CN114441666A - Method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride - Google Patents
Method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 191
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 29
- 239000000243 solution Substances 0.000 claims abstract description 83
- 238000001514 detection method Methods 0.000 claims abstract description 62
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 56
- 239000012085 test solution Substances 0.000 claims abstract description 21
- 239000012088 reference solution Substances 0.000 claims abstract description 9
- 238000004364 calculation method Methods 0.000 claims abstract description 3
- 238000012937 correction Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 66
- 239000002904 solvent Substances 0.000 claims description 27
- 239000013558 reference substance Substances 0.000 claims description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- LLWOSCPRJRUVST-UHFFFAOYSA-N 4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)benzenesulfonic acid Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(O)(=O)=O)C=C1 LLWOSCPRJRUVST-UHFFFAOYSA-N 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 5
- -1 4- [4- [4- (5-methyl-3-phenylisoxazol-4-yl) phenylsulfonyl ] phenyl ] -5-methyl-3-phenylisoxazole Chemical compound 0.000 claims description 4
- ZXIRUKJWLADSJS-UHFFFAOYSA-N 5-methyl-3,4-diphenyl-1,2-oxazole Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=CC=C1 ZXIRUKJWLADSJS-UHFFFAOYSA-N 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 230000005526 G1 to G0 transition Effects 0.000 claims description 2
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- 239000002245 particle Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 229960003925 parecoxib sodium Drugs 0.000 abstract description 8
- ICJGKYTXBRDUMV-UHFFFAOYSA-N trichloro(6-trichlorosilylhexyl)silane Chemical compound Cl[Si](Cl)(Cl)CCCCCC[Si](Cl)(Cl)Cl ICJGKYTXBRDUMV-UHFFFAOYSA-N 0.000 abstract description 8
- 238000000926 separation method Methods 0.000 abstract description 5
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
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- UHNSRFWQBVXBSK-UHFFFAOYSA-N methanol;2,2,2-trifluoroacetic acid Chemical compound OC.OC(=O)C(F)(F)F UHNSRFWQBVXBSK-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 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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- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/16—Injection
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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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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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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- 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
Abstract
The invention discloses a method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, which comprises the following steps: a. preparing a system applicability solution; b. preparing a test solution; c. preparing a control solution; d. detecting the reference solution and the test solution by a high performance liquid chromatography method respectively; e. the impurity content in the 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride sample was obtained by peak area calculation based on the self control plus a correction factor. The invention provides a novel method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, which has high separation degree among various spectral peaks and no interference among the spectral peaks, can simultaneously realize accurate detection of the impurities 1, 6 and 2-6, provides an effective detection method for monitoring the content of the impurities in the 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, and further ensures the product quality of parecoxib sodium and the medication safety of patients.
Description
Technical Field
The invention belongs to the field of chemical analysis and detection, and particularly relates to a method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride.
Background
4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride is a parecoxib sodium intermediate, and the parecoxib sodium chemical name is N- [ [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl]Sulfonyl radical]Propionamide sodium salt (molecular formula: C)19H17N2O4SNa), is a non-steroidal anti-inflammatory drug developed by combining pyroxene and famalaysia, is the first selective cyclooxygenase-2 inhibitor for intravenous and intramuscular injection in the world, has the characteristics of good analgesic effect, quick response, lasting effect, capability of effectively inhibiting allodynia, high gastrointestinal safety, no influence on platelet function, no additional increase of cardiovascular risk and the like compared with the traditional non-selective cyclooxygenase inhibitor, and can obviously reduce the dosage of opioid drugs and related adverse reactions when being combined with opioid drugs. Parecoxib sodium was approved for marketing in europe in 2002. In 5 months 2008, parecoxib sodium for injection is approved to be marketed in china and widely used for short-term treatment of pain after surgery in multiple departments.
In order to ensure the quality of parecoxib sodium products and further ensure the medication safety of patients, a set of accurate and effective liquid chromatography analysis method for intermediate impurities is needed, and the invention provides a method for detecting impurities in an intermediate 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride.
Disclosure of Invention
The invention aims to provide a method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride.
