CN115541771B - Method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam - Google Patents
Method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam Download PDFInfo
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- CN115541771B CN115541771B CN202211323948.1A CN202211323948A CN115541771B CN 115541771 B CN115541771 B CN 115541771B CN 202211323948 A CN202211323948 A CN 202211323948A CN 115541771 B CN115541771 B CN 115541771B
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- benzhydryl
- methylphenol
- tazobactam
- benzophenone hydrazone
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- -1 2-benzhydryl-5-methylphenol Chemical compound 0.000 title claims abstract description 76
- 239000012535 impurity Substances 0.000 title claims abstract description 74
- QYCSNMDOZNUZIT-UHFFFAOYSA-N benzhydrylidenehydrazine Chemical compound C=1C=CC=CC=1C(=NN)C1=CC=CC=C1 QYCSNMDOZNUZIT-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 229960003865 tazobactam Drugs 0.000 title claims abstract description 61
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims description 39
- 238000001514 detection method Methods 0.000 claims abstract description 22
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 13
- 239000000243 solution Substances 0.000 claims description 79
- 238000012360 testing method Methods 0.000 claims description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 239000000523 sample Substances 0.000 claims description 34
- 239000003153 chemical reaction reagent Substances 0.000 claims description 29
- 239000013558 reference substance Substances 0.000 claims description 28
- 238000005303 weighing Methods 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 14
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 14
- 235000019838 diammonium phosphate Nutrition 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 238000004090 dissolution Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 239000012488 sample solution Substances 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims description 6
- 238000007865 diluting Methods 0.000 claims description 5
- XFGAJBXZFCAQAM-UHFFFAOYSA-N [NH4+].[NH4+].CC#N.OP([O-])([O-])=O Chemical group [NH4+].[NH4+].CC#N.OP([O-])([O-])=O XFGAJBXZFCAQAM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 238000010829 isocratic elution Methods 0.000 claims description 4
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims description 3
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 abstract description 14
- 238000004458 analytical method Methods 0.000 abstract description 6
- 238000010790 dilution Methods 0.000 description 12
- 239000012895 dilution Substances 0.000 description 12
- 238000011084 recovery Methods 0.000 description 10
- 238000005259 measurement Methods 0.000 description 9
- 229960000373 tazobactam sodium Drugs 0.000 description 8
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical group COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 description 7
- 239000005696 Diammonium phosphate Substances 0.000 description 7
- 238000012795 verification Methods 0.000 description 7
- 239000012085 test solution Substances 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 230000035945 sensitivity Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000001612 separation test Methods 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 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 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 description 2
- 229960002292 piperacillin Drugs 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8624—Detection of slopes or peaks; baseline correction
- G01N30/8631—Peaks
- G01N30/8634—Peak quality criteria
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- 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
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- Analytical Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
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- Pathology (AREA)
- Quality & Reliability (AREA)
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- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention discloses a detection method of 2-benzhydryl-5-methylphenol and benzophenone hydrazone impurities in tazobactam, which belongs to the field of chemical analysis, adopts a high performance liquid chromatography to detect the 2-benzhydryl-5-methylphenol and benzophenone hydrazone impurities in tazobactam, and can accurately detect the 2-benzhydryl-5-methylphenol and benzophenone hydrazone impurities in tazobactam under the chromatographic detection condition of the high performance liquid chromatography, and the detection method has good separation degree and strong reproducibility.
Description
Technical Field
The invention relates to a method for detecting chemical substances, in particular to a method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam, and belongs to the field of chemical analysis.
Background
Tazobactam is a novel irreversible competitive beta-lactamase inhibitor, the main component is tazobactam sodium, and the tazobactam sodium is an anti-infective agent, and the common dosage forms include injection (powder) and the like. Bacteria sensitive to piperacillin and bacteria resistant to piperacillin due to beta lactamase production have an antibacterial effect. For infection caused by sensitive bacteria, patients who frequently use antibiotics can easily generate drug resistance, so that the curative effect is invalid, the tazobactam sodium can inhibit the activity of beta-lactamase, the enzyme activity is irreversible, the sensitivity of the antibiotics is prevented from being reduced, the generation of drug resistance can be avoided as much as possible, and the antibacterial activity of the antibiotics can be increased. Clinically, the combination of penicillin antibiotics and cephalosporin antibiotics can achieve better anti-inflammatory effect.
