CN108802241A - Liquid chromatography-tandem mass spectrometry method for qualitative analysis in relation to substance in a kind of cefotaxime sodium and tazobactam sodium for injection - Google Patents
Liquid chromatography-tandem mass spectrometry method for qualitative analysis in relation to substance in a kind of cefotaxime sodium and tazobactam sodium for injection Download PDFInfo
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- CN108802241A CN108802241A CN201710310402.5A CN201710310402A CN108802241A CN 108802241 A CN108802241 A CN 108802241A CN 201710310402 A CN201710310402 A CN 201710310402A CN 108802241 A CN108802241 A CN 108802241A
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- sodium
- cefotaxime
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- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 title claims abstract description 119
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 229960000373 tazobactam sodium Drugs 0.000 title claims abstract description 83
- 229960002727 cefotaxime sodium Drugs 0.000 title claims abstract description 74
- 239000000126 substance Substances 0.000 title claims abstract description 63
- 238000002347 injection Methods 0.000 title claims abstract description 57
- 239000007924 injection Substances 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000004451 qualitative analysis Methods 0.000 title claims abstract description 34
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 26
- 239000000872 buffer Substances 0.000 claims abstract description 17
- ALSPKRWQCLSJLV-UHFFFAOYSA-N azanium;acetic acid;acetate Chemical compound [NH4+].CC(O)=O.CC([O-])=O ALSPKRWQCLSJLV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000010828 elution Methods 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000945 filler Substances 0.000 claims abstract description 5
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 5
- 239000013558 reference substance Substances 0.000 claims description 69
- 239000000243 solution Substances 0.000 claims description 65
- 229960004261 cefotaxime Drugs 0.000 claims description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 150000002500 ions Chemical class 0.000 claims description 20
- 239000012085 test solution Substances 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 17
- 239000012634 fragment Substances 0.000 claims description 11
- FHYWAOQGXIZAAF-GHXIOONMSA-N desacetylcefotaxime Chemical compound N([C@@H]1C(N2C(=C(CO)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 FHYWAOQGXIZAAF-GHXIOONMSA-N 0.000 claims description 9
- 229960003865 tazobactam Drugs 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 8
- MCSWUKXFFGUOQE-GHXIOONMSA-N 66340-33-8 Chemical compound N([C@@H]1C(N2C3=C(COC3=O)CS[C@@H]21)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MCSWUKXFFGUOQE-GHXIOONMSA-N 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- 238000004949 mass spectrometry Methods 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 239000003643 water by type Substances 0.000 claims description 6
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 claims description 5
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 claims description 5
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 claims description 5
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- 150000001793 charged compounds Chemical class 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- 238000000889 atomisation Methods 0.000 claims description 4
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical class C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 2
- 150000003851 azoles Chemical class 0.000 claims description 2
- 238000004811 liquid chromatography Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- -1 trans- cefotaxime Chemical compound 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 68
- 239000002019 doping agent Substances 0.000 abstract description 4
- 238000012790 confirmation Methods 0.000 abstract description 3
- 238000005220 pharmaceutical analysis Methods 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 39
- 239000000463 material Substances 0.000 description 9
- MQLRYUCJDNBWMV-GHXIOONMSA-N cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 230000037361 pathway Effects 0.000 description 7
- 230000002101 lytic effect Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 4
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- SCHWIVHZZMAMTP-NCVGIQEBSA-N (6r,7r)-3-[[[4-[(z)-c-[[(6r,7r)-3-(acetyloxymethyl)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl]carbamoyl]-n-methoxycarbonimidoyl]-1,3-thiazol-2-yl]amino]methyl]-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1- Chemical compound N([C@@H]1C(N2C(=C(CNC=3SC=C(N=3)C(=N\OC)\C(=O)N[C@@H]3C(N4C(=C(COC(C)=O)CS[C@@H]43)C(O)=O)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 SCHWIVHZZMAMTP-NCVGIQEBSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 108010073771 Soybean Proteins Proteins 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- VYVRIXWNTVOIRD-LRHBOZQDSA-N ciguatoxin CTX1B Chemical compound C([C@@]12[C@@H](C)[C@@H]([C@@H]3[C@H]([C@H]([C@H](C)[C@H]4O[C@H]5C[C@@H](C)C[C@H]6O[C@@]7(C)[C@H](O)C[C@H]8O[C@H]9C=C[C@H]%10O[C@H]%11C[C@@H]%12[C@H]([C@@H]([C@H]%13O[C@H](C=CC[C@@H]%13O%12)\C=C\[C@H](O)CO)O)O[C@@H]%11C=C[C@@H]%10O[C@@H]9C\C=C/C[C@@H]8O[C@@H]7C[C@@H]6O[C@@H]5C[C@@H]4O3)O)O2)C)[C@H](O)CO1 VYVRIXWNTVOIRD-LRHBOZQDSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019710 soybean protein Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 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
- 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
- G01N30/74—Optical detectors
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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)
- Spectroscopy & Molecular Physics (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention belongs to Pharmaceutical Analysis technical field, it is related to the liquid chromatography-tandem mass spectrometry method for qualitative analysis in relation to substance in a kind of cefotaxime sodium and tazobactam sodium for injection.Filler of this method using octadecylsilane chemically bonded silica as chromatographic column carries out gradient elution using the mobile phase based on volatile acetic acid-ammonium acetate buffer, can efficiently separate and measure cefotaxime sodium and tazobactam sodium for injection and wherein relative substance.In addition, the present invention also uses qualitative analysis of the LC-MS/MS methods to the major impurity peak progress dopant type occurred in cefotaxime sodium and tazobactam sodium for injection, keep the confirmation of impurity structure more quick, investigating the qualitative analysis in relation to substance in the process for preparation stability provides a kind of effective method.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, it is related to the method for qualitative analysis in relation to substance in a kind of compound preparation,
More particularly to the liquid chromatography-tandem mass spectrometry (LC-MS/MS) in relation to substance in a kind of cefotaxime sodium and tazobactam sodium for injection
Method for qualitative analysis.
