CN116818944A - Detection method of dimethyl sulfate in pantoprazole sodium - Google Patents
Detection method of dimethyl sulfate in pantoprazole sodium Download PDFInfo
- Publication number
- CN116818944A CN116818944A CN202310787022.6A CN202310787022A CN116818944A CN 116818944 A CN116818944 A CN 116818944A CN 202310787022 A CN202310787022 A CN 202310787022A CN 116818944 A CN116818944 A CN 116818944A
- Authority
- CN
- China
- Prior art keywords
- dimethyl sulfate
- detection
- sample
- pantoprazole sodium
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000001514 detection method Methods 0.000 title claims abstract description 77
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 title claims abstract description 70
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 229960004048 pantoprazole sodium Drugs 0.000 title claims abstract description 64
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 62
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 58
- 239000000126 substance Substances 0.000 claims abstract description 16
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 claims abstract description 15
- 239000006228 supernatant Substances 0.000 claims abstract description 14
- 239000003085 diluting agent Substances 0.000 claims abstract description 12
- 238000000926 separation method Methods 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 18
- 239000007789 gas Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 238000004090 dissolution Methods 0.000 claims description 8
- 150000002500 ions Chemical class 0.000 claims description 8
- 239000012159 carrier gas Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000005526 G1 to G0 transition Effects 0.000 claims description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 3
- 238000004949 mass spectrometry Methods 0.000 claims description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 3
- 238000011068 loading method Methods 0.000 claims description 2
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 abstract description 7
- 229960005019 pantoprazole Drugs 0.000 abstract description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 abstract description 6
- 239000001632 sodium acetate Substances 0.000 abstract description 6
- 235000017281 sodium acetate Nutrition 0.000 abstract description 6
- 238000004458 analytical method Methods 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 4
- 238000000354 decomposition reaction Methods 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 238000006386 neutralization reaction Methods 0.000 abstract description 2
- 239000002516 radical scavenger Substances 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 62
- 239000000243 solution Substances 0.000 description 57
- 238000012360 testing method Methods 0.000 description 30
- 239000012488 sample solution Substances 0.000 description 16
- 239000013558 reference substance Substances 0.000 description 15
- 238000011084 recovery Methods 0.000 description 12
- 230000014759 maintenance of location Effects 0.000 description 10
- 238000007865 diluting Methods 0.000 description 9
- 238000010998 test method Methods 0.000 description 9
- 238000005259 measurement Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 230000008859 change Effects 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 239000012490 blank solution Substances 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- 230000033228 biological regulation Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000012417 linear regression Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000357 carcinogen Toxicity 0.000 description 2
- 239000003183 carcinogenic agent Substances 0.000 description 2
- 239000012483 derivatization solution Substances 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000012022 methylating agents Substances 0.000 description 2
- 238000000197 pyrolysis Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- YYRIKJFWBIEEDH-UHFFFAOYSA-N 2-(chloromethyl)-3,4-dimethoxypyridine;hydrochloride Chemical compound [Cl-].COC1=CC=[NH+]C(CCl)=C1OC YYRIKJFWBIEEDH-UHFFFAOYSA-N 0.000 description 1
- HJMVPNAZPFZXCP-UHFFFAOYSA-N 5-(difluoromethoxy)-1,3-dihydrobenzimidazole-2-thione Chemical compound FC(F)OC1=CC=C2NC(=S)NC2=C1 HJMVPNAZPFZXCP-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- UXOLDCOJRAMLTQ-UHFFFAOYSA-N ethyl 2-chloro-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(Cl)=NO UXOLDCOJRAMLTQ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical class [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
Classifications
-
- 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
- G01N30/62—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
- G01N2030/042—Standards
- G01N2030/047—Standards external
-
- 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
- G01N2030/065—Preparation using different phases to separate parts of sample
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention provides a detection method of dimethyl sulfate in pantoprazole sodium, and relates to the technical field of analysis and detection. According to the invention, pantoprazole sodium sample and diluent (acetic anhydride, acetic acid and ethyl acetate) are mixed and dissolved, and then are centrifugally separated, the obtained supernatant is subjected to gas chromatography-mass spectrometry detection, and the characteristic peak position of the obtained object to be detected is compared with the characteristic peak position of a dimethyl sulfate standard substance, so that a qualitative detection result and/or a quantitative detection result of dimethyl sulfate are obtained. Acetic anhydride is used as a water scavenger to be combined with water molecules in pantoprazole sodium double hydrate, so that dimethyl sulfate decomposition and hydrolysis are avoided; acetic acid and pantoprazole sodium are subjected to neutralization reaction to generate pantoprazole and sodium acetate, and the sodium acetate is separated out after centrifugal separation, so that interference detection is reduced; ethyl acetate is used as a solvent of pantoprazole and dimethyl sulfate, so that high-sensitivity, rapid, accurate, effective and low-cost detection of the dimethyl sulfate in the pantoprazole sodium is realized.
Description
Technical Field
The invention relates to the technical field of analysis and detection, in particular to a detection method of dimethyl sulfate in pantoprazole sodium.
