Crystal form of cefoperazone sodium and preparation method and application thereof

Abstract

The invention relates to a crystal form of cefoperazone sodium as well as a preparation method and application of the crystal form. The X-ray powder diffraction pattern of the crystal form has characteristic peaks when the 2theta value is 15.5 degrees + / -0.2 degrees, 18.4 degrees + / -0.2 degrees and 19.6 degrees + / -0.2 degrees. The crystal form of the cefoperazone sodium is a crystal structure with specific characteristic peaks, and compared with a crystal form A of the cefoperazone sodium, the novel crystal form of the cefoperazone sodium has lower residual solvents and water residues, higher content and better stability, and is beneficial to storage and preparation of pharmaceutical compositions. And during subsequent use, the pharmaceutical safety of the cefoperazone sodium and the composition thereof can be improved.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and particularly to a crystal form of cefoperazone sodium, a preparation method thereof, and an application thereof. Background Art

[0002] The chemical name of cefoperazone sodium is sodium (7-(((4-ethyl-2,3-dioxo-1-piperazinyl)carbonylamino)(4-hydroxyphenyl)acetylamino)-3-((1-methyl-1H-tetrazol-5-yl)thiomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate), with the molecular formula of C 25 H 26 9NNaO8S2, and the structural formula is shown in the following formula (1). The molecular weight is 667.66, and the appearance is white crystalline powder.

[0003]

[0004] Cefoperazone sodium is a third-generation cephalosporin. It has a weak effect on Gram-positive bacteria and is only sensitive to hemolytic streptococcus and pneumococcus. It is sensitive to most Gram-negative bacteria, has a strong tolerance to β-lactamase, and has a very low ability to induce the production of β-lactamase, making it not easy to induce bacteria to produce drug resistance. Clinically, it is used for infections in various parts such as the respiratory tract, urinary tract, peritoneum, pleura, skin and soft tissues, bones and joints, and facial features caused by various sensitive bacteria, and can also be used for septicemia and meningitis, etc. It has good therapeutic effects and safety for various infection symptoms in the respiratory tract, biliary tract, obstetrics and gynecology, surgery, etc.

[0005] Currently, the commercially available products are mainly A-crystal cefoperazone sodium prepared by a crystallization process, but this crystal form still has room for further improvement: firstly, solvent molecules are easily encapsulated during the crystal growth process, resulting in the residual solvent content in the final product being higher than 0.5% (for example, the acetone residue reaches more than 1.0%), which directly affects the purity index of the preparation; secondly, the content of the active pharmaceutical ingredient is relatively low, resulting in limited efficacy per unit dose; thirdly, the chemical stability is poor, and it is prone to degradation reactions under conventional storage conditions. Specifically, the product needs to be stored strictly in the dark and the environmental temperature should not exceed 20°C. The product has a short shelf life, posing potential risks to the convenience and safety of clinical medication, especially being significantly restricted in the application in primary medical institutions and tropical regions.

[0006] Although prior arts have attempted to alleviate the above problems through formulation process optimization (such as adding stabilizers, improving packaging materials, and filling inert gases), limited by the inherent structural characteristics of Form A, the improvement in stability has never broken through the storage temperature range limit. In recent years, studies have revealed that cefoperazone sodium exhibits polymorphism. However, due to the bottleneck in crystal form screening technology, no alternative crystal form with high crystallization purity, low solvent residue, and wide-temperature-range stability has been discovered so far, which severely restricts the accessibility of this drug in primary healthcare and tropical regions. Summary of the Invention

[0007] An object of the present invention is to provide a new crystal form of cefoperazone sodium with low solvent residue, high active ingredient content, and good stability, as well as a preparation method and application thereof.

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] An object of the present invention is to provide a crystal form of cefoperazone sodium, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 15.5°±0.2°, 18.4°±0.2°, and 19.6°±0.2°.

[0010] According to some specific embodiments, the X-ray powder diffraction pattern of the crystal form further has characteristic peaks at one or more of the 2theta values of 8.1°±0.2°, 12.2°±0.2°, 16.0°±0.2°, 17.6°±0.2°, 19.2°±0.2°, 23.2°±0.2°, 23.5°±0.2°, 23.9°±0.2°, and 28.6°±0.2°.