Background technology
Cefotaxime sodium and tazobactam sodium for injection is Cefotaxime Sodium (Cefotaxime Sodium, CTX) and his azoles bar
The compound preparation of smooth sodium (Tazobactam Sodium, TAZ).CN1425376A disclose a kind of cefotaxime sodium for injection and
The weight ratio of sodium-tazobactam compound preparation, wherein Cefotaxime Sodium and sodium-tazobactam is 5:1；CN102949397A is disclosed
A kind of cefotaxime sodium for injection and Tazobactam Sodium preparation of sodium, the wherein mass ratio of Cefotaxime Sodium and sodium-tazobactam are 1-4:
1；NZ553119A discloses a kind of reagent combination comprising antibiotic, triazole and glucocorticoid, and wherein antibiotic can be selected
Cefotaxime Sodium, and can be combined with sodium-tazobactam；NZ575435A discloses a kind of masticable antibiotic veterinary drug and matches
Side, it includes antibiotic, hydrophobic material, soybean protein powder, disintegrant, solvent, optional flavoring agent and optional preservative,
Wherein antibiotic can select Cefotaxime Sodium, and can be combined with the salt of Tazobactam Sodium.
Cefotaxime Sodium (molecular formula C16H16N5O7S2Na, molecular weight 477.45) it is the semi-synthetic cephalo bacterium of the third generation
Element, sodium-tazobactam (molecular formula C10H11N4O5SNa, molecular weight 322.27) be semi-synthetic beta-lactamase inhibitor, two
Person's drug combination can enhance fungistatic effect and widen antimicrobial spectrum.However, in the steady of cefotaxime sodium and tazobactam sodium for injection
During qualitative research, people are found that a variety of related substances (as shown in Table 1 and Table 2) from the compound preparation, type and
Content will directly affect the quality and performance of preparation, therefore need to establish suitable method to detect the related substance in compound preparation,
But it is there is no at present about the document report in relation to substance method for qualitative analysis in cefotaxime sodium and tazobactam sodium for injection.
Related substance list in 1. Cefotaxime Sodium of table
Related substance list in 2. Tazobactam Sodium of table
Invention content
In order to during study on the stability preferably to cefotaxime sodium and tazobactam sodium for injection in related substance into
Row qualitative analysis and quality monitoring, the present invention is directed to propose a kind of cefotaxime sodium for injection Tazobactam Sodium based on LC-MS/MS
Method for qualitative analysis in relation to substance in sodium.