Background
Pantoprazole sodium is an alkaline proton pump inhibitor, has high selectivity and bioavailability, and is mainly used for treating digestive system diseases such as gastric ulcer, duodenal ulcer and the like.
At present, the synthesis of pantoprazole sodium mostly takes 2-chloromethyl-3, 4-dimethoxy pyridine hydrochloride and 5-difluoromethoxy-2-mercaptobenzimidazole as starting materials, and dimethyl sulfate is taken as a methylation reagent in the pantoprazole sodium raw material synthesis process to convert hydroxy into methoxy. The pantoprazole sodium synthesized by the method may have dimethyl sulfate residues.
Dimethyl sulfate, an organic compound, has the chemical formula (CH) 3 O) 2 SO 2 The method is mainly used as a methylating agent, and the methyl of the methylating agent can be exchanged with acid H atoms of hydroxyl, sulfhydryl, amino or imino under alkaline conditions, and can also be used for organic synthesis of medicines, pesticides, dyes, fragrances and the like.
The european union ECHA ranks dimethyl sulfate into lot 8 high attention Substances (SVHC) at 12, 19, 2012; the carcinogen list published by the world health organization international cancer research institute was initially organized and referenced on the 10 th and 27 th 2017, dimethyl sulfate in the class 2A carcinogen list. Therefore, the detection of the content of the dimethyl sulfate in the pantoprazole sodium has important significance for controlling the quality control of the pantoprazole sodium related preparation.
For example, prior art CN111505182a discloses a method for measuring dimethyl sulfate in a drug by using a combination of derivatization gas chromatography-mass spectrometry, adding a derivatization solution to a drug sample, derivatizing dimethyl sulfate into methyl iodide, and detecting the content of methyl iodide by using a combination of gas chromatography-mass spectrometry to obtain the content of dimethyl sulfate; the derivatization solution is a saturated sodium iodide aqueous solution added with trace sodium thiosulfate. Because pantoprazole sodium is an alkaline substance, dimethyl sulfate is rapidly decomposed when meeting alkali, and hydrolysis occurs when meeting water or moisture, so that the detection result of the dimethyl sulfate content in pantoprazole sodium is inaccurate.
Disclosure of Invention
In view of the above, the invention aims to provide a method for detecting dimethyl sulfate in pantoprazole sodium, which has high sensitivity, high speed and high accuracy for detecting suspected dimethyl sulfate samples in pantoprazole sodium.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a detection method of dimethyl sulfate in pantoprazole sodium, which comprises the following steps:
mixing and dissolving a pantoprazole sodium sample and a diluent, and then centrifugally separating to obtain a supernatant serving as a sample liquid to be detected; the diluent comprises acetic anhydride, acetic acid and ethyl acetate;
carrying out gas chromatography-mass spectrometry detection on the sample liquid to be detected to obtain characteristic peak positions of the object to be detected;
and comparing the characteristic peak position of the object to be detected with the characteristic peak position of the dimethyl sulfate standard substance to obtain a qualitative detection result and/or a quantitative detection result of the dimethyl sulfate in the pantoprazole sodium.
Preferably, the ratio of the mass of the pantoprazole sodium sample to the volume of acetic anhydride is 1g: 1-10 mL.
Preferably, the ratio of the mass of the pantoprazole sodium sample to the volume of acetic acid is 1g: 0.5-6 mL.
Preferably, the ratio of the mass of the pantoprazole sodium sample to the volume of ethyl acetate is 1g: 150-300 mL.
Preferably, the mixed dissolution is an ultrasonic mixed dissolution.
Preferably, the rotational speed of the centrifugal separation is 8000-13000 rpm, and the time is 3-10 min.
Preferably, the separation conditions of the gas chromatograph for gas chromatograph-mass spectrometer detection include: the chromatographic column is a capillary column; adopting temperature programming, wherein the temperature programming is as follows: the initial temperature is maintained at 60 ℃ for 2min, the temperature is raised to 150 ℃ at the speed of 45-55 ℃/min for 2min, and then the temperature is raised to 250 ℃ at the speed of 45-55 ℃/min for 3min; the temperature of the sample inlet is 200 ℃; the flow rate of the carrier gas is 1.0mL/min; the split ratio was 1:1.
Preferably, the stationary phase of the chromatographic column is 5% phenyl-95% dimethylpolysiloxane.
Preferably, the mass spectrometry detection conditions of the gas chromatography-mass spectrometry detection include: the detector is a gas chromatography-mass spectrum detector; the ion source temperature is 230 ℃; the temperature of the four-stage rod is 150 ℃; the auxiliary heater temperature is 250 ℃; the solvent delay time is 3min; the sample loading was 3. Mu.L.
