CN114720577A - Detection method of diethyldiallyl phosphate impurity - Google Patents
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- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 26
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- 239000010452 phosphate Substances 0.000 title claims abstract description 26
- 238000001514 detection method Methods 0.000 title claims abstract description 24
- 150000002500 ions Chemical class 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 26
- 238000012544 monitoring process Methods 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 5
- 238000005173 quadrupole mass spectroscopy Methods 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 21
- 239000013558 reference substance Substances 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 238000002552 multiple reaction monitoring Methods 0.000 claims description 11
- 239000011550 stock solution Substances 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 238000001228 spectrum Methods 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 238000012417 linear regression Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- 230000004044 response Effects 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000010812 external standard method Methods 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 2
- KQROHCSYOGBQGJ-UHFFFAOYSA-N 5-Hydroxytryptophol Chemical compound C1=C(O)C=C2C(CCO)=CNC2=C1 KQROHCSYOGBQGJ-UHFFFAOYSA-N 0.000 claims 1
- 238000004587 chromatography analysis Methods 0.000 claims 1
- QZIQJIKUVJMTDG-OTUWWBTESA-L disodium;[(2s,3r)-3-methyloxiran-2-yl]-dioxido-oxo-$l^{5}-phosphane Chemical compound [Na+].[Na+].C[C@H]1O[C@H]1P([O-])([O-])=O QZIQJIKUVJMTDG-OTUWWBTESA-L 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 7
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- 239000007788 liquid Substances 0.000 abstract description 2
- 238000004949 mass spectrometry Methods 0.000 abstract description 2
- 230000002110 toxicologic effect Effects 0.000 abstract description 2
- 230000001738 genotoxic effect Effects 0.000 description 15
- 231100000024 genotoxic Toxicity 0.000 description 14
- 238000011084 recovery Methods 0.000 description 8
- 238000011160 research Methods 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- -1 diethylpropadiene phosphate Chemical compound 0.000 description 3
- 238000000132 electrospray ionisation Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XMYFZAWUNVHVGI-UHFFFAOYSA-N 3-ethylpent-2-ene Chemical group CCC(CC)=CC XMYFZAWUNVHVGI-UHFFFAOYSA-N 0.000 description 2
- 208000037088 Chromosome Breakage Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000003359 percent control normalization Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000002098 selective ion monitoring Methods 0.000 description 2
- 230000035502 ADME Effects 0.000 description 1
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- 208000005623 Carcinogenesis Diseases 0.000 description 1
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- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000005886 chromosome breakage Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- 231100000089 gene mutation induction Toxicity 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
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- 239000012488 sample solution Substances 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 238000012795 verification 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
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Abstract
The invention discloses a detection method of diethyldiallyl phosphate impurities, which relates to the field of chemical drug analysis and adopts a triple quadrupole mass spectrometry detector to perform detection in an MRM multi-reaction monitoring mode under an ESI positive ion mode. The method for detecting the diethyldiallyl phosphate by using the multi-reaction monitoring mode (MRM) of the high performance liquid mass spectrometry has high sensitivity and strong specificity, and can effectively control the diethyldiallyl phosphate in the fosfomycin sodium to a Toxicological Threshold (TTC), namely 1.5 mu g/day.
Description
Technical Field
The invention relates to the field of chemical drug analysis, and particularly relates to a detection method of diethyldiallyl phosphate impurities.
Background
In the synthesis route of fosfomycin sodium, diethyl allenoate phosphate may be produced after the addition of ethanol in the case of incomplete hydrolysis of the intermediate. The toxicity parameters of diethylallenphosphate were fully predicted by ADME/T Property prediction software ADMET predictor (TM) (version 9.5.0.16) of Simulins Plus, USA, and the impurity may cause genotoxicity and belongs to genotoxic impurity.
Genotoxic impurities (also called genotoxic impurities) generally refer to substances that are capable of causing DNA mutations, chromosomal breaks, or DNA recombinations. Because genotoxic impurities can induce gene mutation at a very low concentration and cause chromosome breakage and rearrangement, the genotoxic impurities have potential carcinogenicity, and in recent years, the attention to the genotoxic impurities is more and more serious, and guiding principles about the genotoxic and carcinogenic impurities are also issued successively by drug regulatory agencies of European Union, United states and the like.
The problem faced at present is that there is no corresponding detection method to study and control the genotoxic impurity diethylallenphosphate in fosfomycin sodium.
And the genotoxic impurities generally require lower control limit, and are more difficult compared with the research of other impurities.
Disclosure of Invention
As the research on genotoxic impurities of fosfomycin sodium is not reported at home and abroad at present, the research on the safety of the fosfomycin sodium is insufficient. The invention aims to solve the technical problem of providing a detection method which has high sensitivity and strong specificity and can effectively control the diethyldiallyl phosphate in the fosfomycin sodium so as to ensure the quality of the medicine. The invention overcomes the defect of the blank research on genotoxic impurities of fosfomycin sodium at present, develops an impurity detection method and is used for controlling the product quality.