Specifically, the present invention provides the liquid phase colors in relation to substance in a kind of cefotaxime sodium and tazobactam sodium for injection
Spectrum-tandem mass spectrum method for qualitative analysis comprising the following steps：
1) chromatographic condition：
Chromatographic column is with octadecylsilane chemically bonded silica (ODS) for filler (stationary phase)；
Mobile phase is made of mobile phase A and Mobile phase B, mobile phase A and Mobile phase B be acetic acid-ammonium acetate buffer and
The mixed solution of methanol, but mixed proportion is different；
Type of elution is gradient elution；
Flow rate of mobile phase is 1.0mL/min；
Sample size is 50 μ L；
Detection wavelength is 230nm；
2) Mass Spectrometry Conditions：
Ion source is electric spray ion source (ESI)；
Detection pattern is positive ion mode；
Scanning range is m/z 100~600；
Dry temperature degree is 350 DEG C；
Dry gas stream amount is 10L/min；
Atomization gas pressure is 35.0psi；
Capillary voltage is 3500V；
1 is split into after column:4；
3) preparation of test solution：
It takes cefotaxime sodium and tazobactam sodium for injection appropriate, water is added to be configured to the solution of 1mg/mL, in being placed at room temperature for 24
After hour, as cefotaxime sodium and tazobactam sodium for injection test solution；
4) preparation of reference substance solution：
It takes cefotaxime reference substance appropriate, 100 times is diluted after adding water to be configured to the solution of 1mg/mL, as cefotaxime pair
According to product solution；
It takes Tazobactam Sodium reference substance appropriate, 100 times is diluted after adding water to be configured to the solution of 1mg/mL, as Tazobactam Sodium pair
According to product solution；
It takes respectively in Cefotaxime Sodium known to structure in relation to related substance known to structure in substance and sodium-tazobactam
In right amount, each self-watering is configured to the related substance reference substance solution of 0.1mg/mL；
5) liquid chromatography tandom mass spectrometry determination：
It respectively will be in the cefotaxime sodium and tazobactam sodium for injection test solution and step 4) prepared in step 3)
Cefotaxime reference substance solution, Tazobactam Sodium reference substance solution and the related substance reference substance solution injection LC-MS/MS connection of preparation
It with instrument, is detected according to the Mass Spectrometry Conditions in the chromatographic condition and step 2) in step 1), and records corresponding liquid chromatogram
Figure, first mass spectrometric figure and second order ms figure；
6) qualitative analysis in relation to substance：
Compare cefotaxime sodium and tazobactam sodium for injection test solution, cefotaxime reference substance solution, Tazobactam Sodium
Reference substance solution, the liquid chromatogram in relation to substance reference substance solution, determine in the liquid chromatogram of test solution with cephalo
The related corresponding chromatographic peak of substance known to thiophene oxime, Tazobactam Sodium and structure, and by the molecule in first mass spectrometric figure from
Main fragment ion peak in sub- peak and second order ms figure is identified, then passes through the molecular ion peak and two in first mass spectrometric figure
Grade mass spectrogram in main fragment ion peak presumption test solution liquid chromatogram in cefotaxime, Tazobactam Sodium and knot
Structure in relation to the related substance representated by chromatographic peak of the substance without correspondence known to structure completes cefotaxime sodium for injection
Qualitative analysis in relation to substance in sodium-tazobactam.
In a preferred embodiment, chromatographic column described in step 1) is Waters XBridge Shield RP18
(250 × 4.6mm, 5 μm) chromatographic column.
In a preferred embodiment, acetic acid-ammonium acetate buffer and methanol in mobile phase A described in step 1)
Volume ratio is 92:8, the volume ratio of acetic acid-ammonium acetate buffer and methanol is 60 in the Mobile phase B:40.
In a preferred embodiment, ammonium acetate is mole dense in acetic acid-ammonium acetate buffer described in step 1)
Degree is 20mmol/L.
In a preferred embodiment, the pH value of acetic acid-ammonium acetate buffer described in step 1) is 6.25.
In a preferred embodiment, the elution requirement of gradient elution described in step 1) is as follows：0 minute, flowing
Phase A is 100v%；15 minutes, mobile phase A 100v%；17 minutes, mobile phase A 72v%, Mobile phase B 28v%；24 points
Clock, mobile phase A 72v%, Mobile phase B 28v%；53 minutes, Mobile phase B 100v%；58 minutes, Mobile phase B was
100v%；63 minutes, mobile phase A 100v%；66 minutes, mobile phase A 100v%.
In a preferred embodiment, cefotaxime sodium and tazobactam sodium for injection test sample described in step 3) is molten
The specific process for preparation of liquid is as described below：Cefotaxime sodium and tazobactam sodium for injection 0.13g is weighed, it is accurately weighed, it is placed in
In 100mL volumetric flasks, constant volume after being dissolved in water shakes up, and is configured to the solution of 1mg/mL, after being placed at room temperature for 24 hours, as
Cefotaxime sodium and tazobactam sodium for injection test solution.
In a preferred embodiment, the specific process for preparation of cefotaxime reference substance solution described in step 4) is such as
It is lower described：Cefotaxime reference substance 10mg is weighed, it is accurately weighed, it is placed in 10mL volumetric flasks, constant volume after being dissolved in water shakes up,
It is configured to the solution of 1mg/mL；Precision measures in 1mL solution to 100mL volumetric flasks, and constant volume after being dissolved in water shakes up, as
Cefotaxime reference substance solution.