According to the detection method provided by the invention, the mixture of acetic anhydride, acetic acid and ethyl acetate is used as a diluent, wherein acetic acid and pantoprazole sodium undergo a neutralization reaction to generate pantoprazole and sodium acetate, pantoprazole and dimethyl sulfate are dissolved in ethyl acetate, sodium acetate is separated out after centrifugal separation, the purity of the obtained supernatant (sample liquid to be detected) is high, and the supernatant obtained by centrifugal separation is detected, so that detection interference can be reduced, and the detection accuracy of dimethyl sulfate is improved. Meanwhile, the invention utilizes the hygroscopicity of acetic anhydride, and the acetic anhydride forms acetic acid with water molecules in pantoprazole sodium double hydrate, thereby avoiding the decomposition of dimethyl sulfate, effectively solving the problems of the decomposition and the hydrolysis of dimethyl sulfate components, and realizing the high-sensitivity, rapid, accurate, effective and low-cost detection of the dimethyl sulfate in pantoprazole sodium.
Drawings
FIG. 1 is a linear plot of dimethyl sulfate peak area versus concentration;
fig. 2 is a graph of the detection of pantoprazole sodium sample 170408;
fig. 3 is a graph of the detection of pantoprazole sodium sample 180311;
fig. 4 is a graph of the detection of pantoprazole sodium sample 191005;
fig. 5 is a graph of the detection of pantoprazole sodium sample 191009;
fig. 6 is a graph of the detection profile of pantoprazole sodium sample 191011.
Detailed Description
The invention provides a detection method of dimethyl sulfate in pantoprazole sodium, which comprises the following steps:
mixing and dissolving a pantoprazole sodium sample and a diluent, and then centrifugally separating to obtain a supernatant serving as a sample liquid to be detected; the diluent comprises acetic anhydride, acetic acid and ethyl acetate;
carrying out gas chromatography-mass spectrometry detection on the sample liquid to be detected to obtain characteristic peak positions of the object to be detected;
and comparing the characteristic peak position of the object to be detected with the characteristic peak position of the dimethyl sulfate standard substance to obtain a qualitative detection result and/or a quantitative detection result of the dimethyl sulfate in the pantoprazole sodium.
The raw materials adopted by the invention are all commercial products unless specified.
According to the invention, pantoprazole sodium sample and diluent are mixed and dissolved, and then are centrifugally separated, and the obtained supernatant is the sample liquid to be detected.
In the present invention, the diluent includes acetic anhydride, acetic acid and ethyl acetate. The invention selects the mixture of acetic anhydride, acetic acid and ethyl acetate as the diluent, because: (1) Acetic anhydride, acetic acid and ethyl acetate are similar substances, and even if the reaction is carried out, other substances are not generated so as to influence the detection result of dimethyl sulfate; (2) ethyl acetate can dissolve pantoprazole; (3) Ethyl acetate can make dimethyl sulfate relatively stable; (4) Acetic acid reacts with pantoprazole sodium to produce pantoprazole and sodium acetate, and sodium acetate is separated out after centrifugal separation, and then supernatant is detected, so that interference detection can be reduced, and the accuracy of a detection result of dimethyl sulfate is improved.
In the present invention, the ratio of the mass of the pantoprazole sodium sample to the volume of acetic anhydride is preferably 1g:1 to 10mL, more preferably 1g:5 to 10mL, more preferably 1g: 6-9 mL. In the present invention, the ratio of the mass of the pantoprazole sodium sample to the volume of acetic acid is preferably 1g:0.5 to 6mL, more preferably 1g:2 to 6mL, more preferably 1g: 3-5 mL. In the present invention, the ratio of the mass of the pantoprazole sodium sample to the volume of ethyl acetate is preferably 1g:150 to 300mL, more preferably 1g:160 to 250mL, more preferably 1g: 180-200 mL.
In the present invention, the temperature of the mixed dissolution is preferably 10 to 40 ℃, more preferably 20 to 30 ℃; the mixing and dissolving time is preferably 10-20 min, more preferably 15min; the mixed dissolution is preferably ultrasonic mixed dissolution, and the power of the ultrasonic mixed dissolution is preferably 300-400W, more preferably 350W.
In the present invention, the rotational speed of the centrifugal separation is preferably 8000 to 13000rpm, more preferably 9000 to 10000rpm, and the time of the centrifugal separation is preferably 3 to 10 minutes, more preferably 3 to 5 minutes.
After obtaining a sample liquid to be detected, the invention carries out gas chromatography-mass spectrometry detection on the sample liquid to be detected to obtain the characteristic peak position of the object to be detected.
In the present invention, the separation conditions of the gas chromatograph for gas chromatograph-mass spectrometer detection include: the chromatographic column is preferably a capillary column, and the stationary phase of the chromatographic column is preferably 5% phenyl-95% dimethylpolysiloxane; a temperature programming is adopted, and the temperature programming is preferably as follows: the initial temperature is maintained at 60 ℃ for 2min, the temperature is raised to 150 ℃ at the rate of 45-55 ℃/min (more preferably 50 ℃/min) for 2min, and then the temperature is raised to 250 ℃ at the rate of 45-55 ℃/min for 3min; the temperature of the sample inlet is preferably 200 ℃; the flow rate of the carrier gas is preferably 1.0mL/min, and the carrier gas is preferably nitrogen; the split ratio is preferably 1:1.