The invention provides a method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, which comprises the following steps:
a. preparing a system applicability solution by taking 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride and a reference substance of impurities thereof;
b. taking a to-be-detected 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride sample to prepare a test solution;
c. diluting the test solution to prepare a reference solution;
d. respectively detecting a test solution and a control solution by adopting a high performance liquid chromatography method, wherein the detection conditions of the high performance liquid chromatography method are as follows:
a chromatographic column: the stationary phase takes phenyl bonded silica gel as a filling agent;
mobile phase: 0.05% trifluoroacetic acid-acetonitrile (40-50: 50-60);
detection wavelength: 200 nm-230 nm;
the column temperature is 20-40 ℃;
e. the content of impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride was obtained by peak area calculation based on the control and the correction factor.
Further, the impurities include at least 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonic acid.
Further, the impurities include one or more of 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonic acid, 5-methyl-3, 4-diphenylisoxazole, and 4- [4- [4- (5-methyl-3-phenylisoxazol-4-yl) phenylsulfonyl ] phenyl ] -5-methyl-3-phenylisoxazole.
Further, in the step a, the solvent for preparing the system applicability solution is acetonitrile; in the step b, the solvent for preparing the test solution is acetonitrile, and in the step c, the solvent for preparing the control solution is acetonitrile.
Further, in the step d, the chromatographic column is YMC Pack Ph, the length is 250mm, the inner diameter is 4.6mm, and the particle size of the packing is 5 μm
Further, in the step d, the detection wavelength is 215 nm.
Further, in the step d, the volume ratio of 0.05% trifluoroacetic acid to acetonitrile is 45: 55;
further, in the step d, the flow rate of the mobile phase is 0.8 ml/min-1.2 ml/min; preferably, the flow rate of the mobile phase is 1.0 ml/min.
Furthermore, in the step d, the sample injection volume is 5-100 mul; preferably, the injection volume is 10. mu.l.
The invention provides a novel detection method for impurity content in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, which has high separation degree among various spectral peaks, is free from interference with each other, can simultaneously realize accurate detection of impurities 1, 6 and 2-6, is simple and convenient to operate, easy to control and low in detection cost, has good linear relation, specificity, precision, stability, sensitivity and repeatability, is high in sample recovery rate and accurate and reliable in detection result, provides an effective detection method for monitoring impurities of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, and further ensures the product quality of parecoxib sodium and the medication safety of patients.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is an HPLC chart of a reference solution of impurity 1 under the detection conditions of example 1 of the present invention.
FIG. 2 is an HPLC chart of a reference solution of impurity 6 under the detection conditions of example 1 of the present invention.
FIG. 3 is a HPLC chart of a control solution of impurities 2-6 under the detection conditions of example 1 of the present invention.
FIG. 4 is a HPLC chart of the mixed solution of impurities under the detection conditions of example 1 of the present invention.
FIG. 5 is an HPLC chart of the test solution under the detection conditions of example 1 of the present invention.
FIG. 6 is a graph showing the main peak purity of a sample in a test solution under the detection conditions of example 1 of the present invention.
FIG. 7 is a HPLC chart of a system suitability solution under detection conditions of example 1 of the present invention.
FIG. 8 is an HPLC plot of a control solution of impurity 1 under chromatographic conditions of comparative experiment 1.
FIG. 9 is an HPLC plot of a control solution of impurity 6 under chromatographic conditions of comparative experiment 1.
FIG. 10 is an HPLC plot of control solutions of impurities 2-6 under chromatographic conditions of comparative experiment 1.
FIG. 11 is an HPLC chart of a system suitability solution under chromatographic conditions of comparative experiment 1.
FIG. 12 is an HPLC plot of a system suitability solution under comparative run 2 chromatographic conditions.
FIG. 13 is an HPLC plot of a system suitability solution under chromatographic conditions for comparative run 3.
FIG. 14 is an HPLC chart of a system suitability solution under chromatographic conditions of comparative experiment 4.
FIG. 15 is a graph of the main peak purity of samples in the system's suitability solution under chromatographic conditions for comparative experiment 4.