Sodium tazobactam (Tazobactam sodium) is known as sodium [2S- (2 a,3b,5 a) ] -3-methyl-7-oxo-3- (1H-1, 2, 3-triazol-1-ylmethyl) -4-thio-1-azabicyclo [3,2,0] heptane-2-carboxylate 4, 4-dioxide, and many impurities exist in the synthetic production process, and impurities such as tazobactam sodium dibenzoyl ester, 2-mercaptobenzothiazole, benzophenone hydrazone, 2-benzhydryl-5-methylphenol affect the quality of the product, so that the impurities in tazobactam need to be separated and detected.
The prior patent CN201711183384.5 discloses a high-performance liquid analysis method of tazobactam intermediate tazobactam dibenzoyl ester, which mainly detects tazobactam dibenzoyl ester impurities in tazobactam, and the prior patent CN201110280096.8 discloses a method for measuring the purity of 2-mercaptobenzothiazole by using a high-performance liquid chromatograph, which mainly detects 2-mercaptobenzothiazole impurities in tazobactam. At present, the detection method for the impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam cannot accurately and sensitively detect the impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam.
Disclosure of Invention
The invention aims to provide a method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam, which is used for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam by adopting a high performance liquid chromatography. The method can accurately detect the impurities of the 2-benzhydryl-5-methylphenol and the benzophenone hydrazone in the tazobactam, and has good separation degree and strong reproducibility.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam adopts high performance liquid chromatography to detect impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam.
Further, the following chromatographic conditions are included: the chromatographic column is COSMOSIL Packed Column C18-PAQ 4.6X250 mm, ID: K68144), the column temperature is 30 ℃, the flow rate is 1.0ml/min, the sample injection volume is 50 μl, the sample holder temperature is 15 ℃, the mobile phase is diammonium hydrogen phosphate-acetonitrile solution, the isocratic elution is carried out, and the detector is a UV detector.
Further, the volume ratio of the diammonium phosphate solution to the acetonitrile solution in the mobile phase is 50:50.
Further, the preparation method of the diammonium phosphate solution comprises the following steps: 1.32g of diammonium hydrogen phosphate was weighed, dissolved by adding 750ml of water, pH adjusted to 2.5 with 5% (V/V) phosphoric acid, and added to 1000ml of water.
Further, the method comprises the following operation steps:
s1, preparing a reference substance solution:
(1) 2-benzhydryl-5-methylphenol control solution: precisely weighing about 20mg of 2-benzhydryl-5-methylphenol reference substance, placing into a 100ml measuring flask, adding acetonitrile for dissolution and dilution to scale, shaking uniformly, precisely weighing 1ml, placing into a 100ml measuring flask, adding solvent for dilution to scale, shaking uniformly;
(2) Benzophenone hydrazone control solution: precisely weighing about 20mg of benzophenone hydrazone reference substance, placing into a 100ml measuring flask, adding acetonitrile for dissolution and dilution to scale, shaking uniformly, precisely weighing 1ml, placing into a 100ml measuring flask, adding solvent for dilution to scale, shaking uniformly;
S2, sample solution: weighing 0.2g of tazobactam sample, transferring to a 100ml volumetric flask after dissolution, and fixing the volume to a scale to prepare a solution containing about 2mg per 1 ml;
s3, detecting the reference substance solution and the test substance solution by adopting a high performance liquid chromatography method respectively to obtain chromatogram data of the reference substance solution and the test substance solution respectively, and calculating the amounts of 2-benzhydryl-5-methylphenol and benzophenone hydrazone impurities in the tazobactam sample.
Further, the chemical formula of the 2-benzhydryl-5-methylphenol isThe molecular formula is C 20H18 O, and the molecular weight is 274.36.
Further, the synthesis process of tazobactam comprises the steps of synthesizing tazobactam from compound 1 through Step1 to Step 9.
Further, compound 1 is
Further, benzophenone hydrazone impurities can be produced during Step2 synthesis.