In order to achieve the above object, the present invention provides the following technical solutions:
a detection method of diethylpropadiene phosphate impurities adopts a triple quadrupole mass spectrometry detector to carry out detection in an MRM multi-reaction monitoring mode under an ESI positive ion mode.
The invention also has the following additional technical features:
preferably, the method comprises the following steps:
(1) accurately weighing a diethyl allephosphate standard substance to prepare a diethyl allephosphate reference substance stock solution and a reference substance solution with gradient concentration;
(2) and calculating the peak area of the quantitative ion pair in the MRM spectrum according to an external standard method.
Preferably, the column uses octadecylsilane bonded silica as packing material.
Preferably, the volume fraction of the mobile phase A is 0.1% formic acid aqueous solution, the mobile phase B is 100% acetonitrile, and the volume ratio of the diluent is methanol: water: formic acid 55: 35: 10, flow rate 0.8ml/min, column temperature 30 ℃, run time 30min, gradient elution procedure as follows:
preferably, the detection conditions are that the temperature of the drying gas is 300 ℃, the flow rate of the drying gas is 5L/min, the pressure of the atomizing gas is 20psi, the temperature of the sheath gas is 400 ℃, the flow rate of the sheath gas is 11L/min, the detection time is 1.6-4.9min, and the rest time does not flow into the mass spectrometer.
Preferably, the multi-reaction monitoring mode parameters of the diethyldiallyl phosphate are as follows:
| Fragmentor | quantifying ion pair/collision energy | Qualitative ion pair/collision energy |
| 87 | 177.09-121(13) | 177.09-103(25) |
。
Preferably, the capillary voltage is 5500V and the nozzle voltage is 500V.
Preferably, the amount of sample is 5. mu.l.
Preferably, the step (2) comprises a linear regression equation of responses of quantitative ions to concentrations, wherein the concentrations comprise 5-7 gradient concentrations.
Compared with the prior art, the invention has the advantages that:
the method for detecting the diethyldiallyl phosphate by using the multi-reaction monitoring mode (MRM) of the high performance liquid mass spectrometry has high sensitivity and strong specificity, and can effectively control the diethyldiallyl phosphate in the fosfomycin sodium to a Toxicological Threshold (TTC), namely 1.5 mu g/day.
The toxicology threshold is specifically defined as the intake of 1.5. mu.g of genotoxic impurities per day, which is considered to be an acceptable risk for most drugs (the risk of carcinogenesis over lifetime is less than 1 in 100000).
The method solves the bottleneck problem in the research process of the fosfomycin sodium genotoxic impurities and the problem of the detection sensitivity of the genotoxic impurities. Can effectively control the quality of the fosfomycin sodium product. The method has the advantages of simple operation, high sensitivity and good separation degree, and provides a feasible and effective analysis method for controlling the product quality. The fosfomycin sodium has a bactericidal effect on gram-positive bacteria and gram-negative bacteria, has a strong antibacterial effect on staphylococcus with various drug resistances, and is a clinical common medicine.
The detection method is applied to enterprise production at present, and stability detection is carried out on fosfomycin sodium, so that product quality is guaranteed.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is a system applicability linear regression equation;
FIG. 2 is a TIC spectrum of diethyldiallyl phosphate;
FIG. 3 is a qualitative ion spectrum of diethyldiallyl phosphate;
FIG. 4 is a quantitative ion spectrum of diethyldiallyl phosphate;
fig. 5 is a resulting linear regression equation.
Detailed Description
Some embodiments of the invention are disclosed below, and those skilled in the art can appropriately modify the process parameters to achieve the invention according to the disclosure herein. The method can be used for controlling impurities of fosfomycin sodium raw material medicines and preparation isomers, and can also be used for controlling impurities of fosfomycin calcium raw materials and preparations, fosfomycin trometamol raw materials and preparation isomers. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
Method development step
According to the structure of diethyldiallyl phosphate, a positive ion mode is selected.
The ratio of mobile phase is adjusted to make the peak type and retention time of chromatographic peak suitable.
Optimization using OPTIMIZER software resulted in voltage, collision energy, quantitative ion pairs, and qualitative ion pairs.
Second, detection method
A chromatographic column using octadecylsilane chemically bonded silica as a filler, wherein a mobile phase A is 0.1% formic acid aqueous solution, a mobile phase B is 100% acetonitrile, and a diluent is methanol: water: formic acid 55: 35: 10, the flow rate is 0.8ml/min, the column temperature is 30 ℃, the sample injection amount is 5 mul, the running time is 30min, and gradient elution is carried out according to the following table.
