CN111413440A - Method for detecting parecoxib sodium sulfate genotoxic impurities - Google Patents
Method for detecting parecoxib sodium sulfate genotoxic impurities Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 107
- 229960003925 parecoxib sodium Drugs 0.000 title claims abstract description 66
- 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 66
- 231100000024 genotoxic Toxicity 0.000 title claims abstract description 34
- 230000001738 genotoxic effect Effects 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 25
- 229910052938 sodium sulfate Inorganic materials 0.000 title claims abstract description 22
- 235000011152 sodium sulphate Nutrition 0.000 title claims abstract description 22
- 239000013558 reference substance Substances 0.000 claims abstract description 138
- 238000001514 detection method Methods 0.000 claims abstract description 48
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- 238000002290 gas chromatography-mass spectrometry Methods 0.000 claims abstract description 4
- 238000004949 mass spectrometry Methods 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 90
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 56
- 239000000523 sample Substances 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 47
- 238000001819 mass spectrum Methods 0.000 claims description 43
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000007789 gas Substances 0.000 claims description 22
- 239000012159 carrier gas Substances 0.000 claims description 20
- 239000012046 mixed solvent Substances 0.000 claims description 20
- 238000004817 gas chromatography Methods 0.000 claims description 16
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 12
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 12
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000001307 helium Substances 0.000 claims description 10
- 229910052734 helium Inorganic materials 0.000 claims description 10
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 10
- 238000012544 monitoring process Methods 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- -1 polydimethylsiloxane Polymers 0.000 claims description 4
- 238000000926 separation method Methods 0.000 abstract description 27
- 239000003814 drug Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 9
- 238000003908 quality control method Methods 0.000 abstract description 3
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- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000003570 air Substances 0.000 description 8
- 238000000691 measurement method Methods 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
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- 238000011002 quantification Methods 0.000 description 5
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- 229960004662 parecoxib Drugs 0.000 description 3
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- 229940122204 Cyclooxygenase inhibitor Drugs 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000003556 assay 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
-
- 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
-
- 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
- G01N30/50—Conditioning of the sorbent material or stationary liquid
- G01N30/52—Physical parameters
- G01N30/54—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
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
-
- 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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/025—Gas 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
- G01N2030/062—Preparation extracting sample from raw material
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Abstract
The invention relates to a detection method of parecoxib sodium sulfate genotoxic impurities. The method comprises the following steps: dissolving a dimethyl sulfate reference substance, a diethyl sulfate reference substance and a diisopropyl sulfate reference substance to obtain a sulfate impurity reference substance solution; dissolving parecoxib sodium to be detected to obtain a sample solution to be detected; carrying out gas chromatography-mass spectrometry on the sulfate impurity reference substance solution and the sample solution to be detected; the chromatographic conditions include: the filler of the gas chromatographic column is selected from one of non-polar filler, low-polar filler and medium-polar filler; the mass spectrometry conditions include: an electrospray ion source and a positive ion scanning mode are selected. The method has high detection precision, high specificity and durability, and simple operation. The separation degree of genotoxic impurities is more than 2.0, and the method can be used for quality control of parecoxib sodium bulk drug.
Description
Technical Field
The invention relates to the field of drug analysis and detection, in particular to a method for detecting parecoxib sodium sulfate genotoxic impurities.
Background
Parecoxib sodium belongs to a non-steroidal anti-inflammatory drug, is the first global selective cyclooxygenase-2 inhibitor capable of being injected into veins and muscles at the same time, and has the characteristics of good analgesic effect, quick response, lasting effect, capability of effectively inhibiting hyperalgesia, 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.
When the parecoxib sodium bulk drug is synthesized and prepared, 3 sulfate ester impurities are generated, namely dimethyl sulfate (R1-B): diethyl sulfate (R1-O), diisopropyl sulfate (R1-P). Sulfate is an art-recognized warning structure, and according to the rules of classification of impurities in the document M7 in international conference on harmonization (ICH) for registration of technical requirements for drugs for human use, i.e., the guidelines for evaluating and controlling DNA-reactive (mutagenic) impurities in drugs to limit potential carcinogenic risk, and the rules of guidance for controlling genotoxic impurities, which are the monograph in chinese pharmacopoeia 2020, the 3 sulfate impurities are 3 classes of genotoxic impurities, which are controlled to allow an intake per day (ADI) of 1.5 μ g/day in accordance with the toxicological attention threshold (TTC). Since the maximum daily dose of parecoxib sodium is 80 mg/day, the limits of these 3 sulfate impurities are calculated as follows: the limit (%) -1.5 μ g/80 mg-0.0018% -18 ppm.