FIG. 16 is an HPLC plot of a system suitability solution under chromatographic conditions of comparative experiment 5
FIG. 17 is an HPLC plot of a control solution of impurity 1 under chromatographic conditions of comparative experiment 6.
FIG. 18 is an HPLC plot of a control solution of impurity 6 under comparative run 6 chromatographic conditions.
FIG. 19 is an HPLC plot of control solutions of impurities 2-6 under comparative run 6 chromatographic conditions.
FIG. 20 is an HPLC plot of a system suitability solution under chromatographic conditions of comparative experiment 6.
FIG. 21 is an HPLC plot of a control solution of impurity 1 under chromatographic conditions of comparative experiment 7.
FIG. 22 is an HPLC plot of a control solution of impurity 6 under chromatographic conditions of comparative experiment 7.
FIG. 23 is an HPLC plot of control solutions of impurities 2-6 under chromatographic conditions of comparative experiment 7.
FIG. 24 is an HPLC plot of a control solution of impurity 1 under chromatographic conditions of comparative experiment 8.
FIG. 25 is an HPLC plot of a control solution of impurity 6 under chromatographic conditions of comparative experiment 8.
FIG. 26 is an HPLC plot of control solutions of impurities 2-6 under chromatographic conditions of comparative experiment 8.
FIG. 27 is a standard curve of impurity 1 in item 2 of Experimental example 1.
FIG. 28 is a standard curve of impurity 6 in item 2 of Experimental example 1.
FIG. 29 is a graph showing the calibration curve of impurities 2 to 6 in item 2 of Experimental example 1.
Detailed Description
The raw materials and equipment used in the embodiment of the invention are known products, and are obtained by purchasing commercially available products or making the products by self.
For example, 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride has a lot number of 20190401; impurity 1 lot number 2018121101, content: 92.7 percent; all were from the pharmaceutical companies with a margin in success. Impurity 6 lot number 201804014, content: 99.6 percent; from Shanghai Farmer Biotech, Inc. Impurity 2-6 lot No. 39224, content: 96.4 percent; from the Beijing Kangpisen pharmaceutical technology Co.
Impurity 1 is named 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonic acid.
Impurity 6 is named 5-methyl-3, 4-diphenylisoxazole.
Impurity 2-6 is named 4- [4- [4- (5-methyl-3-phenylisoxazol-4-yl) phenylsulfonyl ] phenyl ] -5-methyl-3-phenylisoxazole.
An AUW220D model precision electronic balance available from shimadzu; LC-2010CHT model HPLC pump is available from Shimadzu, LC-2030C model HPLC pump is available from Shimadzu, Empower3 workstation is available from Watts; a column of YMC Pack Ph (250 mm. times.4.6 mm, 5 μm) is available from YMC;
example 1 high performance liquid chromatography method for detecting 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride related substance
A chromatographic column: YMC Pack Ph, 4.6 mm. times.250 mm, 5 μm;
mobile phase: 0.05% trifluoroacetic acid-acetonitrile (45: 55)
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
Sample introduction volume: 10 μ L.
A detection step:
an appropriate amount of the impurity 1 control substance was dissolved in a solvent to prepare an impurity 1 control substance solution containing about 130. mu.g of impurity 1 per 1 mL.
An appropriate amount of the impurity 6 control substance was dissolved in a solvent to prepare an impurity 6 control substance solution containing about 130. mu.g of impurity per 1 mL.
Taking a proper amount of the impurity 2-6 reference substance, dissolving the impurity 2-6 reference substance by using a solvent to prepare a reference substance solution containing 130 microgram of the impurity 2-6 per 1 mL.
Appropriate amounts of the 1, 6, 2-6 impurities and the 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride were taken and dissolved in a solvent to prepare a solution containing 1.0mg of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride and 10.0. mu.g of each impurity per 1mL as a system suitability solution.
A proper amount of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride sample to be detected is dissolved in acetonitrile, and then diluted by a solvent to prepare a sample solution containing 1.0mg of the sample per 1 mL.
Taking appropriate amount of reference substances of impurities 1, 6 and 2-3, diluting with solvent, and making into impurity mixed solution.