In a preferred embodiment, the specific process for preparation of Tazobactam Sodium reference substance solution described in step 4) is such as
It is lower described：Tazobactam Sodium reference substance 10mg is weighed, it is accurately weighed, it is placed in 10mL volumetric flasks, constant volume after being dissolved in water shakes up,
It is configured to the solution of 1mg/mL；Precision measures in 1mL solution to 100mL volumetric flasks, and constant volume after being dissolved in water shakes up, as
Tazobactam Sodium reference substance solution.
In a preferred embodiment, related substance known to structure includes in Cefotaxime Sodium described in step 4)
Cefotaxime impurity A (the deacetylated compound of Desacetoxycefotaxime), impurity B (Deacetylcefotaxime), impurity D are (anti-
Formula cefotaxime), impurity E (Deacetylcefotaxime lactone) and 7-ACA (7-amino-cephalosporanic acid), the sodium-tazobactam
Related substance known to middle structure includes Tazobactam Sodium impurity A (2- amino -3- methyl -3- sulfinyls -4- (1H-1,2,3- tri-
Azoles -1- bases) butyric acid).
Filler (such as Waters XBridge of the present invention using octadecylsilane chemically bonded silica as chromatographic column
Shield RP18 chromatographic columns), carry out gradient elution, Neng Gouyou using the mobile phase based on volatile acetic acid-ammonium acetate buffer
Effect ground separation determination cefotaxime sodium and tazobactam sodium for injection and wherein relative substance.In addition, the present invention also uses LC-MS/
MS methods carry out the major impurity peak occurred in cefotaxime sodium and tazobactam sodium for injection the qualitative analysis of dopant type, make miscellaneous
The confirmation of matter structure is more quick, and provide one kind for the qualitative analysis in relation to substance during preparation stability investigation has conscientiously
The method of effect.
Description of the drawings
Fig. 1 is the related material mixing reference substance of Cefotaxime Sodium in volatile buffer salt flow phase system and non-volatile slow
The liquid chromatogram rushed in salt flow phase system compares figure.
Fig. 2 is that the cefotaxime sodium and tazobactam sodium for injection of placement 24 hours at ambient temperature is related with cefotaxime
The liquid chromatogram of material mixing reference substance compares figure.
Fig. 3 is the second order ms figure of cefotaxime bulk pharmaceutical chemicals reference substance.
Fig. 4 is the second order ms figure of Tazobactam Sodium bulk pharmaceutical chemicals reference substance.
Fig. 5 is the second order ms figure of cefotaxime impurity A reference substance.
Fig. 6 is the second order ms figure of cefotaxime impurity B reference substance.
Fig. 7 is the second order ms figure of cefotaxime impurity D reference substances.
Fig. 8 is the second order ms figure of cefotaxime impurity E reference substance.
Fig. 9 is the liquid chromatogram of cefotaxime impurity A reference substance.
Figure 10 is the liquid chromatogram of cefotaxime impurity B reference substance.
Figure 11 is the liquid chromatogram of cefotaxime impurity E reference substance.
Figure 12 is the second order ms figure of unknown impuritie 1 in cefotaxime sodium and tazobactam sodium for injection.
Figure 13 is the second order ms figure of unknown impuritie 2 in cefotaxime sodium and tazobactam sodium for injection.
Figure 14 is the second order ms figure of unknown impuritie 4 in cefotaxime sodium and tazobactam sodium for injection.
Figure 15 is the second order ms figure of unknown impuritie 7 in cefotaxime sodium and tazobactam sodium for injection.
Figure 16 is that the cefotaxime sodium and tazobactam sodium for injection of placement 24 hours and cefotaxime are miscellaneous at ambient temperature
The liquid chromatogram of matter D reference substances compares figure.
Figure 17 is the second order ms figure of unknown impuritie 8 in cefotaxime sodium and tazobactam sodium for injection.
Figure 18 is the second order ms figure of unknown impuritie 9 in cefotaxime sodium and tazobactam sodium for injection.
Figure 19 is the second order ms figure of unknown impuritie 10 in cefotaxime sodium and tazobactam sodium for injection.
Figure 20 is the second order ms figure of unknown impuritie 11 in cefotaxime sodium and tazobactam sodium for injection.
Specific implementation mode
The technical solution in the present invention is made below with reference to the drawings and specific embodiments further elucidated above.It needs
Bright, the following example is only used for explaining the present invention, and is understood not to the limitation present invention.It is not specified in the following example
Technology or condition described in the document of particular technique or condition person according to this field carry out.Unless otherwise stated, following
Reagent, drug and instrument used in embodiment can be obtained by routine business means.
Reagent：Disodium hydrogen phosphate (Na2HPO4), ammonium acetate (CH3COONH4), acetic acid (CH3COOH), methanol (CH3OH), surpass
Pure water (H2O)。
Drug：Cefotaxime sodium and tazobactam sodium for injection.