[0011] According to some specific embodiments, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2theta values of 8.1°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 18.4°±0.2°, and 19.6°±0.2°.

[0012] Furthermore, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2theta values of 8.1°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 23.2°±0.2°, 23.5°±0.2°, and 23.9°±0.2°.

[0013] Furthermore, the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2theta values of 8.1°±0.2°, 12.2°±0.2°, 15.5°±0.2°, 16.0°±0.2°, 17.6°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 19.6°±0.2°, 23.2°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 28.6°±0.2°.

[0014] According to some specific embodiments, the X-ray powder diffraction pattern of the crystal form is substantially the same as Figure 1 consistent.

[0015] According to some specific embodiments, the DSC pattern of the crystal form is substantially as Figure 2 shown.

[0016] According to some specific embodiments, the TGA pattern of the crystal form is substantially as Figure 3 shown.

[0017] According to some specific embodiments, the water content of the crystal form is less than 3%.

[0018] In a second aspect of the present invention, there is provided a method for preparing the crystal form as described above. Cefoperazone acid and a sodium-forming agent are mixed in a reaction solvent, and stirred to carry out a salt-forming reaction to obtain a cefoperazone sodium solution. After filtration, a crystallization solvent is added for crystallization, followed by filtration, washing, and drying to obtain the cefoperazone sodium crystal form;

[0019] Wherein, the reaction solvent includes methanol and other reaction solvents, and the other reaction solvents are selected from one or more of water, ethanol, and acetone;

[0020] The crystallization solvent includes methanol and other crystallization solvents, and the other crystallization solvents are selected from one or more of ethanol, acetone, propanol, isopropanol, butanol, isobutanol, sec-butanol, pentanol, sec-pentanol, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate.

[0021] According to some specific embodiments, in the reaction solvent, the feeding mass ratio of methanol to the other reaction solvents is 2 to 10:1, such as 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1.

[0022] According to some specific embodiments, in the crystallization solvent, the feeding mass ratio of methanol to the other crystallization solvents is 3 to 5:1, such as 3:1, 3.5:1, 4:1, 4.5:1, 5:1.

[0023] According to some specific embodiments, the mass ratio of cefoperazone acid to the reaction solvent is 1:3 to 4, such as 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.

[0024] According to some specific embodiments, the mass ratio of cefoperazone acid to the crystallization solvent is 1:10 to 15, such as 1:10, 1:10.5, 1:11, 1:11.5, 1:12, 1:12.5, 1:13, 1:13.5, 1:14, 1:14.5, 1:15.

[0025] According to some specific embodiments, the sodium-forming agent is selected from one or more of sodium isooctanoate, sodium acetate, crystalline sodium acetate, sodium bicarbonate, sodium carbonate, and sodium lactate.

[0026] According to some specific embodiments, the molar ratio of cefoperazone acid to the sodium-forming agent is 1:(0.95 to 2), such as 1:0.95, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, 1:1.55, 1:1.6, 1:1.65, 1:1.7, 1:1.75, 1:1.8, 1:1.85, 1:1.9, 1:1.95, 1:2.

[0027] According to some specific embodiments, the temperature of the crystallization is controlled to be 0 to 40 °C, such as 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C.

[0028] According to some specific embodiments, the time of the crystallization is controlled to be 0.5 to 5 h, such as 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h.

[0029] According to some specific embodiments, the temperature of the drying is 20 to 60 °C, such as 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C.

[0030] According to some specific embodiments, the drying time is 2 to 10 h, such as 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, 8.5 h, 9 h, 9.5 h, 10 h.

[0031] The third aspect of the present invention provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient comprises the crystal form of cefoperazone sodium as described above.

[0032] According to some specific embodiments, the pharmaceutical composition further comprises a β-lactamase inhibitor.

[0033] The fourth aspect of the present invention provides an application of the crystal form of cefoperazone sodium as described above or the pharmaceutical composition as described above in the preparation of an anti-inflammatory drug.