Table 1 mobile phase gradient elution procedure
A triple quadrupole mass spectrometer is adopted, a multi-reaction monitoring mode (MRM) is adopted under an electrospray ionization (ESI) positive ion mode, the temperature of dry gas is 300 ℃, the flow rate of the dry gas is 5L/min, the pressure of atomized gas is 20psi, the temperature of sheath gas is 400 ℃, the flow rate of the sheath gas is 11L/min, the voltage of a capillary tube is 5500V, the voltage of a nozzle is 500V, the detection time is 1.6-4.9min, the rest time is not flowed into a mass spectrometer, and the parameters of the multi-reaction monitoring mode of diethyl allenoate phosphate are shown in the following table.
TABLE 2 Multi-reaction monitoring mode parameters of diethyldiallyl phosphate
| Fragmentor | Quantitative ion pair (Collision energy) | Qualitative ion pair (Collision energy) |
| 87 | 177.09-121(13) | 177.09-103(25) |
Taking a proper amount of diethyl allenoate phosphate, precisely weighing, placing in a volumetric flask, adding methanol for dissolving, diluting, and preparing into a solution containing 50ng/ml of impurities, wherein the solution is used as a reference substance stock solution. Precisely measuring 0.5ml of reference substance stock solution, placing into a 25ml volumetric flask, adding diluent to dilute to scale, shaking up to obtain 20% reference substance solution (containing about 1ng/ml of impurities); precisely measuring 1.25ml of reference substance stock solution, placing into a 25ml volumetric flask, adding diluent to dilute to scale, shaking up to obtain 50% reference substance solution (containing about 2.5ng/ml of impurities); precisely measuring 2.5ml of a reference substance stock solution, placing the reference substance stock solution into a 25ml volumetric flask, adding a diluent to dilute the reference substance stock solution to a scale, and shaking up to obtain a 100% reference substance solution (containing about 5ng/ml of impurities); precisely measuring 3.75ml of reference substance stock solution, placing into a 25ml volumetric flask, adding diluent to dilute to scale, shaking up to obtain 150% reference substance solution (containing about 7.5ng/ml of impurities); precisely measuring 5ml of the reference substance stock solution, placing the reference substance stock solution into a 25ml volumetric flask, adding the diluent to dilute to a scale, and shaking up to obtain a 200% reference substance solution (containing about 10ng/ml of impurities). Taking a proper amount of a test sample, accurately weighing, placing in a 10ml measuring flask, adding the diluent for dissolving, diluting to a scale, and shaking up to obtain a test sample solution.
And calculating the peak area of the quantitative ion pair in the MRM spectrum according to an external standard method.
Third, method verification
1. System applicability
TABLE 3 System suitability results
And (4) conclusion: referring to FIG. 1, the correlation coefficient r is 1.000, not less than 0.995 by linear regression equation of response of the quantitative ion to concentration.
2. Specificity
TABLE 1 results of specialization
| Sample (I) | Retention time min | Relative deviation% |
| Positioning solution | 3.637 | 0 |
| 100% control solution | 3.638 | 0.01 |
| Resolution solution | 3.638 | 0.01 |
And (4) conclusion: referring to fig. 2, 3 and 4, the relative deviation of the retention time of the impurities in the 100% control solution, the resolution solution and the impurity localization solution is not more than 1.0%.
3. Linearity and range
TABLE 2 Linear results
And (4) conclusion: referring to FIG. 5, the correlation coefficient r is 1.000, not less than 0.995 by linear regression equation of response of the quantitative ion to concentration.
4. Quantitative and detection limits
TABLE 6 test limit solution results
| S/N | Concentration ng/ml | Amount of impurities ng |
| 5.7 | 0.0504 | 0.000252 |
TABLE 7 quantitative limiting solution results
And (4) conclusion: the signal-to-noise ratio of the impurities in the detection limiting solution is greater than 3, and the signal-to-noise ratios of the impurities in the quantification limiting solution are both greater than 10; in 6 continuous quantitative limiting solutions, the RSD of the peak area in the MRM spectrum of the quantitative ions is 8.1 percent and is not more than 30 percent.
5. Accuracy of
TABLE 8 recovery results
And (4) conclusion: the recovery rate is 70.0-130.0%, and the RSD of 9 recovery rate data is 0.7% and not more than 30.0%.
6. Repeatability of
TABLE 9 repeatability results
And (4) conclusion: the recovery rate is 70.0-130.0%, and the RSD of 6 recovery rate data is 1.0% and not more than 30.0%.
7. Intermediate precision
TABLE 10 intermediate precision results
TABLE 11 precision results
And (4) conclusion: the recovery rate is 70.0-130.0%, the RSD of 6 recovery rate data with intermediate precision is 0.4% and not more than 30.0%, and the RSD of 12 recovery rate data is 1.3% and not more than 30.0% through statistics with the repeatability result.