The determination method comprises the following steps: 10. mu.L of each of the above solutions was taken and injected into a liquid chromatograph, and chromatograms were recorded, and the results were shown in FIGS. 1 to 7.
FIG. 1 is an HPLC plot of a control solution of impurity 1, with the retention time of impurity 1 being 3.227 min.
FIG. 2 is an HPLC plot of a control solution of impurity 6, with the retention time of impurity 6 being 10.313 min.
FIG. 3 is an HPLC chart of a control solution of impurities 2-6, with the retention time of impurities 2-6 being 22.663 min.
FIG. 4 is an HPLC chart of the impurity mixed solution of impurity 1, impurity 6 and impurities 2-6, the retention time of impurity 1 is 3.379min, the retention time of impurity 6 is 10.233min, and the retention time of impurities 2-6 is 22.204 min.
FIG. 5 is an HPLC chart of the test solution, and the retention time of the main peak of the sample is 12.887 min.
FIG. 6 is a graph showing the purity of the main peak of a sample in a test solution.
FIG. 7 is an HPLC chart of a system suitability solution, with the sample retention time of 12.854min, impurity 1 retention time of 3.385min, impurity 6 retention time of 10.248min, impurities 2-6 retention time of 22.243min, and degrees of separation between impurity 1, impurity 6, sample and impurities 2-6 of 29.6, 8.1, and 20.0, respectively.
The result shows that under the chromatographic condition, the separation degree between the 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride and impurities is high, and the detection of related substances of the 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride can be realized.
Comparative experiment 1:
a chromatographic column: waters SunFire C184.6mm. times.250 mm, 3.5 μm;
mobile phase A: 0.05% trifluoroacetic acid
Mobile phase B: acetonitrile (ACN)
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
The gradient elution conditions were as follows:
impurity control solutions and system suitability solutions were prepared as described in example 1.
The determination method comprises the following steps: 10. mu.L of the solution was taken and injected into a liquid chromatograph, and chromatograms were recorded, and the results are shown in FIGS. 8 to 11.
FIG. 8 compares the HPLC profile of a control solution of impurity 1 under the chromatographic conditions of test 1, with a retention time of 12.197 min for impurity 1.
FIG. 9 shows an HPLC plot of a control solution of impurity 6 under chromatographic conditions of comparative experiment 1, with a retention time of 17.364min for impurity 6.
FIG. 10 compares the HPLC profiles of the control solutions of impurities 2-6 under the chromatographic conditions of test 1, with impurities 2-6 not eluting.
FIG. 11 shows a HPLC chart comparing the system suitability solution under the chromatographic conditions of test 1, with an impurity 1 retention time of 12.121min, an impurity 6 retention time of 17.382min, a sample (i.e., 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride) retention time of 17.721min, a sample peaked late, and this method failed to detect impurities 2-6.
Comparative experiment 2:
a chromatographic column: waters SunFire C184.6mm. times.250 mm, 3.5 μm;
mobile phase A: acetonitrile
Mobile phase B: 0.05% trifluoroacetic acid
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
The gradient elution conditions were as follows:
system suitability solutions were prepared as described in example 1.
The determination method comprises the following steps: 10. mu.L of the solution was taken and injected into a liquid chromatograph, and a chromatogram was recorded, and the result is shown in FIG. 12.
FIG. 12 is an HPLC chart comparing the system suitability solution under chromatographic conditions of test 2, with a sample retention time of 1.691min, and the sample is susceptible to interference by solvent peaks before peaks appear.
Comparative experiment 3:
a chromatographic column: waters SunFire C184.6mm. times.250 mm, 3.5 μm;
mobile phase: 0.05% trifluoroacetic acid-acetonitrile (45: 55)
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
System suitability solutions were prepared as described in example 1.
The determination method comprises the following steps: 10. mu.L of the solution was taken and injected into a liquid chromatograph, and a chromatogram was recorded, and the result is shown in FIG. 13.