[0034] According to some specific embodiments, the anti-inflammatory drug comprises an anti-acute bronchitis drug and an anti-pneumonia drug.

[0035] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0036] The crystal form of cefoperazone sodium of the present invention has a crystal structure with specific characteristic peaks. Compared with the A crystal form of cefoperazone sodium, the new crystal form of cefoperazone sodium has lower residual solvents and water residues, higher content, and better stability, which is beneficial for storage and preparation of pharmaceutical compositions. When used subsequently, it is beneficial to improve the medication safety of cefoperazone sodium and its compositions.

[0037] The preparation method of the new crystal form of cefoperazone sodium proposed by the present invention is simple, the process is stable, and it is easy to carry out industrial production and promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 XRPD diagram of the crystal form of Example 1;

[0039] Figure 2 DSC diagram of the crystal form of Example 1;

[0040] Figure 3 TGA diagram of the crystal form of Example 1;

[0041] Figure 4 XRPD diagram of crystal form A of Comparative Example 1;

[0042] Figure 5 DSC diagram of crystal form A of Comparative Example 1;

[0043] Figure 6 TGA diagram of crystal form A of Comparative Example 1;

[0044] Figure 7 XRPD diagram of crystal form A of Comparative Example 2. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0045] The present invention will be further elaborated through specific embodiments below, but it is not intended to limit the protection scope of the present invention. Those skilled in the art can make improvements to the preparation method and the instruments used within the scope of the claims, and these improvements should also be regarded as within the protection scope of the present invention. Therefore, the protection scope of this invention patent shall be subject to the appended claims.

[0046] The percentages not specified in the present invention are mass percentages.

[0047] XRPD: X-ray powder diffraction; DSC: differential scanning calorimetry; TGA: thermogravimetric analysis.

[0048] X-ray powder diffraction (XRPD): The XRPD pattern was collected on a Bruker D8 Advance DA VINCI X-ray powder diffractometer, and the XRPD parameters are as shown in Table 1 below.

[0049] Table 1

[0050]

[0051] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC): The TGA and DSC patterns were collected on a TA Q500 / 5000 thermogravimetric analyzer and a TA Q200 / 2000 differential scanning calorimeter respectively, and the test parameters are as shown in Table 2 below.

[0052] Table 2

[0053]

[0054]

[0055] The determination of water content, active ingredient content, and residual solvents refers to the relevant regulations of cefoperazone sodium in Part II of the Chinese Pharmacopoeia 2020 Edition.

[0056] Detection methods and detection conditions for the contents of impurity A and impurity C:

[0057] Related substances: Determined by reference to the high performance liquid chromatography method (General Principles 0512, Section IV of the Chinese Pharmacopoeia 2020 Edition). Prepared freshly before use.

[0058] Test solution: Take this product, weigh accurately, dissolve it with a small amount of water, and quantitatively dilute it with mobile phase A to prepare a solution containing about 0.5 mg per 1 ml.

[0059] Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute it to the mark with mobile phase A, and shake well.

[0060] System suitability solution: Accurately weigh about 2.5 mg each of reference substances of impurity A and impurity C, and place them separately in 10-ml volumetric flasks. For impurity A, first dissolve it with a small amount of acetonitrile, and for impurity C, first dissolve it with a small amount of phosphate buffer solution (take 39.0 ml of 0.2 mol / L sodium dihydrogen phosphate solution and 61.0 ml of 0.2 mol / L disodium hydrogen phosphate solution, mix well, and adjust the pH value to 7.0 with phosphoric acid), then dilute to the mark with mobile phase A to obtain the stock solutions of each impurity reference substance. Accurately weigh about 10 mg of this product, place it in a 20-ml volumetric flask, add 1 ml of water to dissolve it, add 0.3 ml of each stock solution of the impurity reference substance respectively, dilute to the mark with mobile phase A, and shake well.