Reference substance：Cefotaxime reference substance；Tazobactam Sodium reference substance；Cefotaxime impurity A, impurity B, impurity E are (by Shandong
Medicine inspecting institute of province provides)；Cefotaxime impurity D (transisomer of cefotaxime is provided by Zhong Jian institutes)；Cefotaxime Sodium is related
Material mixing reference substance (lot number：Y0000506).
Instrument：Waters 2996；Agilent 1100.
Embodiment one：The determination of liquid chromatography-tandem mass spectrometry condition.
1, chromatographic condition：
Currently, the cefotaxime sodium and tazobactam sodium for injection detection method based on HPLC is usually using phosphate buffer
(such as disodium hydrogen phosphate buffer system) prepares mobile phase.However, since phosphate has fixedness, atomization is easily blocked
Device and contaminated ion source to influence sample ionization, therefore are not suitable for LC-MS analysis, therefore by phosphate-buffered fluid exchange
For volatile acetate buffer (such as acetic acid-ammonium acetate buffer system), the optimization of mobile phase is realized.
Specific chromatographic condition is as described below：
Chromatographic column：Waters XBridge Shield RP18 (250 × 4.6mm, 5 μm)；
Mobile phase A：Acetic acid-ammonium acetate buffer (20mmol/L, pH=6.25)-methanol (92:8v/v)；
Mobile phase B：Acetic acid-ammonium acetate buffer (20mmol/L, pH=6.25)-methanol (60:40v/v)；
Condition of gradient elution：0 minute, mobile phase A 100v%；15 minutes, mobile phase A 100v%；17 minutes, flowing
Phase A is 72v%, Mobile phase B 28v%；24 minutes, mobile phase A 72v%, Mobile phase B 28v%；53 minutes, Mobile phase B
For 100v%；58 minutes, Mobile phase B 100v%；63 minutes, mobile phase A 100v%；66 minutes, mobile phase A was
100v%；
Flow velocity：1.0ml/min；
Sample size：50μL；
Detection wavelength：230nm.
2, Mass Spectrometry Conditions：
Above-mentioned liquid chromatograph is connected with triple quadrupole mass spectrometer and is tested.
Specific source parameters is as described below：
Ion source：ESI；
Detection pattern：Positive ion mode；
Scanning range：m/z 100-600；
Dry temperature degree：350℃；
Dry gas stream amount：10L/min；
Atomization gas pressure：35.0psi；
Capillary voltage：3500V；
It is shunted after column：1:4.
3, sample preparation：
(1) preparation of cefotaxime sodium and tazobactam sodium for injection test solution：
Cefotaxime sodium and tazobactam sodium for injection about 0.13g is weighed, it is accurately weighed, it is placed in 100mL volumetric flasks, adds water
Constant volume after dissolving, shakes up, and is configured to the solution of 1mg/mL, in be placed at room temperature for for 24 hours after sampling analysis, as a result show main component and
Various related substances have good separating degree in chromatograms, therefore using the solution as test solution.
(2) preparation of cefotaxime reference substance solution：
Cefotaxime reference substance about 10mg is weighed, it is accurately weighed, it is placed in 10mL volumetric flasks, constant volume after being dissolved in water shakes
It is even, it is configured to the solution of 1mg/mL；Precision measures in 1mL solution to 100mL volumetric flasks, and constant volume after being dissolved in water shakes up, and makees
For cefotaxime reference substance solution.
(3) preparation of Tazobactam Sodium reference substance solution：
Tazobactam Sodium reference substance about 10mg is weighed, it is accurately weighed, it is placed in 10mL volumetric flasks, constant volume after being dissolved in water shakes
It is even, it is configured to the solution of 1mg/mL；Precision measures in 1mL solution to 100mL volumetric flasks, and constant volume after being dissolved in water shakes up, and makees
For Tazobactam Sodium reference substance solution.
(4) preparation in relation to substance reference substance solution：
The related material mixing reference substance of Cefotaxime Sodium, cefotaxime impurity A, B, D and E about 1mg are weighed respectively, and precision claims
It is fixed, it is placed in 10mL volumetric flasks, constant volume after being dissolved in water shakes up, and is configured to the related substance reference substance solution of 0.1mg/mL.
4, interpretation of result：
It is respectively adopted in mobile phase and the present invention by non-volatile phosphate buffered saline by volatile acetic acid-acetic acid
The related material mixing reference substance solution of mobile phase Cefotaxime sodium of ammonium buffer is analyzed, and chromatogram is recorded,
The results are shown in Figure 1.As shown in Figure 1, the related substance chromatogram of two kinds of analysis methods has high consistency, and can incite somebody to action
Main component is effectively separated with its various impurity, therefore the mobile phase prepared by acetic acid-ammonium acetate buffer can be used for for examination
Qualitative analysis in relation to substance in product solution.