FIG. 13 is an HPLC chart of a system suitability solution under the chromatographic conditions of comparative experiment 3, with an impurity 1 retention time of 9.292min, an impurity 6 retention time of 27.153min, a sample retention time of 35.465min, and no elution of impurities 2-6 within 60 min. Therefore, this method fails to detect impurities 2 to 6.
Comparative experiment 4
A chromatographic column: YMC Pack Ph, 4.6 mm. times.250 mm, 5 μm;
mobile phase: 0.05% trifluoroacetic acid-acetonitrile (35: 65)
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
System suitability solutions were prepared as described in example 1.
The determination method comprises the following steps: 10. mu.L of the solution was taken and injected into a liquid chromatograph, and chromatograms were recorded, and the results are shown in FIGS. 14 to 15.
FIG. 14 compares the HPLC profiles of the system's suitability solutions under run 4 chromatographic conditions for impurity 1 retention time of 3.486min, impurity 6 retention time of 7.984min, sample retention time of 9.084min, and impurity 2-6 retention time of 12.785 min.
FIG. 15 is a graph comparing the purity of the major peaks of samples in the system's suitability solution under run 4 chromatographic conditions, from which it can be seen that the major peaks are impure.
Comparative experiment 5
A chromatographic column: YMC Pack Ph, 4.6 mm. times.250 mm, 5 μm;
mobile phase A: 0.05% trifluoroacetic acid
Mobile phase B: acetonitrile
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
The gradient elution conditions were as follows:
system suitability solutions were prepared as described in example 1.
The determination method comprises the following steps: 10. mu.L of the solution was taken and injected into a liquid chromatograph, and a chromatogram was recorded, and the result is shown in FIG. 16.
FIG. 16 is a HPLC plot of a system's suitability for comparison under run 5 chromatographic conditions, with an impurity 1 retention time of 7.689min, an impurity 6 retention time of 14.968min, a sample retention time of 15.647min, an impurity 2-6 retention time of 16.827, a late sample peak, and interference from unknown impurities; impurity 1 peak front.
Comparative test 6
A chromatographic column: YMC Pack Ph, 4.6 mm. times.250 mm, 5 μm;
mobile phase: 0.05% trifluoroacetic acid-methanol (45: 55)
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
Each of the impurity control solutions and the system suitability solutions were prepared as described in example 1.
The determination method comprises the following steps: 10. mu.L of the solution was taken and injected into a liquid chromatograph, and chromatograms were recorded, and the results are shown in FIGS. 17 to 20.
FIG. 17 compares the HPLC profile of a control solution of impurity 1 under the chromatographic conditions of run 6, with a retention time of 6.298 min for impurity 1.
FIG. 18 compares the HPLC profile of a control solution of impurity 6 under run 6 chromatographic conditions, with a retention time of 40.127min for impurity 6.
FIG. 19 compares the HPLC profiles of the control solutions of impurities 2-6 under the chromatographic conditions of run 6, with impurities 2-6 not eluting.
FIG. 20 compares the HPLC profiles of the system's suitability solutions under run 6 chromatographic conditions, with impurity 1 retention time of 6.310min, impurity 6 retention time of 40.011min, and no elution of the sample and impurities 2-6 within 60 min.
Comparative experiment 7
A chromatographic column: agilent Pursuilt 5PFP, 4.6mm × 150 mm;
mobile phase A: 0.01mol/1KH2PO4(adjusting pH to 3.0 with phosphoric acid)
Mobile phase B: methanol
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
The gradient elution conditions were as follows:
impurity control solutions were prepared as described in example 1. The determination method comprises the following steps: 10. mu.L of the solution was taken and injected into a liquid chromatograph, and chromatograms were recorded, and the results are shown in FIGS. 21 to 23.
FIG. 21 compares the HPLC profile of the reference solution of impurity 1 under the chromatographic conditions of run 7, with the retention time of impurity 1 of 8.743min and an abnormal peak profile of impurity 1.
FIG. 22 compares the HPLC profile of a control solution of impurity 6 under the chromatographic conditions of run 7, with a retention time of 17.442min for impurity 6.
FIG. 23 compares the HPLC profile of a control solution of impurities 2-6 under the chromatographic conditions of run 7, with the retention time of impurities 2-6 of 22.944 min.