[0061] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (4.6 mm × 150 mm, 5 μm); use phosphate buffer solution (take 1.32 g of ammonium hydrogen phosphate, dissolve and dilute to 750 ml with water, adjust the pH value to 2.5 with phosphoric acid)-methanol (99:1) as mobile phase A, and methanol as mobile phase B, with a flow rate of 1.0 ml per minute; the column temperature is 28 °C; the detection wavelength is 254 nm; the injection volume is 20 μl; perform linear gradient elution according to Table 3 below.

[0062] Table 3

[0063]

[0064] System suitability requirements: In the chromatogram of the system suitability solution, impurity C, impurity A, and cefoperazone elute in sequence, and the resolution between each chromatographic peak should meet the requirements. The number of theoretical plates calculated based on the cefoperazone peak should be not less than 3000.

[0065] Assay method: Accurately measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively, and record the chromatogram.

[0066] Limit: If there are impurity peaks in the chromatogram of the test solution, calculate the impurity content by the self-control method of the main component multiplied by the correction factor, and all should meet the corresponding limit regulations in Table 4 below. Peaks less than 0.05 times the main peak area of the reference solution are ignored.

[0067] Table 4

[0068]

[0069] Example 1 Preparation of a new crystal form of cefoperazone sodium

[0070] Preparation of the sodium-forming agent solution: Add 8 g of water and 10 g of methanol, start stirring, add 4.3 g of crystalline sodium acetate, and dissolve until clear for standby.

[0071] Add 40 g of methanol and 10 g of acetone into the reaction flask, put in 20 g of cefoperazone acid, control the temperature at 15 - 25°C, add the prepared sodium-forming agent solution, dissolve, and filter. Control the temperature at 20 - 30°C, add seed crystals, and stir for crystal cultivation for 1 - 2 hours. After the crystal cultivation is completed, add a mixed solution of 160 g of methanol and 40 g of acetone, stir for crystal cultivation for 1 - 2 hours, and after completion, filter. After filtration, wash the crystals twice with a mixed solution of methanol and acetone (where the mass ratio of methanol to acetone is 4:1). Control the drying temperature at 40 - 50°C, dry until the water content is less than 1.0%, and obtain 18 g of cefoperazone sodium, with a water content of 0.8%, a content of 96.2%, an acetone residue of 0.05%, and a methanol residue of 0.1%.

[0072] After detection, the XRPD pattern of the obtained cefoperazone sodium solid is as shown in Figure 1 , and the XRPD data are shown in Table 5 below. The DSC pattern is as shown in Figure 2 , and the TGA pattern is as shown in Figure 3 . Figure 2 The DSC result in Figure 3 shows that the sample has an exothermic decomposition characteristic peak above 210°C.

[0073] Table 5

[0074]

[0075] Table 5 - Continued

[0076]

[0077] Preparation of a new crystal form of cefoperazone sodium in Example 2

[0078] Preparation of the sodium-forming agent solution: Add 10 g of water and 10 g of methanol, start stirring, add 5.2 g of sodium isooctanoate, and dissolve and set aside for use after clarification.

[0079] Add 50 g of methanol into the reaction flask, put in 20 g of cefoperazone acid, control the temperature at 15 - 25°C, add the prepared sodium-forming agent solution, dissolve, and filter. Control the temperature at 20 - 30°C, add seed crystals, and stir for crystal cultivation for 1 - 2 hours. After the crystal cultivation is completed, add a mixed solution of 160 g of methanol and 40 g of ethyl acetate, stir for crystal cultivation for 1 - 2 hours, and after completion, filter. After filtration, wash the crystals twice with a mixed solution of methanol and ethyl acetate (where the mass ratio of methanol to ethyl acetate is 4:1). Control the drying temperature at 40 - 50°C, dry until the water content is less than 1.0%, and obtain 18 g of cefoperazone sodium, with a water content of 0.7%, a content of 96.1%, an ethyl acetate residue of 0.12%, and a methanol residue of 0.1%.

[0080] Preparation of a new crystal form of cefoperazone sodium in Example 3

[0081] Preparation of sodium-forming agent solution: Add 10 g of water and 1 g of sodium bicarbonate, dissolve until clear and set aside. Add 1.6 g of sodium acetate and 10 g of methanol, dissolve until clear and set aside.