In the present invention, the mass spectrometry detection conditions for the gas chromatography-mass spectrometry detection include: the ion source temperature is preferably 230 ℃; the temperature of the quaternary column is preferably 150 ℃; the auxiliary heater temperature is preferably 250 ℃; the solvent delay time is preferably 3min; the sample amount is preferably 3. Mu.L. In the present invention, the detector for gas chromatography-mass spectrometry detection is preferably a gas chromatography-mass spectrometry detector.
After the characteristic peak position of the object to be detected is obtained, the characteristic peak position of the object to be detected is compared with the characteristic peak position of a dimethyl sulfate standard substance, and a qualitative detection result and/or a quantitative detection result of dimethyl sulfate in pantoprazole sodium are obtained. In the invention, the characteristic peak position of the dimethyl sulfate standard substance is preferably derived from a standard substance spectrum chart library of the dimethyl sulfate. In the invention, when chromatographic peaks consistent with the retention time of the dimethyl sulfate standard are present in the mass spectrogram of the sample liquid to be detected, the quantitative detection result of the dimethyl sulfate is obtained by calculating the peak area of fragment ions according to an external standard method.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The equipment, gas, reagents, sample information, and gas quality detection conditions used in the following examples are shown in tables 1 to 5:
table 1 device information
| Name of the name | Numbering device | Model number | Manufacturer' s |
| Gas chromatography-mass spectrometry instrument | HZBL-004-01 | 7890B-5977BMSD | Agilent |
| Electronic balance | HZBL-018-03 | SECURA125-1CN | Sidoris (Sidoris) |
| Electronic balance | HZBL-018-04 | SECURA125-1CN | Sidoris (Sidoris) |
TABLE 2 gas information
| Name of the name | Purity of | Manufacturer' s |
| Helium gas | 99.999％ | Hangzhou Jinjingjingjingjingjingjinggao Co Ltd |
TABLE 3 reagent information
| Name of the name | Level of | Content of | Lot number | Manufacturer' s |
| Acetic anhydride | AR | / | 20180124 | Shanghai Lingfeng chemical Co., ltd |
| Acetic acid | AR | / | 20190619 | SINOPHARM CHEMICAL REAGENT Co.,Ltd. |
| Dimethyl sulfate | / | 98％ | LEADQ78 | BEIJING J&K SCIENTIFIC Ltd. |
| Acetic acid ethyl ester | AR | / | 20181226 | SINOPHARM CHEMICAL REAGENT Co.,Ltd. |
TABLE 4 sample information
| Name of the name | Lot number | Source |
| Pantoprazole sodium | 191005 | HUNAN WARRANT PHARMACEUTICAL Co.,Ltd. |
| Pantoprazole sodium | 170408 | HUNAN WARRANT PHARMACEUTICAL Co.,Ltd. |
| Pantoprazole sodium | 180311 | HUNAN WARRANT PHARMACEUTICAL Co.,Ltd. |
| Pantoprazole sodium | 191009 | HUNAN WARRANT PHARMACEUTICAL Co.,Ltd. |
| Pantoprazole sodium | 191011 | HUNAN WARRANT PHARMACEUTICAL Co.,Ltd. |
TABLE 5 gas chromatography conditions
Example 1
The respective solutions were prepared according to table 6.
TABLE 6 preparation of solutions
Precisely measuring 3 mu L of each reference substance solution and each test substance solution, directly injecting into a gas chromatograph-mass spectrometer, and recording a mass spectrogram. The mass spectrum of the sample solution has chromatographic peaks consistent with the retention time of the components to be detected, and the area of the peak of fragment ions is calculated according to an external standard method, and the dimethyl sulfate is not more than 8.48 mug/g calculated by the raw material (pantoprazole sodium monohydrate) and not more than 9.375 mug/g calculated by the pantoprazole.
TABLE 7 quantitative and qualitative ions of dimethyl sulfate
| Name of the name | Dimethyl sulfate |
| Quantification of ions | 95，96 |
| Qualitative ions | 97 |
1. Specificity-positioning
Peak discrimination is generally examined by peak retention time. The blank solution is required to be free from interference, and the retention time of the peak of the dimethyl sulfate in the solution of the standard sample is required to be consistent with that of the solution of the reference sample.
The test method comprises the following steps: taking blank solution (namely diluent in table 6), reference substance solution, test substance solution and labeled test substance solution, feeding sample, recording mass spectrogram, and observing peak retention time.
The results are shown in Table 8:
TABLE 8 specificity-positioning test results
As can be seen from Table 8, the blank solution was free of interference, and the retention time of the peak of the target component in the labeled sample solution was consistent with that of the control solution. The result meets the specification, and shows that the detection method provided by the invention has good specificity.
2. System applicability and instrument precision
And (5) examining the applicability of the system and the precision of the instrument. The reference substance solution is continuously measured for 6 times, the required peak area RSD is less than or equal to 10 percent, and the retention time RSD is less than or equal to 1.0 percent.