Further, 2-benzhydryl-5-methylphenol impurities are produced during Step9 synthesis.
By adopting the technical scheme, the invention has the following technical progress:
the method can rapidly and accurately detect the impurities of the 2-benzhydryl-5-methylphenol and the benzophenone hydrazone in the tazobactam, and has good separation degree and strong reproducibility.
According to the invention, the impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam can be detected by adopting a high performance liquid chromatography, the sensitivity is high, the baseline separation is good, and the separation degree is good; if high performance liquid chromatography or other methods are used for measurement and analysis, the sensitivity is low, the chromatogram cannot be detected, and the method is not applicable.
According to the invention, by limiting the mobile phase and the elution mode in chromatographic conditions, impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam can be better separated and detected, so that a corresponding chromatogram is obtained, and the baseline separation and the separation degree are good; if the mobile phase and the elution mode of other chromatographic conditions are adopted, the compounds in the tazobactam sample can not be well separated, and the detected compound chromatograms are not separated from part of base lines and have poor separation degree.
Drawings
The invention will be described in further detail with reference to the drawings and the detailed description.
FIG. 1 is a chromatogram of a sample solution of the present invention;
FIG. 2 is a chromatogram of a mixed solution of the present invention;
FIG. 3 is a chromatogram of a 2-benzhydryl-5-methylphenol control solution of the present invention;
FIG. 4 is a chromatogram of a benzophenone hydrazone control solution of the present invention;
FIG. 5 is a blank solvent chromatogram of the present invention;
FIG. 6 is a linear plot of 2-benzhydryl-5-methylphenol for a linear test of the present invention;
FIG. 7 is a graph of benzophenone hydrazone linearity for a linearity test of the present invention;
In the drawings, fig. 1 to 5, the abscissa is Time, and the ordinate is mV; in FIGS. 6 to 7, the abscissa represents the concentration ng/ml, and the ordinate represents the peak area.
Detailed Description
The invention is described in further detail below with reference to the examples and figures 1 to 7:
a method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam adopts high performance liquid chromatography to detect impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam.
Synthesis process of tazobactam+(Step1-Step9)→Specific:
Step1 reagent: 6-APA, hydrogen bromide and sodium nitrite;
step2 reagent: ethanol, methylene dichloride, water and benzophenone hydrazone;
Step3 reagent: ethanol, peracetic acid, water;
Step4 reagent: ammonium acetate, THF, toluene, zinc powder, ethyl acetate, hydrochloric acid, sodium sulphate, activated carbon;
step5 reagent: 2-mercaptobenzothiazole, toluene, methylene chloride;
step6 reagent: hydrochloric acid, dichloromethane and sodium nitrite;
Step7 reagent: triazole, acetone, methylene dichloride and ethyl acetate;
Step8 reagent: acetic acid, potassium permanganate, methylene chloride, ethyl acetate, methyl isobutyl ketone;
step9 reagent: m-cresol, sodium bicarbonate, hydrochloric acid, ethyl acetate and ethanol;
Benzophenone hydrazone impurities may be produced during Step2 synthesis. Also, 2-benzhydryl-5-methylphenol impurities may be produced during Step9 synthesis.
Thus, the tazobactam sample synthesized as described above was tested under the following conditions:
chromatographic column: COSMOSIL Packed Column 5C18-PAQ 4.6X250 mm, ID: K68144);
Column temperature: 30 ℃;
flow rate: 1.0ml/min;
sample injection volume: 50 μl;
sample holder temperature: 15 ℃;
Mobile phase: diammonium hydrogen phosphate-acetonitrile solution;
isocratic elution: the volume ratio of the diammonium phosphate solution to the acetonitrile solution in the mobile phase is 50:50;
a detector: a UV detector;
The preparation method of the diammonium phosphate solution comprises the following steps: 1.32g of diammonium hydrogen phosphate is weighed, 750ml of water is added to dissolve, the pH value is adjusted to 2.5 by 5% (V/V) phosphoric acid, and 1000ml of water is added for later use.