Embodiment two：Qualitative analysis in relation to substance in representative sample.
Qualitative analysis is carried out to related substance in cefotaxime sodium and tazobactam sodium for injection using LC-MS/MS.
1, the selection of representative sample：
In embodiment one under testing conditions finally determining, to impurity reference substance solution, the cefotaxime of one-component
The related material mixing reference substance solution of sodium, cefotaxime sodium and tazobactam sodium for injection test solution are analyzed, and are passed through
Retention time in chromatogram is compared.The results show that cefotaxime sodium and tazobactam sodium for injection test solution and head
Spore thiophene oxime sodium can cover the dopant type in study on the stability sample in relation to the related substance in material mixing reference substance solution,
Therefore emphasis of the present invention carries out qualitative analysis to the related substance in both representative samples.
2, the acquisition of the chromatography and mass spectrometric data in relation to substance and partial impurities reference substance in representative sample：
Acquire cefotaxime sodium and tazobactam sodium for injection test solution, the related material mixing reference substance of Cefotaxime Sodium
Solution, the chromatographic retention of partial impurities reference substance solution, first mass spectrometric and second order ms, result such as table 3 and Fig. 2 institutes
Show.Since all reference substances in relation to substance can not be obtained, therefore positioned using relative retention time involved in miscellaneous Mass Spectra
And the various target impurities arrived.The calculating of relative retention time uses " main peak nearby principle ", i.e., that is closed on Tazobactam Sodium is miscellaneous
Mass peak calculates relative retention time (including impurity 1, impurity 2, impurity 3, impurity 4, impurity 5) so that Tazobactam Sodium is reference, with
The impurity peaks that cefotaxime is closed on cefotaxime be with reference to come calculate relative retention time (including impurity 6, impurity 7, impurity 8,
Impurity 9, impurity 10, impurity 11).
Chromatography and mass spectrometric data in relation to substance in 3. representative sample of table
3, the MS fragment pathways analysis of cefotaxime, Tazobactam Sodium and known impurities：
The second order ms figure of cefotaxime is as shown in figure 3, its possible lytic pathway is as described below.
The second order ms figure of Tazobactam Sodium is as shown in figure 4, its possible lytic pathway is as described below.
The second order ms figure of cefotaxime impurity A is as shown in figure 5, its possible lytic pathway is as described below.
The second order ms figure of cefotaxime impurity B is as shown in fig. 6, its possible lytic pathway is as described below.
The second order ms figure of cefotaxime impurity D (trans- cefotaxime) is as shown in fig. 7, its possible lytic pathway is as follows
It is described.
The second order ms figure of cefotaxime impurity E is as shown in figure 8, its possible lytic pathway is as described below.
4, the Structural Identification in relation to substance in representative sample：
(1) there is the Structural Identification of the related substance of reference substance：
When cefotaxime impurity A, impurity B and impurity E retain with the chromatography of impurity in Fig. 25, impurity 3 and impurity 6 respectively
Between, first mass spectrometric, second order ms it is consistent, therefore impurity 5, impurity 3 and impurity 6 are respectively cefotaxime impurity A, impurity in Fig. 2
B, impurity E, HPLC collection of illustrative plates is respectively as shown in Fig. 9~11.
(2) the structure presumption of the related substance without reference substance：
(a) impurity 1 (its two level mass spectrogram is as shown in figure 12)：
[M+H] of impurity 1+It is 201, coincide with the molecular weight of cefotaxime Side chain cleavage product, two level is mass spectrographic broken
Piece ion is 184,156,144,126,116, can rationally be parsed by the structure, and it is cefotaxime that can estimate impurity 1
Side chain cleavage product.
(b) impurity 2 (its two level mass spectrogram is as shown in figure 13) and impurity 4 (its two level mass spectrogram is as shown in figure 14)：
[M+H] of impurity 2 and impurity 4+It is 414, second order ms master consistent with the molecular weight of cefotaxime impurity B
Want fragment ion also roughly the same with cefotaxime impurity B, it may be the anti-isomerism of cefotaxime impurity B to prompt it
Body, main fragment ion can be parsed rationally by the structure, and initial guess impurity 2 and impurity 4 are the anti-of cefotaxime
Formula isomers.
(c) impurity 7 (its two level mass spectrogram is as shown in figure 15)：
[M+H] of impurity 7+Be 456, it is consistent with the molecular weight of cefotaxime, the main fragment ion of second order ms also with
Cefotaxime is consistent, and it may be the isomer of cefotaxime to prompt it.But further analysis is found：The impurity with
The chromatographic retention of the transisomer (impurity D) of cefotaxime is entirely different (as shown in figure 16), it can be seen that the impurity
It is not the transisomer of cefotaxime.In conclusion " the non-trans isomer that impurity 7 is cefotaxime " can only be obtained
Conclusion.