Fourthly, key technical points
1. Mass spectrometer monitoring mode (MRM): the triple quadrupole mass spectrometer has two quadrupoles, the first quadrupoles uses a selective ion monitoring mode, only diethyldiallyl phosphate parent ions can be allowed to pass through by applying electric charges, collision energy is applied to the diethyldiallyl phosphate parent ions in a collision cell to generate fragment ions (quantitative ion pairs and qualitative ion pairs), the second quadrupoles also uses the selective ion monitoring mode to monitor the quantitative ion pairs and the qualitative ion pairs generated by the diethyldiallyl phosphate parent ions, and the Multiple Reaction Monitoring (MRM) is realized. This way, the monitoring sensitivity and the quantitative accuracy can be greatly improved.
2. Voltage: affecting the efficiency of the diethylprocamphenylphosphate parent ion passing through the first quadrupole. The proper voltage can ensure that the propadiene diethyl phosphate mother ions pass through the first quadrupole as completely as possible, and finally the sensitivity of the detection result is influenced.
3. Collision energy: different collision energy is applied to the diethyldiallyl phosphate parent ions, and different fragment ions can collide. The proper collision energy can ensure that the propadiene diethyl phosphate parent ions accurately collide to obtain quantitative ion pairs and qualitative ion pairs as much as possible.
4. Quantitative ion pair and qualitative ion pair: the quantitative ion pairs, the qualitative ion pairs, of each compound are generally fixed, which is also the reason for the extreme specificity of the MRM mode using the triple quadrupole.
5. Elution procedure: the retention time of the chromatographic peak of the diethylpropylene dienophosphate is influenced, and the elution procedure is proper to ensure that the diethylpropylene dienophosphate quickly goes out of the peak.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A detection method of diethyldiallyl phosphate impurities is characterized in that a triple quadrupole mass spectrometry detector is adopted to perform detection in an ESI positive ion mode and an MRM multiple reaction monitoring mode.
2. The method for detecting diethylallenphosphate impurity of claim 1, comprising the steps of:
(1) accurately weighing a diethyl allenoate phosphate standard substance to prepare a diethyl allenoate phosphate reference substance stock solution and a reference substance solution with gradient concentration;
(2) and calculating the peak area of the quantitative ion pair in the MRM spectrum according to an external standard method.
3. The method for detecting diethylprocamphenylphosphate impurity according to claim 1, wherein octadecylsilane bonded silica is used as a filler in a column for chromatography.
4. The method for detecting diethyl allephosphate impurity according to claim 1, wherein the volume fraction of mobile phase A is 0.1% formic acid aqueous solution, the volume fraction of mobile phase B is 100% acetonitrile, and the volume ratio of the diluent is methanol: water: formic acid 55: 35: 10, flow rate 0.8ml/min, column temperature 30 ℃, run time 30min, gradient elution procedure as follows:
5. the method for detecting diethyl allephosphonate impurity according to claim 1, wherein the detection conditions are a drying gas temperature of 300 ℃, a drying gas flow rate of 5L/min, an atomizing gas pressure of 20psi, a sheath gas temperature of 400 ℃, a sheath gas flow rate of 11L/min, a detection time of 1.6-4.9min, and no flow into a mass spectrometer during the rest of the time.
6. The method for detecting impurity diethyldiallyl phosphate according to claim 1, wherein the parameters of the multi-reaction monitoring mode of diethyldiallyl phosphate are as follows:
。
7. The method for detecting diethylallenphosphate impurity of claim 5, wherein the capillary voltage is 5500V and the nozzle voltage is 500V.
8. The method for detecting diethylprocamphenylphosphate impurity according to claim 1, wherein the amount of sample is 5. mu.l.
9. The method for detecting diethylallephosphate impurity of claim 1, wherein said step (2) comprises a linear regression equation of responses of quantitative ions versus concentration, said concentration comprising 5 to 7 gradient concentrations.
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|---|---|---|---|---|
| WO2016019685A1 (en) * | 2014-08-07 | 2016-02-11 | 富力 | Quality detection method for active ingredient phillyrin |
| CN111257478A (en) * | 2020-03-24 | 2020-06-09 | 上海峰林生物科技有限公司 | Method for analyzing fosfomycin trometamol genotoxic impurities |
| CN111965285A (en) * | 2020-08-21 | 2020-11-20 | 天津市中升挑战生物科技有限公司 | Method for detecting content of tulathromycin |
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| Title |
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| 刘蓉梅, 黄罗生: "高效液相色谱法测定当归中阿魏酸含量方法的探讨", 东南大学学报(医学版), no. 02, 30 March 2003 (2003-03-30) * |
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