Comparative experiment 8
A chromatographic column: agilent Pursuilt 5PFP, 4.6mm × 150 mm;
mobile phase A: water-methanol-trifluoroacetic acid (90: 10: 0.05)
Mobile phase B: water-methanol-trifluoroacetic acid (10: 90: 0.05)
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
The gradient elution conditions were as follows:
impurity control solutions were prepared as described in example 1. .
The determination method comprises the following steps: injecting 10 μ L of the above solution into liquid chromatograph, recording chromatogram, and obtaining results shown in FIGS. 24-26
FIG. 24 compares the HPLC profile of the reference solution of impurity 1 under the chromatographic conditions of run 8, with a retention time of 4.745min for impurity 1 and an abnormal peak profile for impurity 1.
FIG. 25 compares the HPLC profile of a control solution of impurity 6 under the chromatographic conditions of run 8, with a retention time of 16.756min for impurity 6.
FIG. 26 shows a HPLC profile of a control solution of impurities 2-6 under comparative run 8 chromatographic conditions, with impurities 2-6 not eluting.
Thus, impurities 2-6 could not be detected by the method of comparative experiment 8.
Test example 1 methodological study of the detection method of the present invention
In the present test example, the following conditions were used for each test:
a chromatographic column: YM 2-6P 12-6k Ph, 4.6mm × 250mm, 5 μm;
mobile phase: 0.05% trifluoroacetic acid-acetonitrile (45: 55)
Solvent: acetonitrile
Column temperature: 30 ℃; flow rate: 1.0 ml/min; UV detector (detection wavelength 215 nm).
Sample introduction volume: 10 μ L.
1. Specificity test
Preparing impurity reference solution, system applicability solution, sample solution and impurity mixed solution respectively according to the method described in example 1, precisely taking 10 μ L of each solution, injecting into a liquid chromatograph, and recording chromatogram. The results are shown in FIGS. 1 to 7.
The result shows that under the condition of the detection method, the sample and other impurities in the sample have no interference to the determination of the impurity 1, the impurity 6 and the impurity 2-6, and the specificity of the detection method is proved to be strong.
2. Standard curve and linear range
Precisely measuring appropriate amount of reference substance solution containing impurity 1, impurity 6 and impurity 2-6, and diluting with mobile phase to obtain reference substance solutions with a series of concentrations. Precisely taking 10 μ L of reference solutions with different concentrations, respectively, injecting into a liquid chromatograph, and recording chromatogram. The peak areas were measured, respectively, and the results are shown in Table 1.
TABLE 1 Linear relationship
And (3) drawing a standard curve by taking the concentration of the impurity reference substance solution as a horizontal coordinate X and the peak area as a vertical coordinate Y, and calculating a linear regression equation and a correlation coefficient r of the impurity, wherein the standard curve is shown in figure 25.
The result shows that the concentration of the impurity 1 in the detection method of the invention is in a good linear relation with the peak area within the range of 1.8661 mu g/mL-55.9815 mu g/mL, and the linear equation is as follows: y-37, 715.9429X +4, 486.2919, r-1.0000; the concentration of the impurity 6 is in good linear relation with the peak area within the range of 0.1013 mug/mL-3.0400 mug/mL, and the linear equation is as follows: y is 47, 678.0818X +85.6352, r is 0.9998; the concentration of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride is 0.9963 mu g/mL-29.8901 mu g/mL, and the linear relation is good with the peak area, and the linear equation is as follows: Y-35451.5242X-446.8719, r-0.9999; the concentration of the impurity 2-6 is in good linear relation with the peak area within the range of 0.4875 mu g/mL-14.6248 mu g/mL, and the linear equation is as follows: y is 49, 325.2930X-1, 881.7969 and r is 0.9999, and the method is proved to have wide linear range and high accuracy.
3. Precision test
The system suitability solution under item 1 of test example 1 was precisely taken and 10. mu.L was injected into a high performance liquid chromatograph, and the peak areas were measured respectively according to the detection method of the present invention for 6 times, and the results are shown in Table 2.
TABLE 2 results of precision test a broken-down nag
The RSD of the peak area of the impurity 1 is calculated as: 1.18%, RSD of impurity 6 peak area is: 0.51%, RSD of impurity 2-6 peak area is: 0.15%, the detection method of the invention is proved to have excellent precision.
4. Limit of quantification
An appropriate amount of the impurity mixed solution according to item 1 of test example was measured, diluted with a solvent, 10. mu.l was precisely measured, and injected into a liquid chromatograph, and the peak area and the baseline noise were measured according to the detection method of the present invention, and the results are shown in Table 3.
TABLE 3 limit of quantitation test results
| Name of impurity | Concentration (μ g/mL) | Quantitative limit (ng) |
| Impurity 1 | 0.013 | 0.13 |
| Impurity 6 | 0.027 | 0.27 |
| Impurities 2-6 | 0.072 | 0.72 |
The peak heights of the impurity 1, the impurity 6 and the impurity 2-6 are about 10 times of the baseline noise, and the quantitative limit of the impurity 1 is 0.13ng, the quantitative limit of the impurity 6 is 0.27ng and the quantitative limit of the impurity 2-6 is 0.72ng according to the signal-to-noise ratio S/N which is 10.
5. Repeatability test
6 parts of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride of a sample, 10mg each, are precisely weighed and placed in a 10mL measuring flask respectively, and are dissolved and diluted to a scale by adding a solvent to obtain a sample solution. Precisely measuring the 6 parts of test solution by 10 mu L each, detecting according to the detection method of the invention, and calculating the contents of the impurity 1, the impurity 6 and the impurities 2-6 by peak area according to an external standard method, wherein the results are shown in Table 4.
TABLE 4 results of repeatability tests
| Sample numbering | 1 | 2 | 3 | 4 | 5 | 6 | Mean value of |
| Impurity 1 | 0.268％ | 0.265％ | 0.266％ | 0.261％ | 0.258％ | 0.262％ | 0.263％ |
| Impurity 6 | 0.003％ | 0.002％ | 0.003％ | 0.003％ | 0.003％ | 0.003％ | 0.003％ |
| Impurities 2-6 | 0.135％ | 0.132％ | 0.130％ | 0.131％ | 0.129％ | 0.130％ | 0.131％ |
From the above results, the detection method of the present invention was found to have good reproducibility.
6. Stability test of solution
Precisely weighing 10mg of a 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride sample, placing the sample in a 10mL measuring flask, adding a solvent to dissolve the sample, and diluting the sample to a scale to obtain a test solution. And injecting 10 mu L of sample at 0h, 1h, 2h, 3h, 4h and 5h after preparation, recording a chromatogram, and inspecting the stability conditions of the impurity 1, the impurity 6 and the impurity 2-6 in the test solution, wherein the results are shown in a table 5.
TABLE 5 stability test results of test solutions
| Time of standing | 0h | 1h | 2h | 3h | 4h | 5h |
| Impurity 1 | 0.241％ | 0.246％ | 0.251％ | 0.244％ | 0.254％ | 0.250％ |
| Impurity 6 | 0.003％ | 0.003％ | 0.003％ | 0.003％ | 0.003％ | 0.003％ |
| Impurities 2-6 | 0.859％ | 0.857％ | 0.852％ | 0.852％ | 0.842％ | 0.855％ |
From the results, the impurity 1 and the impurity 6 in the test solution are not detected within 5 hours after the preparation, and the detection results of the impurities 2 to 6 have no obvious change, so that the test solution is stable by the detection method.
7. Recovery test
A sample of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride (9 parts, 10mg each) was precisely weighed, and each of the samples was placed in a 10mL measuring flask, and 0.5mL, 1.0mL, and 3 parts, 2.0mL each, of a control solution for each impurity in item 1 of test example was added, dissolved in a solvent and diluted to the mark, and shaken up to give recovery test solutions. And respectively and precisely taking 9 parts of recovery rate sample solution and 10 mu L of each impurity mixed solution under the item 1 of the test example, carrying out sample injection measurement, recording a chromatogram, and calculating the measured amounts of the impurity 1, the impurity 6 and the impurities 2-6, the addition amount of a reference substance and the recovery rate, wherein the results are shown in tables 6-8.