The test method comprises the following steps: taking the reference substance solution for sample injection, recording a mass spectrogram, and calculating the peak area RSD and the retention time RSD.
The system applicability and instrument precision test results are shown in table 9:
table 9 System applicability and Instrument precision test results
| Project | 1 | 2 | 3 | 4 | 5 | 6 | RSD | Acceptable standard |
| Retention time/min | 3.458 | 3.464 | 3.470 | 3.467 | 3.481 | 3.489 | 0.4％ | RSD≤1.0％ |
| Peak area | 3143 | 3387 | 3238 | 3123 | 3070 | 2882 | 5.4％ | RSD≤10％ |
As is clear from Table 9, the control solution was continuously measured 6 times, and the dimethyl sulfate peak area RSD was 5.4% and the retention time RSD was 0.4%. The result meets the regulations, and the system applicability and the instrument precision are good.
3. Quantitative limit
The quantitative limit refers to the minimum amount of the measured object in the sample, and the measured result meets the accuracy and precision requirements. Since GC-MS is a mass spectrum detector with the near position baseline peak height in the blank as noise, a blank solution with 10 times the position baseline peak height was used as its quantification limit. Acceptable criteria are: S/N is approximately equal to 10; the quantitative limit level content should be below the limit of 1/3.
The threshold limit of toxicological concern for genotoxic impurities is 1.5 μg/d, as required by the regulations of the European drug administration and the United states food and drug administration. The daily recommended dose of pantoprazole sodium is 160mg, from which the limit of dimethyl sulfate in pantoprazole sodium is estimated to be about 0.0009%.
The test method comprises the following steps: taking a contrast intermediate solution, continuously diluting and sampling, recording a mass spectrogram until S/N is approximately equal to 10, and calculating a quantitative limit and a quantitative limit concentration.
The test results are shown in Table 10:
table 10 quantitative limit measurement results
| Composition of the components | S/N | Limit of quantification (μg/mL) | Equivalent to content (%) | Corresponds to the limit (%) |
| Dimethyl sulfate | 9.46 | 0.014 | 0.00027 | 32.30 |
As can be seen from Table 10, the limit level of dimethyl sulfate was 0.00027% in the sample, 32.30% in the limit, and the signal to noise ratio was 9.46. The result meets the rule, and the concentration can meet the quantitative detection requirement. The detection method provided by the invention can meet the analysis and evaluation requirements.
4. Detection limit
The detection limit refers to the minimum amount of the test substance in the sample that can be detected. Since GC-MS is a mass spectrum detector with interference to its baseline, 3 times the peak height of the baseline at close blank positions was used as its detection limit. Acceptable criteria are: S/N is approximately equal to 3; the content of the detection limit level should be below the limit of 1/6.
The test method comprises the following steps: taking a contrast intermediate solution, continuously diluting and injecting sample, recording a mass spectrogram until S/N is approximately equal to 3, and calculating a detection limit and a detection limit concentration.
The test results are shown in Table 11:
table 11 detection limit measurement results
| Composition of the components | S/N | Limit of quantification (μg/mL) | Equivalent to content (%) | Corresponds to the limit (%) |
| Dimethyl sulfate | 4.89 | 0.005 | 0.00009 | 10.77 |
As can be seen from Table 11, the detection limit level of dimethyl sulfate corresponds to 0.00009% of the sample content, 10.77% of the limit, and the signal to noise ratio is 4.89. The results meet the requirements, indicating that the concentration can meet the detection requirements.
5. Linearity and range
The linearity means a degree to which a measurement response value is proportional to the concentration of the analyte in the sample within a designed range. Typically expressed by the form of a linear regression equation, at least 5 parts of solutions of different concentrations are formulated over the range of quantitative limit concentration to 200% of limit concentration and the assay is performed. Linear regression analysis was performed with the concentration on the abscissa (X) and the peak area on the ordinate (Y). Acceptable criteria are: the correlation coefficient (R) of the regression equation is more than or equal to 0.990, and the Y-axis intercept is within 25% of the 100% response value.
The test method comprises the following steps: the quantitative limit solution under the quantitative limit term was taken as a linear solution of the LOQ level.
The control intermediate solutions were measured precisely at 50. Mu.L, 80. Mu.L, 100. Mu.L, 150. Mu.L, 200. Mu.L, 25mL measuring flask, 1mL acetic anhydride, 0.5mL acetic acid, and ethyl acetate to scale as 50%, 80%, 100%, 150% and 200% horizontal linear solutions.
And precisely measuring the solution for sample injection, and recording a mass spectrogram. And (3) carrying out linear regression on the concentration (X) of the solution and the corresponding peak area (Y), and calculating a regression equation and correlation coefficients R, slope K and intercept thereof.