(d) impurity 8 (its two level mass spectrogram is as shown in figure 17)：
[M+H] of impurity 8+It is 216, coincide with the molecular weight of another Side chain cleavage product of cefotaxime, second order ms
Fragment ion is 184,156,140,126,113, can rationally be parsed by the structure, and it is cephalo thiophene that can estimate impurity 8
Oxime Side chain cleavage product.
(e) impurity 9 (its two level mass spectrogram is as shown in figure 18)：
[M+H] of impurity 9+It is 470, the second order ms of two level mass spectrometric fragment ion and cefotaxime are completely the same, carry
Showing that the impurity there may be structure similar with cefotaxime, the molecular ion of impurity 9 is bigger than the molecular ion of cefotaxime by 14,
Prompting it, more methyl, fragments characteristic ion 456,396,324,293,277,241 are aobvious than in cefotaxime molecular structure
Show that increased methyl can should rationally be parsed on 3 side chains by the structure in the impurity.
(f) impurity 10 (its two level mass spectrogram is as shown in figure 19) and impurity 11 (its two level mass spectrogram is as shown in figure 20)：
[M+H] of impurity 10 and impurity 11+It is 852, it is consistent with the molecular weight of cefotaxime dimer (impurity F), just
Step speculates that the impurity is impurity F or its isomer, mixes and contains the relatively large impurity F of content, color in reference substance
It is also consistent with impurity 10 to compose retention time, first mass spectrometric, second order ms, presumption impurity 10 is impurity F, and impurity 11 is impurity F
Isomer.
5, result：
Structure and its source analysis in study on the stability cefotaxime sodium and tazobactam sodium for injection in relation to substance are such as
Shown in table 4.
Structure and source analysis in relation to substance in 4. cefotaxime sodium and tazobactam sodium for injection of table
Filler (such as Waters XBridge of the present invention using octadecylsilane chemically bonded silica as chromatographic column
Shield RP18 chromatographic columns), carry out gradient elution, Neng Gouyou using the mobile phase based on volatile acetic acid-ammonium acetate buffer
Effect ground separation determination cefotaxime sodium and tazobactam sodium for injection and wherein relative substance.In addition, the present invention also uses LC-MS/
MS methods carry out the major impurity peak occurred in cefotaxime sodium and tazobactam sodium for injection the qualitative analysis of dopant type, make miscellaneous
The confirmation of matter structure is more quick, and provide one kind for the qualitative analysis in relation to substance during preparation stability investigation has conscientiously
The method of effect.
Claims (10)
1. the liquid chromatography-tandem mass spectrometry qualitative analysis side in relation to substance in a kind of cefotaxime sodium and tazobactam sodium for injection
Method, it is characterised in that：
The method for qualitative analysis includes the following steps：
1) chromatographic condition：
Chromatographic column is using octadecylsilane chemically bonded silica as filler；
Mobile phase is made of mobile phase A and Mobile phase B, and mobile phase A and Mobile phase B are acetic acid-ammonium acetate buffer and methanol
Mixed solution, but mixed proportion is different；
Type of elution is gradient elution；
Flow rate of mobile phase is 1.0mL/min；
Sample size is 50 μ L；
Detection wavelength is 230nm；
2) Mass Spectrometry Conditions：
Ion source is electric spray ion source；
Detection pattern is positive ion mode；
Scanning range is m/z 100~600；
Dry temperature degree is 350 DEG C；
Dry gas stream amount is 10L/min；
Atomization gas pressure is 35.0psi；
Capillary voltage is 3500V；
1 is split into after column:4；
3) preparation of test solution：
It takes cefotaxime sodium and tazobactam sodium for injection appropriate, water is added to be configured to the solution of 1mg/mL, in being placed at room temperature for 24 hours
Afterwards, as cefotaxime sodium and tazobactam sodium for injection test solution；
4) preparation of reference substance solution：
It takes cefotaxime reference substance appropriate, 100 times is diluted after adding water to be configured to the solution of 1mg/mL, as cefotaxime reference substance
Solution；
It takes Tazobactam Sodium reference substance appropriate, 100 times is diluted after adding water to be configured to the solution of 1mg/mL, as Tazobactam Sodium reference substance
Solution；
Take respectively in Cefotaxime Sodium it is appropriate in relation to related substance known to structure in substance and sodium-tazobactam known to structure,
Each self-watering is configured to the related substance reference substance solution of 0.1mg/mL；
5) liquid chromatography tandom mass spectrometry determination：
It will be prepared in the cefotaxime sodium and tazobactam sodium for injection test solution and step 4) prepared in step 3) respectively
Cefotaxime reference substance solution, Tazobactam Sodium reference substance solution and related substance reference substance solution injection LC-MS/MS combination
Instrument is detected according to the Mass Spectrometry Conditions in the chromatographic condition and step 2) in step 1), and record corresponding liquid chromatogram,
First mass spectrometric figure and second order ms figure；
6) qualitative analysis in relation to substance：
Compare cefotaxime sodium and tazobactam sodium for injection test solution, cefotaxime reference substance solution, Tazobactam Sodium control
Product solution, the liquid chromatogram in relation to substance reference substance solution, determine in the liquid chromatogram of test solution with cefotaxime,
The related corresponding chromatographic peak of substance known to Tazobactam Sodium and structure, and by molecular ion peak in first mass spectrometric figure and
Main fragment ion peak in second order ms figure is identified, then passes through the molecular ion peak and second order ms in first mass spectrometric figure
In figure main fragment ion peak presumption test solution liquid chromatogram in cefotaxime, Tazobactam Sodium and structure known to
Related chromatographic peak of the substance without correspondence representated by related substance structure, complete cefotaxime sodium for injection his azoles bar
Qualitative analysis in relation to substance in smooth sodium.
