temperature: 200 ℃;
a detector: hydrogen ion flame detector, temperature 250 ℃;
the headspace conditions were: equilibrium temperature: 80 ℃, equilibration time: 25min, LOOP tube temperature: 170 ℃, TRLINE temperature: 200 ℃, headspace volume: 10 mL.
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| CN115453008A (en) * | 2022-10-13 | 2022-12-09 | 山东科源制药股份有限公司 | Detection method of propafenone hydrochloride residual solvent |
| CN116550006A (en) * | 2023-07-07 | 2023-08-08 | 上海奥浦迈生物科技股份有限公司 | Formula, preparation method and application of chromatographic combination liquid |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115015420A (en) * | 2022-06-01 | 2022-09-06 | 惠州市顺美医疗科技有限公司 | Method for measuring residual organic solvent in rapamycin drug balloon catheter by gas chromatography |
| CN115453008A (en) * | 2022-10-13 | 2022-12-09 | 山东科源制药股份有限公司 | Detection method of propafenone hydrochloride residual solvent |
| CN116550006A (en) * | 2023-07-07 | 2023-08-08 | 上海奥浦迈生物科技股份有限公司 | Formula, preparation method and application of chromatographic combination liquid |
| CN116550006B (en) * | 2023-07-07 | 2023-11-10 | 上海奥浦迈生物科技股份有限公司 | Formula, preparation method and application of chromatographic combination liquid |
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