The operation steps are as follows:
s1, preparing a reference substance solution:
(1) 2-benzhydryl-5-methylphenol control solution: precisely weighing about 20mg of 2-benzhydryl-5-methylphenol reference substance, placing into a 100ml measuring flask, adding acetonitrile for dissolution and dilution to scale, shaking uniformly, precisely weighing 1ml, placing into a 100ml measuring flask, adding solvent for dilution to scale, shaking uniformly;
(2) Benzophenone hydrazone control solution: precisely weighing about 20mg of benzophenone hydrazone reference substance, placing into a 100ml measuring flask, adding acetonitrile for dissolution and dilution to scale, shaking uniformly, precisely weighing 1ml, placing into a 100ml measuring flask, adding solvent for dilution to scale, shaking uniformly;
S2, sample solution: weighing 0.2g of tazobactam sample, transferring to a 100ml volumetric flask after dissolution, and fixing the volume to a scale to prepare a solution containing about 2mg per 1 ml;
s3, detecting the reference substance solution and the test substance solution by adopting a high performance liquid chromatography method respectively to obtain chromatogram data of the reference substance solution and the test substance solution respectively, and calculating the amounts of 2-benzhydryl-5-methylphenol and benzophenone hydrazone impurities in the tazobactam sample.
Example 1
The specific implementation procedure of this embodiment 1 is as follows:
Synthesis process of tazobactam +(Step1-Step9)→
Specific:
Step1 reagent: 6-APA, hydrogen bromide and sodium nitrite;
step2 reagent: ethanol, methylene dichloride, water and benzophenone hydrazone;
Step3 reagent: ethanol, peracetic acid, water;
Step4 reagent: ammonium acetate, THF, toluene, zinc powder, ethyl acetate, hydrochloric acid, sodium sulphate, activated carbon;
step5 reagent: 2-mercaptobenzothiazole, toluene, methylene chloride;
step6 reagent: hydrochloric acid, dichloromethane and sodium nitrite;
Step7 reagent: triazole, acetone, methylene dichloride and ethyl acetate;
Step8 reagent: acetic acid, potassium permanganate, methylene chloride, ethyl acetate, methyl isobutyl ketone;
step9 reagent: m-cresol, sodium bicarbonate, hydrochloric acid, ethyl acetate and ethanol;
Benzophenone hydrazone impurities may be produced during Step2 synthesis. Also, 2-benzhydryl-5-methylphenol impurities may be produced during Step9 synthesis.
Thus, the tazobactam sample synthesized in example 1 above was tested as follows:
1. Instrument, reagent and reference substance
1.1 Instrumentation
Table 1: instrument information
| Name of the name | Model number | Manufacturer/brand |
| High performance liquid chromatograph | LC-2030 | SHIMADZU CORPORATION |
| Ten thousandth electronic balance | T-114 | DENVER INSTRUMENT |
| Electronic balance of ten thousandth | AUW220D | SHIMADZU CORPORATION |
| PH meter | PB-10 | Beijing Sidoris Limited |
1.2 Control
Table 2: control information
| Name of the name | Lot number | Purity of |
| 2-Benzhydryl-5-methylphenol | PITZBT-7-20190814-01 | 90.07％ |
| Benzophenone hydrazone | E2020029 | 98.684％ |
2. Experimental procedure
2.1 Preparation of control solution
(1) Benzophenone hydrazone control solution: precisely weighing about 20mg of benzophenone hydrazone reference substance, placing into a 100ml measuring flask, adding acetonitrile for dissolution and dilution to scale, shaking uniformly, precisely weighing 1ml, placing into a 100ml measuring flask, adding solvent for dilution to scale, and shaking uniformly.
(2) 2-Benzhydryl-5-methylphenol control solution: accurately weighing about 20mg of 2-benzhydryl-5-methylphenol reference substance, placing into a 100ml measuring flask, adding acetonitrile for dissolution and dilution to scale, shaking uniformly, accurately weighing 1ml, placing into a 100ml measuring flask, adding solvent for dilution to scale, and shaking uniformly.
2.2 Mobile phase solution: the volume ratio of the diammonium phosphate solution to the acetonitrile solution is 50:50. The preparation method of the diammonium phosphate solution comprises the following steps: 1.32g of diammonium hydrogen phosphate is weighed, 750ml of water is added to dissolve, the pH value is adjusted to 2.5 by 5% (V/V) phosphoric acid, and 1000ml of water is added for later use.