[0082] Add 50 g of methanol to the reaction flask, put in 20 g of cefoperazone acid, control the temperature at 15 - 25°C, add the prepared sodium-forming agent solution, dissolve, and filter. Control the temperature at 20 - 30°C, add seed crystals, and stir for crystal cultivation for 1 - 2 hours. After the crystal cultivation is completed, add a mixture of 200 g of methanol and 60 g of ethanol, stir for crystal cultivation for 1 - 2 hours. After completion, filter. After filtration, wash the crystals twice with methanol. Control the drying temperature at 40 - 50°C, dry until the water content is less than 1.0%, and obtain 17.5 g of cefoperazone sodium, with a water content of 0.6%, a content of 96.5%, a methanol residue of 0.12%, and an ethanol residue of 0.20%.

[0083] After testing, the crystal forms of cefoperazone sodium prepared in Example 2 and Example 3 are the same as that in Example 1.

[0084] Preparation of cefoperazone sodium A crystal form in Comparative Example 1

[0085] Preparation of sodium-forming agent solution: Add 26.5 g of water and 2.65 g of sodium bicarbonate, dissolve until clear and set aside.

[0086] Add 50 g of acetone to the reaction flask, put in 20 g of cefoperazone acid. Add the prepared sodium bicarbonate solution, dissolve, and filter. Control the temperature at 10 - 25°C, add seed crystals, and crystallize for 2 - 5 hours. Continue to control the temperature at 10 - 25°C, and add 360 g of acetone. After the feeding is completed, carry out crystal cultivation for 2 - 5 hours. After the crystal cultivation is completed, filter. After filtration, wash the crystals with acetone. Control the drying temperature at 40 - 50°C. Dry until the water content is less than 5%, and obtain 19 g of cefoperazone sodium, with a water content of 4.2%, a content of 94.2%, and an acetone residue of 1.5%.

[0087] After testing, the XRPD pattern of the obtained cefoperazone sodium solid is as Figure 4 shown, and it is cefoperazone sodium A crystal form.

[0088] The DSC pattern is as Figure 5 shown, and the TGA pattern is as Figure 6 . Figure 5 The DSC result in Figure 6 shows that the sample has an exothermic decomposition characteristic peak at 198 ± 2°C.

[0089] Comparative Example 2

[0090] This example is basically the same as Comparative Example 1, except for the drying step. After crystal washing in this example, the temperature was controlled at 60°C and dried until the water content was <1.0%, obtaining 18.6 g of cefoperazone sodium, with a water content of 0.8% and a content of 94.5%, and an acetone residue of 0.3%.

[0091] After testing, the XRPD pattern of the obtained cefoperazone sodium solid is as Figure 7 shown, and it is also the A crystal form of cefoperazone sodium.

[0092] The crystal forms obtained in Example 1, Comparative Example 1, and Comparative Example 2 were placed at 60°C and RH60% for 5 days under closed conditions, and the water content of the crystal forms, the content of cefoperazone sodium, the residual amount of the solvent, and the contents of impurity A and impurity C were detected before and after placement according to the internal control method. The test results are shown in Table 6 below.

[0093] Table 6

[0094]

[0095]

[0096] Through the optimization of the crystal structure of cefoperazone sodium, the present invention has significantly overcome the key defects of the existing A crystal form: First, due to the improved molecular arrangement density of the new crystal form, the phenomenon of solvent entrapment inside the crystal is significantly reduced, resulting in a 90% decrease in the residual solvent content compared to Comparative Example 1 and a 50% decrease compared to Comparative Example 2, directly improving the purity of the active pharmaceutical ingredient and reducing the risk of toxic and side effects during clinical use; Second, the increased lattice energy after improvement inhibits the molecular degradation under high-temperature environments, and the accelerated test shows that the related substance content is significantly lower than that of Comparative Example 1 and Comparative Example 2, enabling the drug to be stably stored in the conventional temperature range, greatly reducing the cold-chain transportation cost and broadening the clinical application scenario; Third, the optimized crystallization process increases the content of the active ingredient to more than 96% (the original process ≤94.2%), ensuring the accurate control of the efficacy per unit dose.