Through literature search, at present, no literature and patent for simultaneously detecting the three sulfate impurities is found, and a detection method that the impurity limit of dimethyl sulfate, diethyl sulfate and diisopropyl sulfate is less than 18ppm and the lower limit of quantification is less than 1.8ppm is not reported. Therefore, in the daily factory release work of the parecoxib sodium bulk drug, the qualitative detection and the quantitative determination of the 3 genetic toxicity impurities with extremely low control limits become problems to be solved by analysis and test personnel in the industry urgently.
Disclosure of Invention
Based on the above, the method for detecting the parecoxib sodium sulfate genotoxic impurities is high in detection precision, the detection limit can reach 0.0009 mu g/ml, the quantification limit can reach 0.0018 mu g/m, and the method has high specificity and durability and is simple and convenient to operate. The separation degree of genotoxic impurities is more than 2.0, and the method can be used for quality control of parecoxib sodium bulk drug.
The specific technical scheme is as follows:
a detection method of parecoxib sodium sulfate genotoxic impurities comprises the following steps:
dissolving a dimethyl sulfate reference substance, a diethyl sulfate reference substance and a diisopropyl sulfate reference substance to obtain a sulfate impurity reference substance solution;
dissolving parecoxib sodium to be detected to obtain a sample solution to be detected;
carrying out gas chromatography-mass spectrometry on the sulfate impurity reference substance solution and the sample solution to be detected;
the conditions of the gas chromatography include:
the filler of the gas chromatographic column is selected from one of non-polar filler, low-polar filler and medium-polar filler;
the conditions of the mass spectrum include:
and a positive ion scanning mode, wherein the scanning mode is an SIM monitoring mode.
In a preferred embodiment, the packing material of the gas chromatography column is selected from one of 100% polydimethylsiloxane, 5% diphenyl-1% vinyl-94% dimethylpolysiloxane, and 6% cyanopropylphenyl-94% dimethylpolysiloxane.
In a preferred embodiment, the gas chromatography column is selected from one of DB-1, OV-1, HP-1, BP-1, SE-52, OV-5, DB-5, BP-5, SE-54, HP-5 and RTX-5.
In a preferred embodiment, the solvent for dissolving the dimethyl sulfate control, the diethyl sulfate control and the diisopropyl sulfate control is one or more selected from dimethyl sulfoxide, methanol, tetrahydrofuran and acetonitrile.
In a preferred embodiment, the solvent for dissolving the dimethyl sulfate reference substance, the diethyl sulfate reference substance and the diisopropyl sulfate reference substance is a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 100: 0-0: 100.
In a preferred scheme, the solvent for dissolving the parecoxib sodium to be detected is one or more selected from dimethyl sulfoxide, methanol, tetrahydrofuran and acetonitrile.
In a preferable scheme, the solvent for dissolving the parecoxib sodium to be detected is a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 100: 0-0: 100.
In a preferable scheme, the concentration of the parecoxib sodium to be detected in the sample solution to be detected is 1 mg/ml-25 mg/ml.
In a preferred embodiment, the conditions of the mass spectrum include: the mass to charge ratios of the scanned ions were 95.0, 139.0 and 167.0, respectively.
As can be understood, the first order spectra of mass-to-charge ratios (m/z) were 95.0(R1-O), 139.0(R1-B) and 167.0(R1-P), respectively.
In a preferred embodiment, the mass spectrometer employs an electrospray ion source.
In a preferred embodiment, the conditions of the mass spectrum include: the ion source temperature is 200-250 ℃, and the quadrupole rod temperature is 130-180 ℃.
In a preferred embodiment, the gas chromatography conditions comprise: the gas phase is in constant flow mode.
In a preferred embodiment, the gas chromatography conditions comprise: the carrier gas was helium.
In a preferred embodiment, the gas chromatography conditions comprise: the auxiliary gas is hydrogen and air.
In a preferred embodiment, the carrier gas flow rate is from 0.5ml/min to 5.0ml/min, preferably from 1ml/min to 10ml/min, more preferably from 1ml/min to 5ml/min, and most preferably 2 ml/min.
In a preferred embodiment, the gas chromatography conditions include a sample size of 1 μ L to 10 μ L, preferably 1 μ L to 5 μ L, more preferably 5 μ L.
In a preferred embodiment, the gas chromatography conditions comprise: the initial column temperature is 40-60 ℃, the temperature is programmed to 350 ℃ at the column temperature, and the temperature at the injection port is 150 ℃ at 250 ℃.
In a preferred embodiment, the gas chromatography conditions comprise: the flow dividing ratio is 1-10: 1, and preferably 1: 1.
Compared with the prior art, the invention has the following beneficial effects:
the method realizes the detection of 3 genotoxic impurities, namely dimethyl sulfate, diethyl sulfate and diisopropyl sulfate in the parecoxib sodium raw material medicine in a short time by a gas chromatography-mass spectrometry detection method, and has the advantages of high detection sensitivity, high precision, high specificity and durability and simple and convenient operation. The separation degree of genotoxic impurities is more than 2.0, and the method can be used for quality control of parecoxib sodium bulk drug.