The test results are shown in Table 12 and FIG. 1
Table 12 results of the linear test
As can be seen from table 12 and fig. 1, dimethyl sulfate has a good linear relationship between peak area and concentration (r= 0.9956) in the concentration range of 0.0136 to 0.0904 μg/mL (corresponding to a content of 0.0003 to 0.0018% in the sample and corresponding to a limit concentration of 32.30 to 215.32%).
6. Repeatability of
Repeatability refers to the precision of the results obtained by the same analyst under the same conditions. And calculating the measured quantity of each level, wherein the measured RSD is less than or equal to 15 percent.
Test method
LOQ level control solution: precisely measure 0.03mL of the control intermediate solution, place in a 25mL measuring flask, precisely add 1mL of acetic anhydride, 0.5mL of acetic acid, and dilute to scale with ethyl acetate.
50% level control solution: precisely measure the control intermediate solution 0.05mL and place in a 25mL measuring flask, precisely add acetic anhydride 1mL, acetic acid 0.5mL, dilute to scale with ethyl acetate.
LOQ level addition of standard test solution: taking 50mg of the product, precisely weighing, placing into a 10mL measuring flask, diluting to a scale with LOQ level control solution, ultrasonically dissolving at room temperature and 350W for 15min, centrifuging at 10000rpm for 3min, and taking supernatant.
Adding standard test sample solution at 50% level: taking 50mg of the product, precisely weighing, placing in a 10mL measuring flask, diluting to a scale with a 50% level control solution, ultrasonically dissolving for 15min at room temperature under 350W, centrifuging at 10000rpm for 3min, and taking supernatant.
100% level addition of the standard test solution: taking 50mg of the product, precisely weighing, placing in a 10mL measuring flask, diluting to scale with reference substance solution, ultrasonically dissolving at room temperature and 350W for 15min, centrifuging at 10000rpm for 3min, and taking supernatant.
Taking reference substance solution, test sample solution and labeled test sample solution, sampling, and recording mass spectrogram. The measured quantity and RSD are calculated.
The test results are shown in Table 13:
TABLE 13 repeatability test results
As shown in Table 13, the measured RSD of LOQ-100% level is less than or equal to 7.9%, and the result meets the specification, so that the detection method provided by the invention has good repeatability.
7. Accuracy of
Accuracy refers to the degree to which the result measured by this method is close to a true or reference value, typically expressed in terms of recovery. Taking the product, adding a dimethyl sulfate reference substance, diluting and preparing a solution with the concentration equal to the limit LOQ, 50% and 100%, respectively measuring 3 parts of each level, comparing an actual measurement value with a theoretical value, and calculating the recovery rate, wherein the recovery rate of the LOQ-100% level is in the range of 70-125%, and the recovery rate RSD is less than or equal to 15%.
Test method
LOQ level control solution: precisely measure 0.03mL of the control intermediate solution, place in a 25mL measuring flask, precisely add 1mL of acetic anhydride, 0.5mL of acetic acid, and dilute to scale with ethyl acetate.
50% level control solution: precisely measure the control intermediate solution 0.05mL and place in a 25mL measuring flask, precisely add acetic anhydride 1mL, acetic acid 0.5mL, dilute to scale with ethyl acetate.
LOQ level addition of standard test solution: taking 50mg of the product, precisely weighing, placing into a 10mL measuring flask, diluting to a scale with LOQ level control solution, ultrasonically dissolving at room temperature and 350W for 15min, centrifuging at 10000rpm for 3min, and taking supernatant.
Adding standard test sample solution at 50% level: taking 50mg of the product, precisely weighing, placing in a 10mL measuring flask, diluting to a scale with a 50% level control solution, ultrasonically dissolving for 15min at room temperature under 350W, centrifuging at 10000rpm for 3min, and taking supernatant.
100% level addition of the standard test solution: taking 50mg of the product, precisely weighing, placing in a 10mL measuring flask, diluting to scale with reference substance solution, ultrasonically dissolving at room temperature and 350W for 15min, centrifuging at 10000rpm for 3min, and taking supernatant.
Taking reference substance solution, test sample solution and labeled test sample solution, sampling, and recording mass spectrogram. The recovery rate of dimethyl sulfate and RSD were calculated.
TABLE 14 accuracy test results
As shown in Table 14, the recovery rates of LOQ-100% are between 76.4-88.1%, the recovery rate RSD is 4.5%, and the results meet the regulations, so that the detection method provided by the invention has good accuracy.
8. Solution stability
The condition of the solution changing with time is examined, and a basis is provided for the shelf life of each solution in the later detection. Detecting the reference substance solution and the standard sample solution at different time after preparation, and examining the change condition of the peak area, wherein the difference percentage of the peak area and 0h is within +/-20%.
The test method comprises the following steps: taking a reference substance solution and a standard sample solution, respectively injecting samples at different time after the solution is prepared, recording a mass spectrogram, and calculating the percentage difference from 0 h.