Calculating the formula:
in the formula: a is the amount (mg) of impurities contained in the sample;
b is the addition amount (mg) of isomer impurity reference substance;
c is the measured amount (mg) of the isomer impurity.
TABLE 6 test results of recovery of impurity 1
The result shows that the detection method of the invention detects the impurity 1 in the 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, the recovery rate is between 96.91 and 98.48 percent, and the relative standard deviation is 0.56 percent, thereby proving that the detection method of the invention has good recovery rate and high accuracy.
TABLE 7 test results for recovery of impurity 6
The result shows that the detection method of the invention detects the impurity 6 in the 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, the recovery rate is between 97.00 and 98.00 percent, and the relative standard deviation is 0.66 percent, which proves that the detection method of the invention has good recovery rate and high accuracy.
TABLE 8 test results for recovery of impurities 2-6
The result shows that the detection method of the invention detects 2-6 impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, the recovery rate is 97.64-98.82%, and the relative standard deviation is 1.74%, thus proving that the detection method of the invention has good recovery rate and high accuracy.
In conclusion, the invention provides a novel detection method for related substances in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, which has the advantages of high separation degree between various spectral peaks, no interference between the spectral peaks, capability of simultaneously and accurately detecting the impurity 6, the impurity 1 and the impurity 2-6, simple and convenient operation, easy control, low detection cost, good linear relation, specificity, precision, stability, sensitivity and repeatability, high sample recovery rate and accurate and reliable detection result, provides an effective detection method for monitoring the 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride, and further ensures the product quality of parecoxib sodium and the medication safety of patients.
Claims (9)
1. A method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride is characterized by comprising the following steps: it comprises the following steps:
a. preparing a system applicability solution by taking 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride and a reference substance of impurities thereof;
b. taking a to-be-detected 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride sample to prepare a test solution;
c. diluting the test solution to prepare a reference solution;
d. respectively detecting a test solution and a control solution by adopting a high performance liquid chromatography method, wherein the detection conditions of the high performance liquid chromatography method are as follows:
a chromatographic column: the stationary phase takes phenyl bonded silica gel as a filling agent;
mobile phase: 0.05% trifluoroacetic acid-acetonitrile (volume ratio 40-50: 50-60);
detection wavelength: 200 nm-230 nm;
the column temperature is 20-40 ℃;
e. the content of impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride was obtained by peak area calculation based on the control and the correction factor.
2. The detection method according to claim 1, characterized in that: the impurities include at least 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonic acid.
3. The detection method according to claim 2, characterized in that: the impurities comprise one or more of 4- (5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonic acid, 5-methyl-3, 4-diphenylisoxazole, and 4- [4- [4- (5-methyl-3-phenylisoxazol-4-yl) phenylsulfonyl ] phenyl ] -5-methyl-3-phenylisoxazole.
4. The detection method according to claim 1, characterized in that: in the step a, a solvent for preparing the system applicability solution is acetonitrile; in the step b, the solvent for preparing the test solution is acetonitrile; in the step c, the solvent for preparing the control solution is acetonitrile.
5. The detection method according to claim 1, characterized in that: in the step d, the chromatographic column is YMC Pack Ph, the length is 250mm, the inner diameter is 4.6mm, and the particle size of the filler is 5 μm.
6. The detection method according to claim 1, characterized in that: in the step d, the detection wavelength is 215 nm.
7. The detection method according to claim 1, characterized in that: in the step d, the volume ratio of the 0.05 percent trifluoroacetic acid to the acetonitrile is 45: 55.
8. The detection method according to claim 1, characterized in that: in the step d, the flow rate of the mobile phase is 0.8 ml/min-1.2 ml/min; preferably, the flow rate of the mobile phase is 1.0 ml/min.
9. The detection method according to claim 1, characterized in that: in the step d, the sample injection volume is 5-100 mul; preferably, the injection volume is 10. mu.l.
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