2.3 Test sample solution: weighing 0.2g of tazobactam sample, adding a mobile phase solution for dissolution, transferring to a 100ml volumetric flask, and fixing the volume to a scale by using the mobile phase solution to prepare a solution with the concentration of about 2mg in each 1ml, and measuring.
3. Instrument detection conditions
Chromatographic column: COSMOSIL Packed Column 5C18-PAQ 4.6X250 mm, ID: K68144);
Column temperature: 30 ℃;
flow rate: 1.0ml/min;
sample injection volume: 50 μl;
sample holder temperature: 15 ℃;
Mobile phase: diammonium hydrogen phosphate-acetonitrile solution;
isocratic elution: the volume ratio of the diammonium phosphate solution to the acetonitrile solution in the mobile phase is 50:50;
a detector: a UV detector;
4. Detection result
The detection results of the related substances in tazobactam, namely 2-benzhydryl-5-methylphenol and benzophenone hydrazone are not detected, and are shown in the figure 1, and the results are shown in the following table:
Table 3: detection result
5. Method verification
5.1 Interference and impurity localization test
And (3) observing the interference condition of a blank solvent, a main component (tazobactam) and other impurities on the measurement of 2-benzhydryl-5-methylphenol and benzophenone hydrazone.
Preparing a blank solvent, tazobactam sodium solution and 2-benzhydryl-5-methylphenol and benzophenone hydrazone solution, and respectively carrying out sample injection analysis. And (3) positioning impurity peaks, and evaluating the separation condition of adjacent other impurity peaks of the 2-benzhydryl-5-methylphenol and benzophenone hydrazone peaks.
The following solutions were prepared separately:
(1) Blank solvent: mobile phase solution.
(2) Tazobactam sodium solution: a sample of tazobactam was taken, dissolved in the mobile phase and diluted to a solution of about 2mg per 1 ml.
(3) 2-Benzhydryl-5-methylphenol solution: taking a proper amount of 2-benzhydryl-5-methylphenol reference substance, placing the reference substance into a sample injection bottle, adding 1ml of mobile phase to dissolve, and shaking uniformly.
(4) Benzophenone hydrazone solution: taking a proper amount of benzophenone hydrazone reference substance, placing the benzophenone hydrazone reference substance into a sample injection bottle, adding 1ml of mobile phase to dissolve the benzophenone hydrazone reference substance, and shaking the mixture uniformly.
(5) Mixing solution: weighing 17.64mg of tazobactam, placing into a 10ml measuring flask, adding a blank solvent, performing ultrasonic treatment to dissolve, diluting to a scale with the blank solvent, and shaking uniformly; weighing 0.6ml, placing into a sample injection bottle, adding 0.2ml of 2-benzhydryl-5-methylphenol solution and 0.2ml of benzophenone hydrazone solution, and shaking uniformly.
(6) And precisely measuring 50 mu l of each solution, respectively carrying out sample injection measurement, recording a chromatogram, and observing the interference condition of main components and impurities in a blank solvent and tazobactam sodium solution on the measurement of 2-benzhydryl-5-methylphenol and benzophenone hydrazone. And the separation between each impurity and the impurity peak, and between the impurity and the main peak was evaluated.
Acceptable standards for interference tests: the blank solvent, the main component (tazobactam) and other impurities should have no interference to the measurement of the 2-benzhydryl-5-methylphenol, benzophenone hydrazone peaks.
Acceptable standard of impurity positioning and separation test: the main peak and the adjacent impurity peak can be effectively separated; the main impurities should be well separated from each other (separation degree > 1.5).
Referring to fig. 2-5, the impurity localization and separation test results are shown in the following table:
table 4: impurity positioning and separation test results
Conclusion: the interference test results show that: the blank solvent, the main component (tazobactam) and other impurities have no interference to the measurement of the 2-benzhydryl-5-methylphenol and the benzophenone hydrazone. Impurity positioning and separation test results show that: the separation degree of the 2-benzhydryl-5-methylphenol and the benzophenone hydrazone from adjacent impurities is good, the main peak, the adjacent impurity peaks and the main impurity peaks are effectively separated, and the separation degree is more than 1.5. And verifying compliance with the requirements.
5.2 Linearity and Range
Preparing serial concentration solutions of each impurity and main component, respectively precisely measuring 20 μl, and detecting with liquid chromatograph, and recording chromatogram. The measured peak area was plotted against the concentration of the analyte, and linear regression was performed by the least square method. And evaluating the degree of direct proportional relation between the peak area and the concentration of the measured object.
Acceptable standards: correlation coefficient r is more than or equal to 0.990, y-axis intercept the ratio of the 100% response value is less than or equal to 25%.
The linear test results of 2-benzhydryl-5-methylphenol are shown in FIG. 6 and the following table:
table 5: 2-benzhydryl-5-methylphenol linearity test results
Note that: the limit of the 2-benzhydryl-5-methylphenol is less than or equal to 0.1%, and the 100% response value refers to the y value corresponding to the concentration of tazobactam (2 mg/ml) in the test solution of 0.1%.
Benzophenone hydrazone linearity test results, see fig. 7 and the following table:
table 6: benzophenone hydrazone linearity test results
Note that: the limit of benzophenone hydrazone is less than or equal to 10ppm, and the "100% response value" refers to the y value corresponding to the concentration of tazobactam (2 mg/ml) in the test solution in percentage of 0.0010%.
Conclusion: the correlation coefficient r of the linear equation of the 2-benzhydryl-5-methylphenol and the benzophenone hydrazone is more than 0.999, the ratio of the y-axis intercept to the 100% response value is less than or equal to 25%, and the verification requirement is met.
5.3 Limit of detection and amount
The S/N signal-to-noise ratio method is used to determine the limit of detection (LOD) and limit of quantification (LOQ).
The mixed reference substance solution with known concentration is diluted gradually and then injected, the measured peak signal is compared with the baseline noise, the corresponding concentration is determined to be a detection limit according to the S/N signal to noise ratio of about 3:1 (or 2:1), and the corresponding concentration is determined to be a quantitative limit according to the S/N signal to noise ratio of about 10:1. The test results are shown in the following table:
table 7: limit of detection, limit of quantification result
5.4 Precision of instrument sample injection
And taking the result of repeated sampling of the reference substance solution for 5 times for evaluation. Acceptable standards: RSD is less than or equal to 2.0 percent. The test results are shown in the following table:
Table 8: sample injection precision test result
5.5 Repeatability test
The measurement of 6 samples was repeated, and the Relative Standard Deviation (RSD) of the impurity content was calculated to verify the precision of the method. The results are shown in the following table:
acceptable standards: reporting limit is less than or equal to X < 0.1%: RSD is less than or equal to 30 percent;
0.1％≤X＜0.5％：RSD≤20％；
0.5％≤X＜1％：RSD≤10％；
1％≤X＜5％：RSD≤5％；
X is more than or equal to 5 percent: RSD is less than or equal to 2.5 percent. (X: impurity content)
Table 9: test sample repeatability test results
Conclusion: and verifying compliance with the requirements.
The impurity content of 2-benzhydryl-5-methylphenol and benzophenone hydrazone is not detected in the test sample, and the standard test sample detection is needed, namely the reference substance solution and the test sample solution are mixed to prepare the standard test sample.
The Relative Standard Deviation (RSD) of the impurity content was calculated by repeating the measurement of 6 parts of the labeled test sample to verify the precision of the method. The results are shown in the following table:
Acceptable standards: RSD is less than or equal to 2.5 percent.
Table 10: labeling test sample repeatability test results
| Name of the name | 2-Benzhydryl-5-methylphenol | Benzophenone hydrazone |
| 1 | 321016 | 5466 |
| 2 | 320703 | 5403 |
| 3 | 319944 | 5497 |
| 4 | 319045 | 5365 |
| 5 | 319725 | 5428 |
| 6 | 318853 | 5460 |
| RSD | 0.3％ | 0.9％ |
Conclusion: the Relative Standard Deviation (RSD) of the 2-benzhydryl-5-methylphenol and the benzophenone hydrazone is less than 2.5%, and the requirements are verified.