The test results are shown in tables 15 to 16:
TABLE 15 stability test results (control solution)
TABLE 16 stability test results (labeled test solution)
As is clear from tables 15 to 16, the percentage difference between the measurement result of the control solution placed at room temperature for 4 hours and 0 hour is-6.7%, and the percentage difference between the measurement result of the standard sample solution placed at room temperature for 1.5 hours and 0 hour is-0.5%. The result meets the rule, and the result shows that the reference substance solution is stable at room temperature for 4 hours, and the reference substance solution is stable at room temperature for 1.5 hours.
9. Durability of
Durability refers to the degree of tolerance to which the measurement results are unaffected when there is a small variation in the measurement conditions, providing a basis for established methods for routine testing. And measuring the content of the dimethyl sulfate under the conditions that the temperature of the sample inlet changes by +/-20 ℃ and the initial temperature changes by +/-5 ℃. The recovery rate of the components to be detected in the solution of the standard test sample is required to be 70-125%. Durability test chromatographic conditions are shown in table 17:
table 17 durability test chromatographic conditions
| Change item | Sample inlet temperature (DEG C) | Initial column temperature (. Degree. C.) |
| 1 | 180 | 55 |
| 2 | 200 | 60 |
| 3 | 220 | 65 |
The test method comprises the following steps: taking blank solution, reference substance solution and standard sample solution, respectively measuring under the different conditions, and recording chromatograms. And calculating the recovery rate of dimethyl sulfate.
Test results:
9.1 changing factors: sample inlet temperature
The sample inlet temperature was measured at 180 ℃ and 220 ℃ respectively, and other conditions were consistent with the standard, and the results are shown in table 18:
table 18 durability test results (sample inlet temperature variation)
As shown in Table 18, the recovery rate of the peak to be measured in the sample solution under the condition of the temperature change of the sample inlet + -20 ℃ is 47.4-82.3%, and the result is not in accordance with the regulation. The results show that the small change of the temperature of the sample inlet has an influence on the detection result and is not durable. Because dimethyl sulfate is detected, and the high temperature can lead to the pyrolysis of the dimethyl sulfate, the invention can prevent the pyrolysis of the dimethyl sulfate by controlling the temperature of the sample inlet at 200 ℃, and the detection accuracy of the dimethyl sulfate is improved.
9.2 changing factors: initial temperature
The initial temperatures were determined at 55℃and 65℃respectively, and other conditions were consistent with the standards, and the results are shown in Table 19:
table 19 durability test results (initial temperature Change)
As is clear from Table 19, the recovery rate of the standard sample solution was 43.7 to 82.3% at the initial temperature change.+ -. 5 ℃ and was not satisfactory. The above results indicate that small changes in the starting temperature have an effect on the detection results and are not durable.
Durability: under the conditions that the temperature of the sample inlet varies by +/-20 ℃ and the initial temperature varies by +/-5 ℃, the recovery rate of the solution of the standard sample is 43.7-82.3%, and the result does not meet the specification. The detection method provided by the invention is not durable to small changes of the temperature of the sample inlet and the initial temperature.
The results of the verification are summarized in table 20:
table 20 summary of verification results
/>
/>
As can be seen from Table 20, the method provided by the invention has the advantages that through the system applicability and the precision, the specificity, the quantitative limit and the detection limit, the linearity and the range, the repeatability and the accuracy test of the instrument, all parameters are within the acceptable range; solution stability tests show that the reference substance solution is stable at room temperature for 4 hours, and the solution added with the standard sample solution is stable at room temperature for 1.5 hours; durability tests show that the method is not durable to small changes of initial temperature and sample inlet temperature. The above results indicate that the method is suitable for checking dimethyl sulfate in pantoprazole sodium.
Example 2
Pantoprazole sodium sample detection
Preparing a pantoprazole sodium sample into a sample solution according to the method, sampling, and recording a mass spectrum. The content of dimethyl sulfate was calculated.
The samples were tested according to the established method, the results of which are shown in fig. 2-6 and table 21, wherein fig. 2 is a spectrum of pantoprazole sodium sample 170408, fig. 3 is a spectrum of pantoprazole sodium sample 180311, fig. 4 is a spectrum of pantoprazole sodium sample 191005, fig. 5 is a spectrum of pantoprazole sodium sample 191009, and fig. 6 is a spectrum of pantoprazole sodium sample 191011.
Table 21 pantoprazole sodium sample detection results
As can be seen from table 21 and fig. 2 to 6, the detection results of dimethyl sulfate in 5 pantoprazole sodium samples were all less than LOD.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (9)
1. The method for detecting dimethyl sulfate in pantoprazole sodium is characterized by comprising the following steps of:
mixing and dissolving a pantoprazole sodium sample and a diluent, and then centrifugally separating to obtain a supernatant serving as a sample liquid to be detected; the diluent comprises acetic anhydride, acetic acid and ethyl acetate;
carrying out gas chromatography-mass spectrometry detection on the sample liquid to be detected to obtain characteristic peak positions of the object to be detected;
and comparing the characteristic peak position of the object to be detected with the characteristic peak position of the dimethyl sulfate standard substance to obtain a qualitative detection result and/or a quantitative detection result of the dimethyl sulfate in the pantoprazole sodium.
