Cefoperazone sodium and sulbactam sodium polymer for injection and specific impurity analysis method

Abstract

The invention discloses a cefoperazone sodium and sulbactam sodium polymer for injection and a specific impurity analysis method, relates to the field of medicine detection, and aims to provide the cefoperazone sodium and sulbactam sodium polymer for injection, which is high in sensitivity and good in stability, and the specific impurity analysis method. Chromatographic conditions are as follows: a chromatographic column adopts a C18 column; the mobile phase A is a 1mmol / L-10 mmol / L tetrabutylammonium hydroxide solution, the pH value of the tetrabutylammonium hydroxide solution is adjusted to 3.0-4.0 by using a phosphoric acid solution, the mobile phase B is acetonitrile, and gradient elution is carried out; the column temperature is 25-40 DEG C; the flow velocity is 0.5 mL / min to 1.5 mL / min; the sample size is 10 [mu] L; the detection wavelength is 220nm; the sample concentration is 1 mg / mL to 10 mg / mL. The method has the advantages of high detection sensitivity, good reproducibility, high stability and the like, and is suitable for detecting cefoperazone sodium and sulbactam sodium polymers for injection and specific impurities.

Description

Technical Field

[0001] The invention relates to the field of medical detection, and in particular to a cefoperazone sodium and sulbactam sodium polymer for injection and a specific impurity analysis method. Background Art

[0002] Cefoperazone sodium and sulbactam sodium for injection is a compound antibiotic preparation. Cefoperazone sodium is a third-generation cephalosporin, and sulbactam is a spectrum enzyme inhibitor with poor stability against β-lactamase. The combination of the two has a strong antibacterial effect on a variety of bacteria. β-lactam antibiotics are commonly used anti-infective drugs in clinical practice. Such drugs are prone to produce polymer impurities and induce allergic reactions. According to the relevant data provided by the Drug Evaluation Center of the State Food and Drug Administration and the National Center for Adverse Drug Reaction Monitoring, immediate allergic reactions are the most concerned adverse reactions of β-lactam antibiotics. The allergens that trigger such allergic reactions are not the drugs themselves, but the polymer impurities in β-lactam antibiotics. Polymer impurities can be divided into exogenous impurities and endogenous impurities according to their sources. Exogenous impurities usually come from the fermentation process, while endogenous impurities are the general term for oligomers or polymers produced by the self-polymerization of antibiotics under certain conditions. With the continuous improvement of the production process, exogenous impurities have been significantly reduced, and endogenous impurities have become the focus of current research and attention on β-lactam antibiotics.

[0003] According to the existing production process conditions, high molecular polymers mainly come from oligomers and polymers formed by endogenous polymerization under certain conditions. Polymer impurities with different polymerization degrees generally have similar biological properties, and the sensitization of polymer impurities will also increase with the increase of polymerization degree. As a third-generation antibiotic, Cefoperazone Sodium and Sulbactam Sodium for Injection have the common characteristics of β-lactam antibiotics. A certain amount of impurities will also be generated during the synthesis and storage process. Therefore, in order to further ensure the quality and safety of Cefoperazone Sodium and Sulbactam Sodium for Injection, strengthening the detection and analysis of key polymers and specific impurities is of great significance for clinical safety medication.

[0004] Polymer detection is an important detection item for quality control in the process of drug development. Currently, no relevant reports have been found on the detection method of cefoperazone sodium and sulbactam sodium polymers for injection. Due to its structural characteristics, the polymer is mainly related to cefoperazone sodium. The method for detecting cefoperazone sodium polymers recorded in the Chinese Pharmacopoeia is molecular exclusion chromatography using a dextran gel G-10 chromatographic column. The total polymer is detected and is easily interfered by other small molecular impurities with greater polarity in the drug, thereby affecting the quantitative accuracy of polymer impurities. A liquid chromatography C18 method is established to optimize the composition and proportion of the mobile phase, separate the polymer from other chromatographic peaks, that is, the polymer and specific impurity analysis method described in the present invention, detect the polymer, and perform methodological verification on the established reversed-phase liquid chromatography method.

[0005] Specific impurities (impurity I and impurity J) are all cefoperazone degradation impurities, which will gradually increase during the stability study. In order to further control the quality and safety of cefoperazone sodium and sulbactam sodium for injection, the qualitative characterization of impurities I and impurity J should be strengthened, and quantitative control should be performed on them. However, impurities I and impurity J are unstable impurities, which are not easy to prepare and obtain, and no relevant reports have been found at present. Impurities I and impurity J in this study are found by method transformation through two-dimensional liquid chromatography, and then detected by liquid chromatography-mass spectrometry. At the same time, impurities I and impurity J are collected, and liquid-mass detection is performed using HILIC mode to determine the structural formula and chemical name of impurities I and impurity J. Liquid chromatography C18 method is established, mobile phase composition and ratio are optimized, specific impurities are separated from other chromatographic peaks, that is, polymer and specific impurity analysis method described in the present invention, specific impurities are detected, and the established reversed-phase liquid chromatography method is verified by methodology. Summary of the invention

[0006] The purpose of the present invention is to provide a high-sensitivity and stable cefoperazone sodium and sulbactam sodium polymer for injection and a specific impurity analysis method.

[0007] The present invention provides a polymer of cefoperazone sodium and sulbactam sodium for injection and a method for analyzing specific impurities. The method for analyzing the polymer of cefoperazone sodium and sulbactam sodium for injection and specific impurities is to analyze the polymer and specific impurities by HPLC. The specific operation is as follows:

[0008] Step 1: Preparation of test solution

[0009] Take cefoperazone sodium and sulbactam sodium for injection, place in a volumetric bottle, add solvent to dissolve and quantitatively dilute to the scale to obtain a test solution with a concentration of 1-10 mg / mL;

[0010] Step 2: Preparation of control solution

[0011] Take the test solution prepared in step 1, place it in a volumetric flask, quantitatively dilute it to the mark with solvent, shake well, and obtain a control solution with a concentration of 0.01-0.1 mg / mL;

[0012] The chromatographic conditions are as follows: a C18 column is used as the chromatographic column; mobile phase A is 1 mmol / L to 10 mmol / L tetrabutylammonium hydroxide solution, wherein the pH value of the tetrabutylammonium hydroxide solution is adjusted to 3.0 to 4.0 with a phosphoric acid solution; mobile phase B is acetonitrile, and gradient elution is performed; column temperature is 25°C to 40°C; flow rate is 0.5 mL / min to 1.5 mL / min; injection volume is 10 μL; detection wavelength is 220 nm; sample concentration is 1 mg / mL to 10 mg / mL;

[0013] The gradient elution program was as follows: 0→5 min, the amount of mobile phase A was 78%, and the amount of mobile phase B was 22%; 7→50 min, the amount of mobile phase A was 75%, and the amount of mobile phase B was 25%; 75→110 min, the amount of mobile phase A was 60%, and the amount of mobile phase B was 40%; 111→120 min, the amount of mobile phase A was 78%, and the amount of mobile phase B was 22%.

[0014] Further, the polymer is polymer A and impurity O;

[0015] The polymer A is (6R, 7R)-7-((R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamide)-2-(-4-(((6R, 7R)-7-(R)-2-(4-ethyl 2,3-dioxopiperazine-1-carboxamide)-2-(4-hydroxyphenyls)-acetylamino)-3-(((1-methyl-1H-tetrol-5-ylethylene) (((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5-thio-1-azabicyclo[4.2.0]oct-2-yl-2-oct-2-en-2-one-2-ene-2-carbonyl)oxy)phenyl)acetamido)-3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5-thio-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid);

[0016] The impurity O is (6R, 7R)-7-((6R, 7R)-7-((R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamide)-2-(-4-hydroxyphenyl)acetamide)-3-((((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxamide)-3-thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxamide)

[0017] Furthermore, the specific impurities are impurity I and impurity J;

[0018] The impurity I is 2-(carboxyl((R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-(4-hydroxyphenyl)acetamido)methyl)-5-methylene-5,6-dihydro-2H-1,3-thiazine-4-carboxylic acid;

[0019] The impurity J is 2-(carboxy((R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-(4-hydroxyphenyl)acetamido)methyl)-5-methyl-2H-1,3-thiazine-4-carboxylic acid.

[0020] Furthermore, the solvent in step 1 is a mixture of mobile phase A and mobile phase B in a volume ratio of 78:22.

[0021] Furthermore, the chromatographic column model is Kromasil 100-5-C18, with specifications of 250 mm×4.6 mm, 5 μm, and a ghost peak trapping column: 50 mm chromatographic column.

[0022] Furthermore, the mobile phase A is a 5mmol / L tetrabutylammonium hydroxide solution, wherein the pH value of the tetrabutylammonium hydroxide solution is adjusted to 3.6 with a phosphoric acid solution, the mobile phase B is acetonitrile, and the gradient elution is performed; the column temperature is 30°C; the flow rate is 1.2mL / min; the injection volume is 10μl; the detection wavelength is 220nm; the sample concentration is 4mg / mL; the gradient elution program is: 0→5min, the amount of mobile phase A is 78%, and the amount of mobile phase B is 22%; 7→50min, the amount of mobile phase A is 75%, and the amount of mobile phase B is 25%; 75→110min, the amount of mobile phase A is 60%, and the amount of mobile phase B is 40%; 111→120min, the amount of mobile phase A is 78%, and the amount of mobile phase B is 22%.

[0023] Further, the preparation of HPLC test system suitability solution:

[0024] Mixed impurity solution: Take appropriate amount of sulbactam impurity A, polymer A, and impurity O reference substance, dissolve in solvent and quantitatively dilute to make a solution containing about 0.4 mg per 1 ml;

[0025] System suitability solution (1): Take about 100 mg of the test sample dried at 105°C for 2.5 hours, place it in a 25 ml volumetric flask, add 1 ml of the mixed impurity solution, dissolve it with solvent and dilute to the mark, shake well;

[0026] System suitability solution (2): Take about 100 mg of the test sample dried at 60°C for 14 days, place it in a 25 ml volumetric flask, dissolve it with solvent and dilute it to the mark, and shake well.

[0027] Furthermore, after the system suitability solution is injected into the liquid chromatograph, the separation degree between the impurity A peak and the sulbactam impurity A peak in the chromatogram of the system suitability solution (1) should be no less than 1.5, and the separation degree between the cefoperazone peak and the impurity G peak should be no less than 1.5, and the retention time of polymer A and impurity O is located. The retention time of specific impurities I and impurity J is located in the chromatogram of the system suitability solution (2).

[0028] Further, the HPLC detection system sensitivity solution was prepared:

[0029] Take the control solution, place it in a volumetric flask, quantitatively dilute it to the scale with solvent, shake well, and obtain a sensitivity solution with a concentration of 0.0005-0.005 mg / mL.

[0030] Furthermore, after the sensitivity solution is injected into the liquid chromatograph, the signal-to-noise ratio of the cefoperazone peak in the chromatogram is greater than 10.

[0031] The present invention has the following beneficial effects:

[0032] The present invention is mainly aimed at separating polymers, specific impurities, possible degradation impurities and some process impurities in cefoperazone sodium and sulbactam sodium for injection, specifically including the following impurities:

[0033]

[0034]

[0035]

[0036]

[0037]

[0038] The detection method provided by the present invention can more effectively separate the cefoperazone sodium sulbactam sodium polymer for injection and specific impurities from other related substances. The present invention has the advantages of high detection sensitivity, good reproducibility, high stability, etc., and is suitable for the inspection of cefoperazone sodium sulbactam sodium polymer for injection and specific impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is the system suitability (1) spectrum;

[0040] Figure 2 is the system suitability (2) spectrum;

[0041] Figure 3 The sample and mixed impurity spectrum (1);

[0042] Figure 4 is the spectrum of the test sample and mixed impurities (2);

[0043] Figure 5 The spectrum of the test sample and mixed impurities (1) is detected at a wavelength of 210nm. DETAILED DESCRIPTION

[0044] In order to make the objectives, technical solutions and advantages of the embodiments of the present invention more clearly understood, the spirit of the contents disclosed by the present invention will be described in detail below. After understanding the embodiments of the contents of the present invention, any technician in the relevant technical field can change and modify them according to the techniques taught by the contents of the present invention without departing from the spirit and scope of the contents of the present invention.

[0045] The exemplary embodiments of the present invention and the description thereof are used to explain the present invention but are not intended to limit the present invention.

[0046] Example 1

[0047] 1) Solvent preparation

[0048] Mobile phase A-mobile phase B (78:22).

[0049] 2) Preparation of system suitability solution

[0050] Mixed impurity solution: Take appropriate amounts of sulbactam impurity A, polymer A, and impurity O reference substance, dissolve them in solvent, and quantitatively dilute them to make a solution containing approximately 0.4 mg per 1 mL.

[0051] System suitability solution (1): Take about 100 mg of the test sample dried at 105°C for 2.5 hours, place it in a 25 mL volumetric flask, add 1 mL of the mixed impurity solution, dissolve it with solvent and dilute to the mark, and shake well.

[0052] System suitability solution (2): Take about 100 mg of the test sample dried at 60°C for 14 days, place it in a 25 mL volumetric flask, dissolve it with solvent and dilute it to the mark, and shake well.

[0053] 3) Preparation of test solution

[0054] Take 100 mg of cefoperazone sodium and sulbactam sodium for injection, place it in a 25 mL volumetric bottle, add solvent to dissolve and quantitatively dilute to the scale.

[0055] 4) Preparation of control solution

[0056] Take 1 mL of the above test solution, place it in a 100 mL volumetric flask, quantitatively dilute it to the scale with solvent, and shake well.

[0057] 5) Preparation of sensitivity solution

[0058] Take 5 mL of the above control solution, place it in a 100 mL volumetric flask, quantitatively dilute it to the scale with solvent, and shake well.

[0059] Example 2

[0060] This example is the optimization and determination of the chromatographic conditions used in the analysis method of cefoperazone sodium and sulbactam sodium for injection

[0061] (1) Determination of detection wavelength

[0062] When the detection wavelength is 210nm, the response value is higher than that at 220nm. However, due to the terminal absorption of organic solvents, we choose to increase the sample concentration and detect at a wavelength of 220nm. At this concentration, the signal-to-noise ratio of the sensitive solution is greater than 10, which meets the requirements.

[0063] (2) Optimal chromatographic conditions

[0064] Chromatographic column: Kromasil 100-5-C18, specification is 250mm×4.6mm, 5μm, plus ghost peak trapping column: 50mm chromatograph, mobile phase A is 5mmol / L tetrabutylammonium hydroxide solution, wherein the pH value of the tetrabutylammonium hydroxide solution is adjusted to 3.6 with phosphoric acid solution, mobile phase B is acetonitrile, gradient elution; column temperature is 30℃; flow rate is 1.2mL / min; injection volume is 10μl; detection wavelength is 220nm; sample concentration is 4mg / mL; gradient elution program is: 0→5min, mobile phase A is 78%, mobile phase B is 22%; 7→50min, mobile phase A is 75%, mobile phase B is 25%; 75→110min, mobile phase A is 60%, mobile phase B is 40%; 111→120min, mobile phase A is 78%, mobile phase B is 22%.

[0065] pass Figures 1 to 5 It can be determined that the separation between the polymer peak and the specific impurity peak and its adjacent impurity peak meets the requirements, and the above-mentioned optimal detection wavelength and optimal chromatographic conditions are determined.

[0066] (3) Methodological validation

[0067] The above-mentioned optimal chromatographic conditions were used to verify the test product of Example 1.

[0068] 1) Detection limit and quantification limit Take about 50 mg of cefoperazone reference substance and sulbactam reference substance, respectively, and place them in 25 mL volumetric flasks. Dilute them quantitatively with solvent until the signal-to-noise ratio of the sample solution is greater than 10, which is the quantification limit. The results are 0.95 μg / mL for cefoperazone and 0.91 μg / mL for sulbactam. The signal-to-noise ratio is greater than 3, which is the detection limit. The results are 0.28 μg / mL for cefoperazone and 0.27 μg / mL for sulbactam.

[0069] 2) Cefoperazone linearity: About 50 mg of cefoperazone reference substance was taken and placed in a 25 mL volumetric flask, and diluted to the scale with a solvent. 4.0 mL, 2.0 mL, 1.0 mL, 0.5 mL, 0.2 mL, and 0.05 mL were accurately measured and placed in 100 mL volumetric flasks, respectively, and diluted to the scale with a solvent as cefoperazone linear solutions. The chromatographic conditions of the present invention were used for determination, and linear regression was performed with concentration C as the abscissa and peak area A as the ordinate. The regression equation was A=15.8002C+1.0768, and the correlation coefficient R=1.0000.

[0070] 3) Sulbactam linearity: About 50 mg of sulbactam reference substance was taken and placed in a 25 mL volumetric flask, and diluted to the scale with a solvent. 4.0 mL, 2.0 mL, 1.0 mL, 0.5 mL, 0.2 mL, and 0.05 mL were accurately measured and placed in 100 mL volumetric flasks, respectively, and diluted to the scale with a solvent as sulbactam linear solutions. The chromatographic conditions described in the present invention were used for determination, and linear regression was performed with the concentration C as the abscissa and the peak area A as the ordinate. The regression equation was A=3.0680C-0.2097, and the correlation coefficient R=0.9999.

[0071] 4) Precision The precision was measured on different dates, by different analysts, using different equipment according to the above test conditions. Six measurements were performed and the maximum absolute values ​​of changes in polymer A, impurity O, impurity I and impurity J of the test solution were calculated 12 times. The results are shown in Table 1. The absolute values ​​of the maximum changes in precision were all less than 0.01%.

[0072] 5) Separation According to the system suitability test requirements, the system suitability solution was measured under the chromatographic conditions of the present invention. The separation between the impurity A peak and the sulbactam impurity A peak in the chromatogram of the system suitability solution (1) was 2.8, which was greater than 1.5, and the separation between the cefoperazone peak and the impurity G peak was 2.5, which was greater than 1.5. The retention time of polymer A and impurity O was located. The retention time of specific impurities I and impurity J was located in the chromatogram of the system suitability solution (2).

[0073] 6) Stability of solution at room temperature Under the chromatographic conditions described in the present invention, a test solution of cefoperazone sodium and sulbactam sodium for injection was prepared with a solvent, placed at room temperature, and sampled and checked at 0 and 2 hours. The results are shown in Table 2. It can be seen from Table 2 that after the cefoperazone sodium and sulbactam sodium solution for injection was placed at room temperature for 2 hours, the absolute value of the change of impurity J exceeded 0.05%, indicating that the cefoperazone sodium and sulbactam sodium solution for injection was unstable when placed at room temperature and needed to be freshly prepared before use.

[0074] 7) 4°C Solution Stability Under the chromatographic conditions described in the present invention, a test solution of cefoperazone sodium and sulbactam sodium for injection was prepared with a solvent, placed at 4°C, and sampled at 0, 2, and 4 hours. The results are shown in Table 3. It can be seen from Table 3 that after the cefoperazone sodium and sulbactam sodium solution for injection was placed at 4°C for 2 hours, the absolute value of the change of each impurity did not exceed 0.05%. After 4 hours, the absolute value of the change of impurity I exceeded 0.05%, indicating that the cefoperazone sodium and sulbactam sodium solution for injection was stable after being placed at 4°C for 2 hours.

[0075] 8) Durability The test solution of cefoperazone sodium and sulbactam sodium for injection was taken, and the flow rate, column temperature, mobile phase A salt concentration and pH, and chromatographic column of the chromatographic conditions described in the present invention were slightly changed to examine the durability of the chromatographic conditions. The results showed that slight changes in the above chromatographic conditions did not affect the detection of cefoperazone sodium and sulbactam sodium polymers for injection and specific impurities.

[0076] Table 1 Precision results

[0077]

[0078] Table 2 Room temperature solution stability results

[0079]

[0080]

[0081] Table 3 4℃ solution stability results

[0082]

Claims

1. A polymer of cefoperazone sodium and sulbactam sodium for injection and a method for analyzing specific impurities, characterized in that The method for analyzing the polymer and specific impurities of cefoperazone sodium and sulbactam sodium for injection is to analyze the polymer and specific impurities by HPLC, and the specific operation is as follows: Step 1: Preparation of test solution Take cefoperazone sodium and sulbactam sodium for injection, place in a volumetric bottle, add solvent to dissolve and quantitatively dilute to the scale to obtain a test solution with a concentration of 1-10 mg / mL; Step 2: Preparation of control solution Take the test solution prepared in step 1, place it in a volumetric flask, quantitatively dilute it to the mark with solvent, shake well, and obtain a control solution with a concentration of 0.01-0.1 mg / mL; The chromatographic conditions are as follows: a C18 column is used as the chromatographic column; mobile phase A is 1 mmol / L to 10 mmol / L tetrabutylammonium hydroxide solution, wherein the pH value of the tetrabutylammonium hydroxide solution is adjusted to 3.0 to 4.0 with a phosphoric acid solution; mobile phase B is acetonitrile, and gradient elution is performed; column temperature is 25°C to 40°C; flow rate is 0.5 mL / min to 1.5 mL / min; injection volume is 10 μL; detection wavelength is 220 nm; sample concentration is 1 mg / mL to 10 mg / mL; The gradient elution program was as follows: 0→5 min, the amount of mobile phase A was 78%, and the amount of mobile phase B was 22%; 7→50 min, the amount of mobile phase A was 75%, and the amount of mobile phase B was 25%; 75→110 min, the amount of mobile phase A was 60%, and the amount of mobile phase B was 40%; 111→120 min, the amount of mobile phase A was 78%, and the amount of mobile phase B was 22%.

2. The polymer of cefoperazone sodium and sulbactam sodium for injection and the specific impurity analysis method according to claim 1, characterized in that The polymer is polymer A and impurity O; The polymer A is (6R, 7R)-7-((R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamide)-2-(-4-(((6R, 7R)-7-(R)-2-(4-ethyl 2,3-dioxopiperazine-1-carboxamide)-2-(4-hydroxyphenyls)-acetylamino)-3-(((1-methyl-1H-tetrol-5-ylethylene) (((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5-thio-1-azabicyclo[4.2.0]oct-2-yl-2-oct-2-en-2-one-2-ene-2-carbonyl)oxy)phenyl)acetamido)-3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5-thio-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid); The impurity O is (6R, 7R)-7-((6R, 7R)-7-((R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamide)-2-(-4-hydroxyphenyl)acetamide)-3-((((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxamide)-3-thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxamide) 3. The polymer of cefoperazone sodium and sulbactam sodium for injection and the specific impurity analysis method according to claim 1, characterized in that The specific impurities are impurity I and impurity J; The impurity I is 2-(carboxyl((R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-(4-hydroxyphenyl)acetamido)methyl)-5-methylene-5,6-dihydro-2H-1,3-thiazine-4-carboxylic acid; The impurity J is 2-(carboxy((R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-(4-hydroxyphenyl)acetamido)methyl)-5-methyl-2H-1,3-thiazine-4-carboxylic acid.