2. method for qualitative analysis according to claim 1, it is characterised in that：
Chromatographic column described in step 1) is Waters XBridge Shield RP18 chromatographic columns.
3. method for qualitative analysis according to claim 1, it is characterised in that：
The volume ratio of acetic acid-ammonium acetate buffer and methanol is 92 in mobile phase A described in step 1):8, in the Mobile phase B
The volume ratio of acetic acid-ammonium acetate buffer and methanol is 60:40.
4. method for qualitative analysis according to claim 1, it is characterised in that：
The molar concentration of ammonium acetate is 20mmol/L in acetic acid-ammonium acetate buffer described in step 1).
5. method for qualitative analysis according to claim 1, it is characterised in that：
The pH value of acetic acid-ammonium acetate buffer described in step 1) is 6.25.
6. method for qualitative analysis according to claim 1, it is characterised in that：
The elution requirement of gradient elution described in step 1) is as follows：0 minute, mobile phase A 100v%；15 minutes, mobile phase A was
100v%；17 minutes, mobile phase A 72v%, Mobile phase B 28v%；24 minutes, mobile phase A 72v%, Mobile phase B was
28v%；53 minutes, Mobile phase B 100v%；58 minutes, Mobile phase B 100v%；63 minutes, mobile phase A 100v%；66
Minute, mobile phase A 100v%.
7. method for qualitative analysis according to claim 1, it is characterised in that：
The specific process for preparation of cefotaxime sodium and tazobactam sodium for injection test solution described in step 3) is as described below：Claim
Cefotaxime sodium and tazobactam sodium for injection 0.13g is taken, it is accurately weighed, it is placed in 100mL volumetric flasks, constant volume after being dissolved in water,
It shakes up, is configured to the solution of 1mg/mL, after being placed at room temperature for 24 hours, as cefotaxime sodium and tazobactam sodium for injection for examination
Product solution.
8. method for qualitative analysis according to claim 1, it is characterised in that：
The specific process for preparation of cefotaxime reference substance solution described in step 4) is as described below：Weigh cefotaxime reference substance
10mg, it is accurately weighed, it is placed in 10mL volumetric flasks, constant volume after being dissolved in water shakes up, and is configured to the solution of 1mg/mL；Precision amount
It takes in 1mL solution to 100mL volumetric flasks, constant volume after being dissolved in water shakes up, as cefotaxime reference substance solution.
9. method for qualitative analysis according to claim 1, it is characterised in that：
The specific process for preparation of Tazobactam Sodium reference substance solution described in step 4) is as described below：Weigh Tazobactam Sodium reference substance
10mg, it is accurately weighed, it is placed in 10mL volumetric flasks, constant volume after being dissolved in water shakes up, and is configured to the solution of 1mg/mL；Precision amount
It takes in 1mL solution to 100mL volumetric flasks, constant volume after being dissolved in water shakes up, as Tazobactam Sodium reference substance solution.
10. method for qualitative analysis according to claim 1, it is characterised in that：
Related substance known to structure includes that Desacetoxycefotaxime is deacetylated in Cefotaxime Sodium described in step 4)
Object, Deacetylcefotaxime, trans- cefotaxime, Deacetylcefotaxime lactone and 7-amino-cephalosporanic acid, it is described he
Related substance known to structure includes 2- amino -3- methyl -3- sulfinyls -4- (1H-1,2,3- triazoles -1- in zababatin sodium
Base) butyric acid.
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