Drawings
FIG. 1 is a mass spectrum of a R1-O, R1-B, R1-P control solution;
FIG. 2 is a mass spectrum of a test solution;
FIG. 3 is a mass spectrum of a detection limit solution of R1-O, R1-B, R1-P;
FIG. 4 is a mass spectrum of R1-O, R1-B, R1-P quantitative limiting solution;
FIG. 5 is a detection map of the R1-O, R1-B, R1-P impurity in a sample to be detected;
FIG. 6 is a detection spectrum of R1-O, R1-B, R1-P impurity in a labeled sample;
FIG. 7 is a R1-O, R1-B, R1-P working curve.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
1. Instrument for measuring the position of a moving object
The invention adopts a gas chromatography tandem quadrupole mass spectrometer for detection, and the instrument can be Agilent5975B MSD tandem 6890GC or Agilent5975C MSD tandem 7890 GC.
The filler of the gas chromatographic column can be one of non-polar filler, low-polar filler and medium-polar filler.
Wherein the nonpolar filler can be 100% Dimethyl polysiloxane and 100% polydimethylsiloxane, and the trade name can be OV-1, DB-1, HP-1 and BP-1.
The less polar filler may be 5% Phenyl 1% vinyl-94% dimethyl polysiloxane, 5% diphenyl-1% vinyl-94% dimethylpolysiloxane available under the trade names OV-5, DB-5, SE-52, SE-54, HP-5, RTX-5, BP-5.
The medium polarity filler may be 6% cyanophenyl-94% dimethyl polysiloxane, 6% cyanopropylphenyl-94% dimethylpolysiloxane, available under the trade name DB-624.
2. Reagent
Dimethyl sulfate R1-O control, diethyl sulfate R1-B control, diisopropyl sulfate control R1-P, parecoxib sodium control, dimethyl sulfoxide DMSO, methanol, tetrahydrofuran, and acetonitrile.
3. Examination of Experimental conditions
Parecoxib sodium is very easy to dissolve in water, is easy to dissolve in methanol and acetone, and is slightly soluble in acetonitrile. The 3 potential genotoxic impurities R1-O, R1-B and R1-P are all ester structures, are insoluble in water and can be dissolved in ethanol and ether. By further examining the solubility of sulfate impurities, R1-O, R1-B and R1-P were soluble in methanol, acetonitrile, tetrahydrofuran and DMSO.
The test selects to prepare the parecoxib sodium raw material drug into a to-be-detected sample solution with the concentration of 0.1-50.0 mg/ml for investigation, and the result shows that after impurities with the limit level of less than 18ppm (less than 18ppm, namely, each impurity in the to-be-detected sample solution with the concentration of 0.1mg/ml is less than 0.0018 mu g/ml) are added into the to-be-detected sample solution with the concentration of 0.1mg/ml, the response of each impurity cannot meet the requirement of quantitative detection, and when the to-be-detected sample solution with the concentration of 50mg/ml is prepared, the to-be-detected sample takes longer to dissolve, which brings difficulty to the preparation of the to-be-detected sample, and residues. Therefore, in the present invention, it is preferable that the concentration of the sample to be measured is 1mg/ml to 25 mg/ml.
On the basis, the following examples 1 to 7 are set, and the influence of each experimental condition on the separation degree of the parecoxib sodium sulfate genotoxic impurities is examined.
Example 1
1) Preparation of the solution
Accurately weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding DMSO, dissolving, and diluting until the concentration of the R1-O reference substance is 1 mu g/ml, the concentration of the R1-B reference substance is 1 mu g/ml, the concentration of the R1-P reference substance is 1 mu g/ml and the concentration of the parecoxib sodium reference substance is 25mg/ml to obtain a separation solution.
2) Instruments and detection conditions:
the instrument comprises the following steps: agilent5975B MSD tandem 6890GC
A chromatographic column: gas chromatography column SE-54
In the constant-current mode, helium is taken as carrier gas, hydrogen and air are taken as auxiliary gas, and the flow rate of the carrier gas is as follows: 1 ml/min.
Column temperature: and (4) a temperature raising program is carried out, wherein the initial temperature is 40 ℃, the temperature is continuously raised to 300 ℃, and the temperature of a sample inlet is 200 ℃.
The sample size is 5 mu L.
The detector is a mass spectrum detector, the mass spectrometer adopts an electrospray ion source and a positive ion scanning mode, the scanning mode is a SIM monitoring mode, and the mass-to-charge ratios (m/z) of scanned ions are R1-O95.0, R1-B139.0 and R1-P167.0 respectively.
Setting mass spectrum: the ion source temperature is 220 ℃ and the quadrupole rod temperature is 150 ℃.
3) Measurement method and results
Injecting sample according to the above detection conditions, running for 20min, recording mass spectrum, and inspecting the separation degree of each impurity.