4. The polymer of cefoperazone sodium and sulbactam sodium for injection and the specific impurity analysis method according to claim 1, characterized in that The solvent in step 1 is a mixture of mobile phase A and mobile phase B in a volume ratio of 78:

22.

5. The polymer of cefoperazone sodium and sulbactam sodium for injection and the specific impurity analysis method according to claim 1, characterized in that The chromatographic column model is Kromasil 100-5-C18, with specifications of 250 mm×4.6 mm, 5 μm, and a ghost peak trapping column: 50 mm chromatographic column.

6. The polymer of cefoperazone sodium and sulbactam sodium for injection and the specific impurity analysis method according to claim 1, characterized in that The mobile phase A is a 5mmol / L tetrabutylammonium hydroxide solution, wherein the pH value of the tetrabutylammonium hydroxide solution is adjusted to 3.6 with a phosphoric acid solution, the mobile phase B is acetonitrile, and the gradient elution is performed; the column temperature is 30°C; the flow rate is 1.2mL / min; the injection volume is 10μl; the detection wavelength is 220nm; the sample concentration is 4mg / mL; the gradient elution program is: 0→5min, the amount of mobile phase A is 78%, and the amount of mobile phase B is 22%; 7→50min, the amount of mobile phase A is 75%, and the amount of mobile phase B is 25%; 75→110min, the amount of mobile phase A is 60%, and the amount of mobile phase B is 40%; 111→120min, the amount of mobile phase A is 78%, and the amount of mobile phase B is 22%.

7. The polymer of cefoperazone sodium and sulbactam sodium for injection and the specific impurity analysis method according to claim 1, characterized in that Preparation of HPLC test system suitability solution: Mixed impurity solution: Take appropriate amount of sulbactam impurity A, polymer A, and impurity O reference substance, dissolve in solvent and quantitatively dilute to make a solution containing about 0.4 mg per 1 ml; System suitability solution (1): Take about 100 mg of the test sample dried at 105°C for 2.5 hours, place it in a 25 ml volumetric flask, add 1 ml of the mixed impurity solution, dissolve it with solvent and dilute to the mark, shake well; System suitability solution (2): Take about 100 mg of the test sample dried at 60°C for 14 days, place it in a 25 ml volumetric flask, dissolve it with solvent and dilute it to the mark, and shake well.

8. The polymer of cefoperazone sodium and sulbactam sodium for injection and the specific impurity analysis method according to claim 7, characterized in that After the system suitability solution is injected into the liquid chromatograph, the separation degree between the impurity A peak and the sulbactam impurity A peak in the chromatogram of the system suitability solution (1) should be no less than 1.5, and the separation degree between the cefoperazone peak and the impurity G peak should be no less than 1.5, and the retention time of polymer A and impurity O is located. The retention time of specific impurities I and impurity J is located in the chromatogram of the system suitability solution (2).

9. The polymer of cefoperazone sodium and sulbactam sodium for injection and the specific impurity analysis method according to claim 1, characterized in that HPLC detection system sensitivity solution preparation: Take the control solution, place it in a volumetric bottle, quantitatively dilute it to the scale with solvent, shake well, and obtain a sensitivity solution with a concentration of 0.0005-0.005 mg / mL.

10. The polymer of cefoperazone sodium and sulbactam sodium for injection and the specific impurity analysis method according to claim 9, characterized in that After the sensitivity solution was injected into the liquid chromatograph, the signal-to-noise ratio of the cefoperazone peak in the chromatogram was greater than 10.

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