5.6 Solution stability
The solution stability test is used for verifying the rule of time variation of the sample solution and the reference solution, and provides a basis for placing the solutions during the later detection.
(1) Stability of test solution
Placing the sample solution at 15 deg.C, sampling and detecting at intervals, recording chromatogram, and calculating content according to reference.
Acceptable standards: change value during storage
Reporting limit is less than or equal to X < 0.1%: the variation value is less than or equal to 40 percent;
X is more than or equal to 0.1 percent and less than 0.2 percent: the variation value is less than or equal to 30 percent;
X is more than or equal to 0.5 percent and less than 1 percent: the variation value is less than or equal to 20 percent;
x is more than or equal to 1 percent and less than 5 percent: the variation value is less than or equal to 10 percent;
x is more than or equal to 5 percent: the variation value is less than or equal to 5 percent; no new impurity peak appears (X: impurity content;)
Stability results of tazobactam test solutions are shown in the following table:
table 11: stability results of tazobactam test solution
Conclusion: the tazobactam test solution is stable in 12 hours at 15 ℃, and the variation value does not exceed the verification requirement.
(2) Stability of control solution
Placing the reference substance solution at 15 ℃, sampling and detecting after a certain time interval, recording a chromatogram, and calculating the change value of the relative content.
Acceptable standards: the change value is less than or equal to 5% during storage.
The test results are shown in the following table:
table 12: stability results of control solution
Conclusion: the reference substance solution is placed for 12 hours at 15 ℃, the change values are less than 5%, and the verification requirements are met.
5.7 Accuracy
The accuracy of the method was verified by adding a known amount of control to the test sample, and determining the impurity recovery. The evaluation was performed by using the measurement results of 6 samples at the same concentration.
Acceptable standards: x < 0.5%: the recovery rate is 80-120%, and the RSD is less than or equal to 10%;
X is more than or equal to 0.5 percent and less than or equal to 5 percent: the recovery rate is 90-110%, and the RSD is less than or equal to 5%;
X > 5%: the recovery rate is 95-105%, RSD is less than or equal to 2.5% (X is the impurity content).
Benzophenone hydrazone recovery test results are shown in the following table:
Table 13: benzophenone hydrazone recovery test results
Conclusion: the percentage of the concentration of the solution corresponding to the test sample is 10ppm, the recovery rate of the benzophenone hydrazone is 92%, and the RSD is 3.2%, thereby meeting the verification requirement.
The recovery rate test results of 2-benzhydryl-5-methylphenol are shown in the following table:
Table 14: recovery test results of 2-benzhydryl-5-methylphenol
Conclusion: the recovery rate of the 2-benzhydryl-5-methylphenol is 100% and the RSD is 0.5% when the concentration of the solution corresponding to the sample solution is 0.1%, which meets the verification requirement.
5.8 Conclusion
From the above experiments, it can be seen that: the system adaptability meets the requirements, so that the system used by the method is effective and applicable; the specificity test meets the requirements, which shows that the method can accurately and selectively analyze and detect the impurities; the detection limit test meets the requirements, which shows that the detection limit of the method is set reasonably and the sensitivity of the detection method is higher; the quantitative limit test meets the requirements, which shows that the method can accurately measure the amounts of 2-benzhydryl-5-methylphenol and benzophenone hydrazone impurities in tazobactam, and has sensitive quantitative detection capability; the accuracy test meets the requirements, which shows that the method has better precision and higher accuracy of analysis results; the repeatability test meets the requirement, and shows that the method has repeatability and feasibility.
The verification items meet the requirements, and the method provided by the application can be used for detecting 2-benzhydryl-5-methylphenol and benzophenone hydrazone impurities in tazobactam.
In conclusion, the embodiment of the application proves that the impurities of the 2-benzhydryl-5-methylphenol and the benzophenone hydrazone in the tazobactam are detected by adopting a high performance liquid chromatography, and the impurities of the 2-benzhydryl-5-methylphenol and the benzophenone hydrazone are accurately and sensitively detected by limiting the chromatographic detection conditions, so that the detection method has high sensitivity, good separation degree and strong reproducibility.
The above embodiments are only for illustrating the technical solution of the present application, and not for limiting the same; although the application has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application, and all belong to the protection scope of the present application.
Claims (6)
1. A detection method of impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam is characterized by comprising the following steps: detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam by high performance liquid chromatography, wherein the chemical formula of the 2-benzhydryl-5-methylphenol isThe high performance liquid chromatography column temperature is 30 ℃, the flow rate is 1.0ml/min, the sample injection volume is 50 mu l, the sample holder temperature is 15 ℃, the mobile phase is diammonium hydrogen phosphate-acetonitrile solution, the volume ratio of diammonium hydrogen phosphate solution to acetonitrile solution in the mobile phase is 50:50, the isocratic elution is carried out, the detector is a UV detector, and the detection method comprises the following operation steps:
S1, preparing a reference substance solution: (1) 2-benzhydryl-5-methylphenol control solution: precisely weighing 2-benzhydryl-5-methylphenol reference substance, placing into a 100ml measuring flask, adding acetonitrile for dissolving and diluting to scale, shaking uniformly, precisely weighing 1ml, placing into a 100ml measuring flask, adding solvent for diluting to scale, and shaking uniformly; (2) benzophenone hydrazone control solution: precisely weighing benzophenone hydrazone reference substance, placing into a 100ml measuring flask, adding acetonitrile for dissolving and diluting to scale, shaking uniformly, precisely weighing 1ml, placing into a 100ml measuring flask, adding solvent for diluting to scale, shaking uniformly;
S2, sample solution: weighing 0.2g tazobactam sample, adding a mobile phase for dissolution, transferring to a 100ml volumetric flask, and fixing the volume to a scale;
s3, detecting the reference substance solution and the test substance solution by adopting a high performance liquid chromatography method respectively to obtain chromatogram data of the reference substance solution and the test substance solution respectively, and calculating the amounts of 2-benzhydryl-5-methylphenol and benzophenone hydrazone impurities in the tazobactam sample.
2. The method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam according to claim 1, wherein the method for preparing the solution of diammonium hydrogen phosphate is characterized by comprising the following steps: 1.32g of diammonium hydrogen phosphate was weighed, 750ml of water was added to dissolve the diammonium hydrogen phosphate, the pH was adjusted to 2.5 with 5% phosphoric acid, and water was added to 1000ml.
3. The method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam according to claim 1, wherein the molecular formula of 2-benzhydryl-5-methylphenol is C 20H18 O and the molecular weight is 274.36.
4. The method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam according to claim 1, wherein the tazobactam is synthesized by a compound 1 through a Step1 to Step9 reaction, and the compound 1 has a chemical formula ofThe reagents used in the specific synthetic steps are as follows:
Step1 reagent: 6-APA, hydrogen bromide and sodium nitrite;
step2 reagent: ethanol, methylene dichloride, water and benzophenone hydrazone;
Step3 reagent: ethanol, peracetic acid, water;
Step4 reagent: ammonium acetate, THF, toluene, zinc powder, ethyl acetate, hydrochloric acid, sodium sulphate, activated carbon;
step5 reagent: 2-mercaptobenzothiazole, toluene, methylene chloride;
step6 reagent: hydrochloric acid, dichloromethane and sodium nitrite;
Step7 reagent: triazole, acetone, methylene dichloride and ethyl acetate;
Step8 reagent: acetic acid, potassium permanganate, methylene chloride, ethyl acetate, methyl isobutyl ketone;
step9 reagent: m-cresol, sodium bicarbonate, hydrochloric acid, ethyl acetate and ethanol.
5. The method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam according to claim 4, wherein the impurities of benzophenone hydrazone are generated during Step2 synthesis.
6. The method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam according to claim 4, wherein the impurities of 2-benzhydryl-5-methylphenol are generated during Step9 synthesis.
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| CN109721617A (en) * | 2019-01-30 | 2019-05-07 | 齐鲁天和惠世（乐陵）制药有限公司 | A kind of preparation method of Tazobactam Sodium |
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| CN109721617A (en) * | 2019-01-30 | 2019-05-07 | 齐鲁天和惠世（乐陵）制药有限公司 | A kind of preparation method of Tazobactam Sodium |
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