The results showed that all the impurities peaked within 20min and were completely separated from one another, however, DMSO interfered with the diethyl sulfate assay.
Example 2
1) Preparation of the solution
Accurately weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding methanol, dissolving, and diluting until the concentration of the R1-O reference substance is 1 mu g/ml, the concentration of the R1-B reference substance is 1 mu g/ml, the concentration of the R1-P reference substance is 1 mu g/ml and the concentration of the parecoxib sodium reference substance is 25mg/ml to obtain a separation solution.
2) Instruments and detection conditions:
the instrument comprises the following steps: agilent5975B MSD tandem 6890GC
A chromatographic column: gas chromatographic column DB-624
In the constant-current mode, helium is taken as carrier gas, hydrogen and air are taken as auxiliary gas, and the flow rate of the carrier gas is as follows: 1 ml/min.
Column temperature: and (4) a temperature raising program is carried out, wherein the initial temperature is 40 ℃, the temperature is continuously raised to 300 ℃, and the temperature of a sample inlet is 200 ℃.
The sample size is 5 mu L.
The detector is a mass spectrum detector, the mass spectrometer adopts an electrospray ion source and a positive ion scanning mode, the scanning mode is a SIM monitoring mode, and the mass-to-charge ratios (m/z) of scanned ions are R1-O95.0, R1-B139.0 and R1-P167.0 respectively.
Setting mass spectrum: the ion source temperature is 220 ℃ and the quadrupole rod temperature is 150 ℃.
3) Measurement method and results
Injecting sample according to the above detection conditions, running for 20min, recording mass spectrum, and inspecting the separation degree of each impurity.
The results show that all the impurities are subjected to peak-forming within 20min, the sulfate impurity has a tail in the peak pattern, the impurities cannot be completely separated, and the mass spectrum signal response of the sulfate impurity at the concentration of 1 mu g/ml is different from that of the sulfate impurity at the concentration of a nonpolar chromatographic column and a weak polar chromatographic column.
Example 3
1) Preparation of the solution
Accurately weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding tetrahydrofuran, dissolving, and diluting until the concentration of the R1-O reference substance is 1 mu g/ml, the concentration of the R1-B reference substance is 1 mu g/ml, the concentration of the R1-P reference substance is 1 mu g/ml and the concentration of the parecoxib sodium reference substance is 1mg/ml, wherein the solutions are used as separation degree solutions.
2) Instruments and detection conditions:
the instrument comprises the following steps: agilent5975B MSD tandem 6890GC
A chromatographic column: gas chromatographic column DB-5
In the constant-current mode, helium is taken as carrier gas, hydrogen and air are taken as auxiliary gas, and the flow rate of the carrier gas is as follows: 5 ml/min.
Column temperature: and (4) a temperature raising program, wherein the initial temperature is 60 ℃, the temperature is continuously raised to 350 ℃, and the temperature of a sample inlet is 180 ℃.
The sample size is 10 mu L.
The detector is a mass spectrum detector, the mass spectrometer adopts an electrospray ion source and a positive ion scanning mode, the scanning mode is a SIM monitoring mode, and the mass-to-charge ratios (m/z) of scanned ions are R1-O95.0, R1-B139.0 and R1-P167.0 respectively.
Setting mass spectrum: the ion source temperature was 250 ℃ and the quadrupole temperature was 160 ℃.
3) Measurement method and results
Injecting sample according to the above detection conditions, running for 20min, recording mass spectrum, and inspecting the separation degree of each impurity.
The result shows that the base line of the spectrogram is stable, all the impurities are subjected to peak emergence within 20 minutes, the peak types of the components are good, and the separation degree among the impurities reaches more than 2.0.
Example 4
1) Preparation of the solution
Accurately weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding methanol, dissolving, and diluting until the concentration of the R1-O reference substance is 1 mu g/ml, the concentration of the R1-B reference substance is 1 mu g/ml, the concentration of the R1-P reference substance is 1 mu g/ml and the concentration of the parecoxib sodium reference substance is 1mg/ml, wherein the solutions are used as separation degree solutions.
2) Instruments and detection conditions:
the instrument comprises the following steps: agilent5975C MSD tandem 7890GC
A chromatographic column: gas chromatography column DB-1
In the constant-current mode, helium is taken as carrier gas, hydrogen and air are taken as auxiliary gas, and the flow rate of the carrier gas is as follows: 2 ml/min.
Column temperature: and (4) a temperature raising program is carried out, wherein the initial temperature is 40 ℃, the temperature is continuously raised to 280 ℃, and the temperature of a sample inlet is 150 ℃.
The sample size is 1 mu L.
The detector is a mass spectrum detector, the mass spectrometer adopts an electrospray ion source and a positive ion scanning mode, the scanning mode is a SIM monitoring mode, and the mass-to-charge ratios (m/z) of scanned ions are R1-O95.0, R1-B139.0 and R1-P167.0 respectively.