2. The detection method according to claim 1, wherein the ratio of the mass of the pantoprazole sodium sample to the volume of acetic anhydride is 1g: 1-10 mL.
3. The detection method according to claim 1, wherein the ratio of the mass of the pantoprazole sodium sample to the volume of acetic acid is 1g: 0.5-6 mL.
4. The detection method according to claim 1, wherein the ratio of the mass of the pantoprazole sodium sample to the volume of ethyl acetate is 1g: 150-300 mL.
5. The method according to any one of claims 1 to 4, wherein the mixed dissolution is ultrasonic mixed dissolution.
6. The method according to claim 1, wherein the centrifugal separation is performed at a rotational speed of 8000 to 13000rpm for 3 to 10 minutes.
7. The method according to claim 1, wherein the separation conditions of the gas chromatograph for gas chromatograph-mass spectrometer detection include: the chromatographic column is a capillary column; adopting temperature programming, wherein the temperature programming is as follows: the initial temperature is maintained at 60 ℃ for 2min, the temperature is raised to 150 ℃ at the speed of 45-55 ℃/min for 2min, and then the temperature is raised to 250 ℃ at the speed of 45-55 ℃/min for 3min; the temperature of the sample inlet is 200 ℃; the flow rate of the carrier gas is 1.0mL/min; the split ratio was 1:1.
8. The method of claim 7, wherein the stationary phase of the chromatographic column is 5% phenyl-95% dimethylpolysiloxane.
9. The method according to claim 1, wherein the mass spectrometry detection conditions of the gas chromatography-mass spectrometry detection include: the ion source temperature is 230 ℃; the temperature of the four-stage rod is 150 ℃; the auxiliary heater temperature is 250 ℃; the solvent delay time is 3min; the sample loading was 3. Mu.L.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310787022.6A CN116818944A (en) | 2023-06-30 | 2023-06-30 | Detection method of dimethyl sulfate in pantoprazole sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310787022.6A CN116818944A (en) | 2023-06-30 | 2023-06-30 | Detection method of dimethyl sulfate in pantoprazole sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116818944A true CN116818944A (en) | 2023-09-29 |
Family
ID=88121651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310787022.6A Pending CN116818944A (en) | 2023-06-30 | 2023-06-30 | Detection method of dimethyl sulfate in pantoprazole sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116818944A (en) |
-
2023
- 2023-06-30 CN CN202310787022.6A patent/CN116818944A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107367562B (en) | Analysis and detection method and application of polymyxin B sulfate | |
| CN110031557B (en) | Method for detecting 5-isoquinoline methyl sulfonate and 5-isoquinoline ethyl sulfonate in fasudil hydrochloride | |
| CN114994212A (en) | High performance liquid chromatography detection method for hydroxylamine residue in medicine | |
| CN109696509B (en) | Method for detecting dimethyl sulfate residue in medicine by liquid chromatography-mass spectrometry | |
| CN113295805B (en) | Method for detecting hydrazine hydrate in medicine | |
| CN110988167B (en) | Method for detecting genotoxic impurities in gatifloxacin | |
| CN111679029A (en) | Method for detecting p-hydroxybenzaldehyde in itopride hydrochloride | |
| CN114264752B (en) | Detection method of methyl bromoacetate | |
| CN116818944A (en) | Detection method of dimethyl sulfate in pantoprazole sodium | |
| CN109425666B (en) | LC-MS analysis method of acyl chloride derivative | |
| CN113109473B (en) | Formaldehyde derivatization test method | |
| CN113311087B (en) | Method for measuring content of terephthalic acid in copolyester plastic | |
| CN108414648B (en) | Method for detecting residual solvent in rocuronium bromide by using headspace gas chromatography | |
| CN113820409A (en) | Method for detecting related substances in mother nucleus of moxifloxacin | |
| CN107976489B (en) | Method for determining residual pyridine in pregabalin | |
| CN115097026B (en) | Method for detecting pyrazolopyrimidine benzenesulfonate compounds from medicines | |
| CN115452973B (en) | Method for detecting ethyl chloroformate in thiamphenicol hydrochloride glycine ester | |
| CN115267003B (en) | Method for detecting isomer content of S (-) -4-chloro-3-hydroxybutyric acid ethyl ester | |
| CN116754695B (en) | Derivatization detection method for chlorosulfonyl isocyanate | |
| CN115825292B (en) | Method for detecting S-glycidol in glycidyl R-butyrate | |
| CN117630202B (en) | Method for detecting buspirone hydrochloride intermediate impurities | |
| CN113686999B (en) | High performance liquid chromatography detection method for aniline residues in saccharide compounds | |
| CN117825573A (en) | Method for detecting content of hydroxylamine hydrochloride in bulk drug and application | |
| CN115684413A (en) | Method for detecting dimethyl sulfate and diethyl sulfate in hydroxychloroquine sulfate | |
| CN114487134A (en) | Method for detecting hydroxylamine hydrochloride in itopride hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |