CN107941977B - High performance liquid phase analysis method of tazobactam diphenylmethyl ester serving as tazobactam intermediate product - Google Patents
High performance liquid phase analysis method of tazobactam diphenylmethyl ester serving as tazobactam intermediate product Download PDFInfo
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- CN107941977B CN107941977B CN201711183384.5A CN201711183384A CN107941977B CN 107941977 B CN107941977 B CN 107941977B CN 201711183384 A CN201711183384 A CN 201711183384A CN 107941977 B CN107941977 B CN 107941977B
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- PHGXFQIAGFMIHJ-NWSQWKLXSA-N benzhydryl (2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(=O)OC(C=1C=CC=CC=1)C=1C=CC=CC=1)(=O)=O)N1C=CN=N1 PHGXFQIAGFMIHJ-NWSQWKLXSA-N 0.000 title claims abstract description 31
- 239000013067 intermediate product Substances 0.000 title claims abstract description 22
- JUNWSLGCXPTCAU-QZWDGIGVSA-N tazobactam intermediate Chemical compound O=C/C=C/N[C@@H](C(O)=O)[C@]([S](=O)=O)(C)CN1C=CN=N1 JUNWSLGCXPTCAU-QZWDGIGVSA-N 0.000 title claims abstract description 15
- 238000004458 analytical method Methods 0.000 title claims abstract description 12
- 239000007791 liquid phase Substances 0.000 title claims description 5
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 13
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 10
- QGPGUZIKJKOKRF-UHFFFAOYSA-M potassium;acetonitrile;dihydrogen phosphate Chemical group [K+].CC#N.OP(O)([O-])=O QGPGUZIKJKOKRF-UHFFFAOYSA-M 0.000 claims abstract description 7
- 238000010828 elution Methods 0.000 claims abstract description 6
- 238000010829 isocratic elution Methods 0.000 claims abstract description 3
- 229960003865 tazobactam Drugs 0.000 claims description 17
- 239000012071 phase Substances 0.000 claims description 13
- 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 claims description 12
- 239000000523 sample Substances 0.000 claims description 11
- 238000012360 testing method Methods 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- -1 tazobactam benzhydryl ester Chemical class 0.000 claims description 7
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 239000013068 control sample Substances 0.000 claims description 2
- 239000012488 sample solution Substances 0.000 claims description 2
- 238000001514 detection method Methods 0.000 abstract description 10
- 239000012086 standard solution Substances 0.000 abstract description 9
- 238000011084 recovery Methods 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 6
- 239000007788 liquid Substances 0.000 abstract description 5
- 238000012937 correction Methods 0.000 abstract description 2
- 239000011159 matrix material Substances 0.000 abstract description 2
- 238000002347 injection Methods 0.000 abstract 1
- 239000007924 injection Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 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 description 5
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 5
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 5
- 229960005256 sulbactam Drugs 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- IYNDLOXRXUOGIU-LQDWTQKMSA-M benzylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-LQDWTQKMSA-M 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 229960003324 clavulanic acid Drugs 0.000 description 2
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000012496 blank sample Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- RFMIKMMOLPNEDG-QVUDESDKSA-M tazobactam sodium Chemical compound [Na+].C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C([O-])=O)(=O)=O)N1C=CN=N1 RFMIKMMOLPNEDG-QVUDESDKSA-M 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
- Investigating Or Analysing Biological Materials (AREA)
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Abstract
The invention relates to a high performance liquid analysis method of tazobactam diphenylmethyl ester serving as a tazobactam intermediate product, belonging to the field of chemical detection. The conditions of the high performance liquid chromatography are as follows: the chromatographic column is a C18 chromatographic column; the mobile phase is acetonitrile-potassium dihydrogen phosphate buffer solution; the flow rate is 0.8-1.3 ml/min; the column temperature is 25-35 ℃; the detector wavelength is 225-235 nm; the sample injection volume is 20 uL; the elution mode is isocratic elution. The content of tazobactam diphenylmethyl ester has a good linear relation within the concentration range of 0.2-1.0 mg/ml, the correlation coefficient is 0.9998, and the average recovery rate of tazobactam diphenylmethyl ester is over 90 percent and the relative standard deviation is less than 2.0 percent by adopting a method of matching blank matrix with standard solution to carry out standard correction. The method has the advantages of simple and convenient operation, good chromatographic peak shape, accurate and reliable data and good reproducibility.
Description
Technical Field
The invention relates to a high performance liquid analysis method of tazobactam diphenylmethyl ester serving as a tazobactam intermediate product, belonging to the field of chemical detection.
Background
Tazobactam (sodium) is a novel blue enzyme alkyl sulfone β -lactamase inhibitor after clavulanic acid and sulbactam, is an irreversible β -lactamase inhibitor, has strong inactivation effect on A enzymes, has stronger enzyme inhibition effect than sulbactam, has better stability than clavulanic acid, can enhance the antibacterial activity of antibiotics, can expand antibacterial spectrum, reduce adverse reaction, and has wide clinical application prospect.
At present, the synthesis of tazobactam mainly comprises three synthetic routes according to different used starting materials, wherein sulbactam, penicillin G potassium salt and 6-aminopenicillanic acid (6-APA) are respectively used as the starting materials. The sulbactam is taken as a starting material, and the sulbactam has the two defects of high raw material price and low reaction yield, and cannot be used for actual production; penicillin G potassium salt is used as a starting material, and the reaction yield is slightly inferior due to the fact that the material source is not as wide as 6-APA, so that the route is also mainly used for theoretical research; the research of synthesizing tazobactam by using 6-APA as a starting material is the most active, and the method is also an industrial synthesis route adopted at home and abroad.
The detection method for the intermediate product generated in the tazobactam synthesis process is not published by the current detection standard at home and abroad, the target is mainly placed in the use condition of finished product clinical medical treatment due to the difference of the cultural development degree at home and abroad, and the reports of the related detection method for the intermediate product are few.
Because no good and effective detection means exist at present, the establishment of a method for detecting the content of intermediate product tazobactam diphenylmethyl ester generated when 6-APA is used as a starting material for synthesizing tazobactam is very important.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a high-efficiency liquid phase analysis method of tazobactam diphenylmethyl ester serving as a tazobactam intermediate product, which is simple and quick to operate, good in reproducibility and accurate and reliable in data.
The invention relates to a high performance liquid chromatography analysis method of tazobactam diphenylmethyl ester as a tazobactam intermediate product, which comprises the following high performance liquid chromatography conditions:
a chromatographic column: a C18 chromatography column;
mobile phase: acetonitrile-potassium dihydrogen phosphate buffer solution;
flow rate: 0.8-1.3 ml/min;
column temperature: 25-35 ℃;
detector wavelength: 225-235 nm;
sample introduction volume: 20 uL;
and (3) an elution mode: isocratic elution.
The volume ratio of the acetonitrile to the potassium dihydrogen phosphate buffer solution is 50-55: 45-50, and the pH value of the mobile phase is 3.5-4.5.
Preferably, the chromatographic conditions are:
the specification of the C18 chromatographic column is 250 multiplied by 4.6mm, 5 mu m;
mobile phase: acetonitrile-potassium dihydrogen phosphate buffer solution, wherein the volume ratio of the acetonitrile to the potassium dihydrogen phosphate buffer solution is 55:45, and the pH value of a mobile phase is 4;
detector wavelength: 230 nm;
flow rate: 1.0 ml/min;
column temperature: at 30 ℃.
The high performance liquid phase analysis method of tazobactam diphenylmethyl ester as tazobactam intermediate product includes the following steps:
(1) respectively preparing a control sample solution and a test sample solution of tazobactam diphenylmethyl ester;
(2) making a standard curve;
(3) and (4) analyzing and determining the content of the test sample by using high performance liquid chromatography.
The content of tazobactam diphenylmethyl ester has a good linear relation within the concentration range of 0.2-1.0 mg/ml, the correlation coefficient is above 0.999, standard correction is carried out by adopting a method of blank matrix matching with standard solution, the average recovery rate of tazobactam diphenylmethyl ester is above 90%, and the relative standard deviation is less than 2.0%. The method is suitable for measuring the content of tazobactam diphenylmethyl ester serving as a tazobactam intermediate product.
Compared with the prior art, the invention has the following advantages:
(1) the detection method is simple and convenient to operate, and has good chromatographic peak shape, accurate and reliable data and good reproducibility;
(2) the content of tazobactam diphenylmethyl ester can be accurately measured, and the reaction process is monitored, so that the reaction time is reasonably controlled, and a reference is provided for the synthesis of tazobactam diphenylmethyl ester.
Drawings
FIG. 1 is a high performance liquid chromatogram of the test article of example 1;
FIG. 2 is a standard curve of the concentration-peak area of tazobactam benzhydryl ester of the present invention;
FIG. 3 is a high performance liquid chromatogram of the test article of example 2;
FIG. 4 is a high performance liquid chromatogram of the sample of example 3.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
1. The main chromatographic conditions were:
the column size was C18 (250X 4.6mm, 5 μm); the column temperature was 25 ℃; the detection wavelength is 230 nm; the mobile phase is acetonitrile-potassium dihydrogen phosphate buffer solution (volume ratio is 55:45, pH is 4); the flow rate is 1.0 ml/min; the sample amount is 20 mul; the elution time was 15 min.
2. The testing steps are as follows:
(1) preparation of Standard solutions
Accurately weighing 50.0mg of tazobactam diphenylmethyl ester standard substance, placing the tazobactam diphenylmethyl ester standard substance into a 50ml volumetric flask, adding a mobile phase for dilution, fixing the volume to a scale, shaking up, and preparing into a standard solution with the concentration of 1 mg/ml; respectively and precisely weighing 2ml, 4ml, 6ml, 8ml and 10ml of the standard solution, placing the standard solution into a 10ml volumetric flask, fixing the volume to 10ml by using a mobile phase, and preparing tazobactam and diphenylmethyl ester standard solutions with the concentrations of 0.2mg/ml, 0.4mg/ml, 0.6mg/ml, 0.8mg/ml and 1.0 mg/ml;
(2) preparation of test solution
Precisely weighing 25.0mg of the sample, placing the sample in a 25ml volumetric flask, adding the mobile phase for dissolving to a constant volume, standing and testing.
(3) Determination of tazobactam diphenylmethyl ester in tazobactam
And (3) measuring tazobactam diphenylmethyl ester serving as a tazobactam intermediate product according to the high performance liquid chromatography condition, wherein the content is 86.141%.
And (4) conclusion: as can be seen from the attached figure 1, the peak pattern is good, and the retention time of the tazobactam diphenylmethyl ester standard substance under the chromatographic condition is basically consistent with that of the tazobactam intermediate product; as can be seen from the attached FIG. 2, the standard curve of tazobactam diphenylmethyl ester is good in linearity, R2＝0.9998。
Example 2
1. The main chromatographic conditions were:
the column size was C18 (250X 4.6mm, 5 μm); the column temperature is 30 ℃; the detection wavelength is 230 nm; the mobile phase is acetonitrile-potassium dihydrogen phosphate buffer solution (volume ratio is 55:45, pH is 4); the flow rate is 0.8 ml/min; the sample amount is 20 mul; the elution time was 15 min.
2. The testing steps are as follows:
(1) preparation of Standard solutions
The same as in example 1.
(2) Preparation of test solution
The same as in example 1.
(3) Determination of tazobactam diphenylmethyl ester in tazobactam
And (3) measuring tazobactam diphenylmethyl ester serving as a tazobactam intermediate product according to the high performance liquid chromatography condition, wherein the content is 86.141%.
And (4) conclusion: as can be seen from FIG. 3, the peak pattern is good, the retention time of the tazobactam diphenylmethyl ester standard under the chromatographic conditions is basically consistent with that of the tazobactam intermediate product, and the retention time is prolonged at the flow rate.
Example 3
1. The main chromatographic conditions were:
the column size was C18 (250X 4.6mm, 5 μm); the column temperature was 35 ℃; the detection wavelength is 230 nm; the mobile phase is acetonitrile-potassium dihydrogen phosphate buffer solution (volume ratio is 50:50, pH is 4); the flow rate is 1.0 ml/min; the sample amount is 20 mul; the elution time was 15 min.
2. The testing steps are as follows:
(1) preparation of Standard solutions
The same as in example 1.
(2) Preparation of test solution
The same as in example 1.
(3) Determination of tazobactam diphenylmethyl ester in tazobactam
And (3) measuring tazobactam diphenylmethyl ester serving as a tazobactam intermediate product according to the high performance liquid chromatography condition, wherein the content is 85.816%.
And (4) conclusion: as can be seen from the attached FIG. 4, the peak type of the mobile phase ratio is slightly worse, and the retention time of the tazobactam diphenylmethyl ester standard under the chromatographic condition is basically consistent with that of the tazobactam intermediate product.
And (4) measuring the recovery rate and the precision by adopting a blank standard adding method. Adding 3 concentrations of 0.2mg/ml, 0.4mg/ml and 0.6mg/ml standard substances into blank samples, measuring each concentration sample for 5 times, recording peak areas, respectively substituting into a regression equation, and respectively calculating the recovery rate and the RSD according to the formula. The results are shown in Table 1.
TABLE 1 recovery and precision test results
And (4) conclusion: as can be seen from Table 1, the recovery rate of the method is above 90%, the RSD of the tazobactam diphenylmethyl ester peak area is less than 2.0%, and the recovery rate and the system precision of the method are good.
Claims (5)
1. A high performance liquid phase analysis method of tazobactam diphenylmethyl ester which is a tazobactam intermediate product is characterized in that: the conditions of the high performance liquid chromatography are as follows:
a chromatographic column: a C18 chromatography column;
mobile phase: acetonitrile-potassium dihydrogen phosphate buffer solution;
flow rate: 0.8-1.3 ml/min;
column temperature: 25-35 ℃;
detector wavelength: 230 nm;
sample introduction volume: 20 mu L of the solution;
and (3) an elution mode: isocratic elution;
the volume ratio of the acetonitrile to the potassium dihydrogen phosphate buffer solution is 50-55: 45-50, and the pH value of the mobile phase is 3.5-4.5.
2. The method for the high performance liquid chromatography analysis of tazobactam benzhydryl ester, which is an intermediate product of tazobactam, according to claim 1, wherein: the flow rate was 1.0 ml/min.
3. The method for the high performance liquid chromatography analysis of tazobactam benzhydryl ester, which is an intermediate product of tazobactam, according to claim 1, wherein: the column temperature was 30 ℃.
4. The method for the high performance liquid chromatography analysis of tazobactam benzhydryl ester, which is an intermediate product of tazobactam, according to claim 1, wherein: the specification of the C18 chromatographic column is 250X 4.6mm, 5 μm.
5. The method for the high performance liquid chromatography analysis of tazobactam benzhydryl ester, which is an intermediate product of tazobactam, according to claim 1, wherein: the method comprises the following steps:
(1) respectively preparing a control sample solution and a test sample solution of tazobactam diphenylmethyl ester;
(2) making a standard curve;
(3) and (4) analyzing and determining the content of the test sample by using high performance liquid chromatography.
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| CN114276368B (en) * | 2021-12-23 | 2023-12-26 | 山东鑫泉医药有限公司 | Synthesis method of tazobactam diphenyl methyl ester |
| CN115541771B (en) * | 2022-10-27 | 2024-08-30 | 海南通用三洋药业有限公司 | Method for detecting impurities of 2-benzhydryl-5-methylphenol and benzophenone hydrazone in tazobactam |
Citations (3)
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|---|---|---|---|---|
| CN101650355A (en) * | 2008-08-11 | 2010-02-17 | 广州威尔曼新药开发中心有限公司 | New method for detecting compound ceftazidime and tazobactam sodium |
| CN105085544A (en) * | 2015-08-19 | 2015-11-25 | 齐鲁天和惠世制药有限公司 | Synthesis method of tazobactam diphenylmethyl ester |
| CN105748482A (en) * | 2016-03-18 | 2016-07-13 | 海南通用三洋药业有限公司 | Cefoperazone sodium and tazobactam sodium pharmaceutical composition for injection |
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| US20150246931A1 (en) * | 2012-09-06 | 2015-09-03 | Hospira, Inc. | Process for the preparation of tazobactam |
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Patent Citations (3)
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| CN101650355A (en) * | 2008-08-11 | 2010-02-17 | 广州威尔曼新药开发中心有限公司 | New method for detecting compound ceftazidime and tazobactam sodium |
| CN105085544A (en) * | 2015-08-19 | 2015-11-25 | 齐鲁天和惠世制药有限公司 | Synthesis method of tazobactam diphenylmethyl ester |
| CN105748482A (en) * | 2016-03-18 | 2016-07-13 | 海南通用三洋药业有限公司 | Cefoperazone sodium and tazobactam sodium pharmaceutical composition for injection |
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| Title |
|---|
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| 注射用头孢西丁钠他唑巴坦钠的有关物质及稳定性研究;李娇娜 等;《沈阳药科大学学报》;20141031;第31卷(第10期);778-782,788 * |
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