Setting mass spectrum: the ion source temperature was 220 ℃ and the quadrupole temperature was 130 ℃.
3) Measurement method and results
Injecting sample according to the above detection conditions, running for 20min, recording mass spectrum, and inspecting the separation degree of each impurity.
The result shows that the base line of the spectrogram is stable, all the impurities are subjected to peak emergence within 20 minutes, the peak types of the components are good, and the separation degree among the impurities reaches more than 2.0. However, diethyl sulfate and diisopropyl sulfate are less than 24 hours stable in solvents.
Example 5
1) Preparation of the solution
Accurately weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, dissolving, and diluting until the concentration of the R1-O reference substance is 1 mu g/ml, the concentration of the R1-B reference substance is 1 mu g/ml, the concentration of the R1-P reference substance is 1 mu g/ml and the concentration of the parecoxib sodium reference substance is 10mg/ml to obtain a separation degree solution.
2) Instruments and detection conditions:
the instrument comprises the following steps: agilent5975C MSD tandem 7890GC
A chromatographic column: gas chromatographic column BP-5
In the constant-current mode, helium is taken as carrier gas, hydrogen and air are taken as auxiliary gas, and the flow rate of the carrier gas is as follows: 2 ml/min.
Column temperature: and (4) a temperature raising program, wherein the initial temperature is 40 ℃, the temperature is continuously raised to 280 ℃, and the temperature of a sample inlet is 220 ℃.
The sample size is 5 mu L.
The detector is a mass spectrum detector, the mass spectrometer adopts an electrospray ion source and a positive ion scanning mode, the scanning mode is a SIM monitoring mode, and the mass-to-charge ratios (m/z) of scanned ions are R1-O95.0, R1-B139.0 and R1-P167.0 respectively.
Setting mass spectrum: the ion source temperature was 250 ℃ and the quadrupole temperature was 140 ℃.
3) Measurement method and results
Injecting sample according to the above detection conditions, running for 20min, recording mass spectrum, and inspecting the separation degree of each impurity.
The result shows that the base line of the spectrogram is stable, all the impurities are subjected to peak emergence within 20 minutes, the peak types of the components are good, and the separation degree among the impurities reaches more than 2.0. The stability of the sulfate impurity solution reaches more than 48 hours.
Example 6
1) Preparation of the solution
Accurately weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, dissolving, and diluting until the concentration of the R1-O reference substance is 1 mu g/ml, the concentration of the R1-B reference substance is 1 mu g/ml, the concentration of the R1-P reference substance is 1 mu g/ml and the concentration of the parecoxib sodium reference substance is 10mg/ml to obtain a separation degree solution.
2) Instruments and detection conditions:
the instrument comprises the following steps: agilent5975C MSD tandem 7890GC
A chromatographic column: gas chromatographic column RTX-5
In the constant-current mode, helium is taken as carrier gas, hydrogen and air are taken as auxiliary gas, and the flow rate of the carrier gas is as follows: 2 ml/min.
Column temperature: and (4) a temperature rising program is carried out, wherein the initial temperature is 40 ℃, the temperature is continuously raised to 350 ℃, and the temperature of a sample inlet is 250 ℃.
The sample size is 5 mu L.
The detector is a mass spectrum detector, the mass spectrometer adopts an electrospray ion source and a positive ion scanning mode, the scanning mode is a SIM monitoring mode, and the mass-to-charge ratios (m/z) of scanned ions are R1-O95.0, R1-B139.0 and R1-P167.0 respectively.
Setting mass spectrum: the ion source temperature is 230 ℃ and the quadrupole rod temperature is 150 ℃.
3) Measurement method and results
Injecting sample according to the above detection conditions, running for 20min, recording mass spectrum, and inspecting the separation degree of each impurity.
The result shows that the base line of the spectrogram is stable, all the impurities are subjected to peak emergence within 20 minutes, the peak types of the components are good, and the separation degree among the impurities reaches more than 2.0. The stability of the sulfate impurity solution reaches more than 48 hours.
Example 7
1) Preparation of the solution
Accurately weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, dissolving, and diluting until the concentration of the R1-O reference substance is 1 mu g/ml, the concentration of the R1-B reference substance is 1 mu g/ml, the concentration of the R1-P reference substance is 1 mu g/ml and the concentration of the parecoxib sodium reference substance is 10mg/ml to obtain a separation degree solution.
2) Instruments and detection conditions:
the instrument comprises the following steps: agilent5975C MSD tandem 7890GC
A chromatographic column: gas chromatographic column HP-5
In the constant-current mode, helium is taken as carrier gas, hydrogen and air are taken as auxiliary gas, and the flow rate of the carrier gas is as follows: 2 ml/min.
Column temperature: and (4) a temperature raising program, wherein the initial temperature is 40 ℃, the temperature is continuously raised to 330 ℃, and the temperature of a sample inlet is 220 ℃.
Sample size 5 mu L
The detector is a mass spectrum detector, the mass spectrometer adopts an electrospray ion source and a positive ion scanning mode, the scanning mode is a SIM monitoring mode, and the mass-to-charge ratios (m/z) of scanned ions are R1-O95.0, R1-B139.0 and R1-P167.0 respectively.
Setting mass spectrum: the ion source temperature was 250 ℃ and the quadrupole temperature was 150 ℃.
3) Measurement method and results
Injecting sample according to the above detection conditions, running for 20min, recording mass spectrum, and inspecting the separation degree of each impurity.
The result shows that the base line of the spectrogram is stable, all the impurities are subjected to peak emergence within 20 minutes, the peak types of the components are good, and the separation degree among the impurities reaches more than 2.0. The stability of the sulfate impurity solution reaches more than 48 hours.
From the results of examples 1 to 7, the following conclusions were drawn:
1) the solvent for dissolving each control and sample is preferably one or more of DMSO, methanol, tetrahydrofuran and acetonitrile. More preferably, the solvent for dissolving each of the control and the sample is DMSO, methanol, tetrahydrofuran, and a mixed solvent of methanol and tetrahydrofuran, and more preferably, the solvent for dissolving each of the control and the sample is a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 100: 0-0: 100.
2) When a chromatographic column with medium polarity is adopted, the peak type of sulfate impurities has tailing, the impurities cannot be completely separated, and the mass spectrum signal response of the sulfate impurities at the concentration of 1 mu g/ml is not as good as that of a chromatographic column with non-polarity and weak polarity. Preferred packing materials are non-polar and weakly polar chromatography columns.
4. Determination of the composition
1) Preparation of the solution
Accurately weighing an R1-O reference substance, an R1-B reference substance and an R1-P reference substance respectively, adding a mixed solvent of methanol and tetrahydrofuran with a volume ratio of 50:50, dissolving and diluting until the concentration of the R1-O reference substance is 1 mu g/ml, the concentration of the R1-B reference substance is 1 mu g/ml and the concentration of the R1-P reference substance is 1 mu g/ml, and obtaining 3 sulfuric acid impurity reference substance solutions.
Accurately weighing parecoxib sodium reference substance, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, dissolving, and diluting to obtain a solution with the parecoxib sodium reference substance concentration of 10mg/ml, wherein the solution is used as a test solution.
Accurately weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, dissolving, and diluting until the concentration of the R1-O reference substance is 1 mug/ml, the concentration of the R1-B reference substance is 1 mug/ml, the concentration of the R1-P reference substance is 1 mug/ml and the concentration of the parecoxib sodium reference substance is 10mg/ml, wherein the mixed solvent is used as a sample solution to be added.
2) Referring to the apparatus and detection conditions of example 5 above, the following are specific:
the instrument comprises the following steps: agilent5975C MSD tandem 7890GC
A chromatographic column: gas chromatographic column BP-5
In the constant-current mode, helium is taken as carrier gas, hydrogen and air are taken as auxiliary gas, and the flow rate of the carrier gas is as follows: 2 ml/min.
Column temperature: and (4) a temperature raising program, wherein the initial temperature is 40 ℃, the temperature is continuously raised to 280 ℃, and the temperature of a sample inlet is 220 ℃.
The sample size is 5 mu L.
The detector is a mass spectrum detector, the mass spectrometer adopts an electrospray ion source and a positive ion scanning mode, the scanning mode is a SIM monitoring mode, and the mass-to-charge ratios (m/z) of scanned ions are R1-O95.0, R1-B139.0 and R1-P167.0 respectively.
Setting mass spectrum: the ion source temperature was 250 ℃ and the quadrupole temperature was 140 ℃.
3) Measurement method and results
And sequentially injecting 3 sulfuric acid impurity reference substance solutions, test sample solutions and standard test sample solutions according to the detection conditions, and running for 20min, wherein the results are shown in table 1 and figures 1-2. Wherein, Table 1 shows the specificity results, FIG. 1 shows the mass spectrograms of R1-O reference substance solution, R1-B reference substance solution and R1-P reference substance solution, and FIG. 2 shows the mass spectrogram of the test substance solution.
TABLE 1
The results show that: the peak positions of target impurities in the maps of the blank solution and the test solution are not interfered; no interference peak is generated near the target peak of the standard sample; the peak-off time of the target peak of the impurity in the solution of the added standard sample and the solution of the reference substance are consistent.
5. Determination of detection limits and quantification limits
And continuously diluting the concentration of the impurity reference substance, carrying out sample injection test on the reference substance solution with each concentration to obtain a mass spectrogram, and determining the detection limit and the quantitative limit of 3 sulfate genotoxic impurities according to the mass spectrogram of each concentration.
Accurately weighing an R1-O reference substance, an R1-B reference substance and an R1-P reference substance, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, dissolving and diluting until the concentration of the R1-O reference substance is 0.0009 mu g/ml, the concentration of the R1-B reference substance is 0.0009 mu g/ml and the concentration of the R1-P reference substance is 0.0009 mu g/ml, thus obtaining a detection limit solution.
With reference to the apparatus and detection conditions of example 5 above, a sample was taken for measurement and a mass spectrum was recorded as shown in FIG. 3.
FIG. 3 shows that SNR of mass spectra is greater than 3, and 0.0009 μ g/ml is determined as detection limit of three sulfate gene impurities.
Accurately weighing an R1-O reference substance, an R1-B reference substance and an R1-P reference substance, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, dissolving and diluting until the concentration of the R1-O reference substance is 0.0018 mu g/ml, the concentration of the R1-B reference substance is 0.0018 mu g/ml and the concentration of the R1-P reference substance is 0.0018 mu g/ml, thus obtaining a quantification limit solution.
With reference to the apparatus and detection conditions of example 5 above, a sample was taken for measurement and a mass spectrum was recorded as shown in FIG. 4.
FIG. 4 shows that SNR of mass spectrum is greater than 10, and 0.0018. mu.g/ml is determined as the limit of quantification of three sulfate gene impurities.
6. Precision survey
1) Precisely weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, dissolving, and diluting until the concentration of the R1-O reference substance is 0.018 mu g/ml, the concentration of the R1-B reference substance is 0.018 mu g/ml, the concentration of the R1-P reference substance is 0.018 mu g/ml and the concentration of the parecoxib sodium reference substance is 10mg/ml to obtain a precise solution.
With reference to the apparatus and detection conditions of example 5, 5 probes were continuously injected, run for 20 minutes each time, and mass spectra were recorded to examine the degree of separation between genotoxic impurities and the reproducibility of peak area of each impurity. The result shows that the base line of the spectrogram is stable, each component generates a peak within 20 minutes, the separation degree among impurities is good, and the repeatability of the peak area of each impurity is good.
2) Precisely weighing an R1-O reference substance, an R1-B reference substance, an R1-P reference substance and a parecoxib sodium reference substance, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, dissolving, and diluting until the concentration of the R1-O reference substance is 0.0018 mu g/ml, the concentration of the R1-B reference substance is 0.0018 mu g/ml, the concentration of the R1-P reference substance is 0.0018 mu g/ml and the concentration of the parecoxib sodium reference substance is 1mg/ml, wherein the precision is taken as a solution.
With reference to the apparatus and detection conditions of example 5, 5 probes were continuously injected, run for 20 minutes each time, and mass spectra were recorded to examine the degree of separation between genotoxic impurities and the reproducibility of peak area of each impurity. The result shows that the base line of the spectrogram is stable, each component generates a peak within 20 minutes, the separation degree among impurities is good, and the repeatability of the peak area of each impurity is good.
The results show that the system applicability is good when the 3 genotoxic impurities of the sulfate are 0.0018 mu g/ml and 0.018 mu g/ml.
7. Method for detecting parecoxib sodium sulfate ester gene impurity
1) Preparation of the solution
Accurately weighing an R1-O reference substance, an R1-B reference substance and an R1-P reference substance respectively, adding a mixed solvent of methanol and tetrahydrofuran with the volume ratio of 50:50, dissolving and diluting to obtain 3 sulfuric acid impurity reference substance solutions with the concentration of the R1-O reference substance of 1 mu g/ml, the concentration of the R1-B reference substance of 1 mu g/ml and the concentration of the R1-P reference substance of 1 mu g/ml.
Accurately weighing the parecoxib sodium raw material medicine to be detected, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, and diluting the mixture after dissolving to obtain a sample solution to be detected with parecoxib concentration of 1 mg/ml.
2) With reference to the apparatus and detection conditions of example 5 above, each sample solution to be tested was injected 2 times, run for 20 minutes each time, and record mass spectra. The result shows that the impurities R1-O, R1-B and R1-P in the sample solution to be tested are both less than the detection limit (0.0009 mu g/ml).
3) Accurately weighing the parecoxib sodium raw material medicine to be detected, adding a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 50:50, and diluting the mixture after dissolving to obtain a sample solution to be detected with parecoxib concentration of 10 mg/ml.
With reference to the apparatus and detection conditions of example 5 above, each sample solution to be tested was injected 2 times, run for 20 minutes each time, and record mass spectra. The detection map of the sample to be detected is shown in figure 5, and the result shows that the impurities R1-O, R1-B and R1-P in the solution of the sample to be detected are still less than the detection limit (0.0009 mu g/ml), which indicates that after the concentration of the solution of the sample to be detected is increased by 10 times, the genotoxic impurities R1-O, R1-B and R1-P are still not detected.
4) Adding the same amounts of genotoxic impurity R1-O, R1-B and R1-P reference substances into a to-be-detected sample solution with the to-be-detected parecoxib concentration of 10mg/ml respectively to ensure that the concentrations are 0.018ug/ml, thus obtaining a sample labeling solution.
5) With reference to the apparatus and detection conditions of example 5 above, each sample solution to be tested was injected 2 times, run for 20 minutes each time, and record mass spectra. The sample detection spectrum is shown in FIG. 6, and the result shows that each impurity peak is correspondingly generated in the retention time of each impurity.
And calculating the content of the impurities by adopting the single impurity peak area signal of the corresponding impurity reference substance to make a working curve and calculating the content of each impurity in the detected sample according to the average value (2 parts of average) of the single response peak area in the sample to be detected and the concentration of the sample. The standard working curves of the R1-O, R1-B and R1-P impurity controls are shown in FIG. 7.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (14)
1. A detection method of parecoxib sodium sulfate genotoxic impurities is characterized by comprising the following steps:
dissolving a dimethyl sulfate reference substance, a diethyl sulfate reference substance and a diisopropyl sulfate reference substance to obtain a sulfate impurity reference substance solution;
dissolving parecoxib sodium to be detected to obtain a sample solution to be detected;
carrying out gas chromatography-mass spectrometry on the sulfate impurity reference substance solution and the sample solution to be detected;
the conditions of the gas chromatography include:
the filler of the gas chromatographic column is selected from one of non-polar filler, low-polar filler and medium-polar filler;
the conditions of the mass spectrum include:
and a positive ion scanning mode, wherein the scanning mode is an SIM monitoring mode.
2. The method for detecting parecoxib sodium sulfate genotoxic impurities as claimed in claim 1, wherein the filler of the gas chromatographic column is selected from one of 100% polydimethylsiloxane, 5% diphenyl-1% vinyl-94% dimethylpolysiloxane, and 6% cyanopropylphenyl-94% dimethylpolysiloxane.
3. The method for detecting parecoxib sodium sulfate genotoxic impurities as claimed in claim 2, wherein the gas chromatographic column is one selected from DB-1, OV-1, HP-1, BP-1, SE-52, OV-5, DB-5, BP-5, SE-54, HP-5, RTX-5 and DB-624.
4. The method for detecting parecoxib sodium sulfate genotoxic impurities as claimed in claim 1, wherein the solvent for dissolving the dimethyl sulfate control, the diethyl sulfate control and the diisopropyl sulfate control is one or more selected from dimethyl sulfoxide, methanol, tetrahydrofuran and acetonitrile.
5. The method for detecting parecoxib sodium sulfate genotoxic impurities according to claim 4, wherein the solvent for dissolving the dimethyl sulfate reference substance, the diethyl sulfate reference substance and the diisopropyl sulfate reference substance is a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 100: 0-0: 100.
6. The method for detecting parecoxib sodium sulfate genotoxic impurities according to claim 1, wherein a solvent for dissolving the parecoxib sodium to be detected is one or more selected from dimethyl sulfoxide, methanol, tetrahydrofuran and acetonitrile.
7. The method for detecting parecoxib sodium sulfate genotoxic impurities according to claim 6, wherein a solvent for dissolving the parecoxib sodium to be detected is a mixed solvent of methanol and tetrahydrofuran in a volume ratio of 100: 0-0: 100.
8. The method for detecting parecoxib sodium sulfate genotoxic impurities according to claim 1, wherein the concentration of parecoxib sodium to be detected in the sample solution to be detected is 1mg/ml to 25 mg/ml.
9. The method for detecting the parecoxib sodium sulfate genotoxic impurity according to any one of claims 1-8, wherein the conditions of the mass spectrum include: the mass to charge ratios of the scanned ions were 95.0, 139.0 and 167.0, respectively.
10. The method for detecting parecoxib sodium sulfate genotoxic impurities as claimed in claim 9, wherein the conditions of mass spectrometry include: the ion source temperature is 200-250 ℃, and the quadrupole rod temperature is 130-180 ℃.
11. The method for detecting parecoxib sodium sulfate genotoxic impurities as claimed in any one of claims 1-8, wherein the conditions of the gas chromatography include: the carrier gas was helium.
12. The method for detecting parecoxib sodium sulfate genotoxic impurities as claimed in claim 11, wherein the conditions of the gas chromatograph include: the flow rate of the carrier gas is 0.5 ml/min-5.0 ml/min.
13. The method for detecting the parecoxib sodium sulfate genotoxic impurities as claimed in any one of claims 1 to 8, wherein the gas chromatography conditions include a sample injection amount of 1 μ L-10 μ L.
14. The method for detecting parecoxib sodium sulfate genotoxic impurities as claimed in any one of claims 1-8, wherein the conditions of the gas chromatography include: the initial column temperature is 40-60 ℃, the temperature is programmed to 350 ℃ and the injection port temperature is 150 ℃ and 200 ℃.
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