[0097] In addition, the performance of the crystal form of the present invention in terms of dissolution rate and solution stability is basically equivalent to that of crystal form A, and it can be expected that the bioavailability and pharmacokinetic behavior of the present invention have no significant difference from those of crystal form A.

[0098] As an injectable powder for injection, the clinical efficacy of cefoperazone sodium directly depends on the physicochemical properties of the solution after dissolution (such as pH, osmotic pressure, particle size distribution). According to the general consensus in pharmacy, when the key parameters of the solution are the same, the bioavailability and pharmacokinetic behavior of the active ingredient will have no significant difference. Therefore, the technological progress of the present invention focuses on solving the bottleneck problems in the production and circulation links of the active pharmaceutical ingredient, and its effects have been fully verified by objective data such as physicochemical property comparison and stability accelerated test.

[0099] The above embodiments are only for illustrating the technical concept and features of the present invention, and the purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. It is not intended to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. A crystal form of cefoperazone sodium, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2theta values ​​of 15.5°±0.2°, 18.4°±0.2°, and 19.6°±0.2°.

2. The crystal form of cefoperazone sodium according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystal form also has characteristic peaks at one or more of the 2theta values ​​of 8.1°±0.2°, 12.2°±0.2°, 16.0°±0.2°, 17.6°±0.2°, 19.2°±0.2°, 23.2°±0.2°, 23.5°±0.2°, 23.9°±0.2°, and 28.6°±0.2°.

3. The crystal form of cefoperazone sodium according to claim 1, characterized in that: The X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2theta values ​​of 8.1°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 18.4°±0.2°, and 19.6°±0.2°.

4. The crystal form of cefoperazone sodium according to claim 3, characterized in that: The X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2theta values ​​of 8.1°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 18.4°±0.2°, 19.6°±0.2°, 23.2°±0.2°, 23.5°±0.2°, and 23.9°±0.2°.

5. The crystal form of cefoperazone sodium according to claim 4, characterized in that: The X-ray powder diffraction pattern of the crystal form has characteristic peaks at 2theta values ​​of 8.1°±0.2°, 12.2°±0.2°, 15.5°±0.2°, 16.0°±0.2°, 17.6°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 19.6°±0.2°, 23.2°±0.2°, 23.5°±0.2°, 23.9°±0.2°, and 28.6°±0.2°.

6. The crystalline form of cefoperazone sodium according to any one of claims 1 to 5, characterized in that: The X-ray powder diffraction pattern of the crystal form is basically consistent with Figure 1.

7. The crystalline form of cefoperazone sodium according to any one of claims 1 to 5, characterized in that: The moisture content of the crystalline form is less than 3%.

8. A method for preparing the crystal form according to any one of claims 1 to 7, characterized in that: The cefoperazone acid and the sodium-forming agent are mixed in a reaction solvent, stirred for salt-forming reaction, and a cefoperazone sodium solution is obtained, filtered, Add a crystallization solvent for crystallization, filter, wash, and dry to obtain the cefoperazone sodium crystal form; Wherein, the reaction solvent includes methanol and other reaction solvents, and the other reaction solvents are selected from one or more of water, ethanol, and acetone; The crystallization solvent includes methanol and other crystallization solvents, and the other crystallization solvents are selected from one or more of ethanol, acetone, propanol, isopropanol, butanol, isobutanol, sec-butanol, amyl alcohol, sec-amyl alcohol, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate.

9. The preparation method according to claim 8, characterized in that: In the reaction solvent, the feed mass ratio of the methanol to the other reaction solvent is 2 to 10:1; and / or, In the crystallization solvent, the feeding mass ratio of the methanol to the other crystallization solvent is 3 to 5:

1.

10. The preparation method according to claim 8, characterized in that: The feed mass ratio of the cefoperazone acid to the reaction solvent is 1:3-4; and / or the feed mass ratio of the cefoperazone acid to the crystallization solvent is 1:10-15.

11. The preparation method according to claim 8, characterized in that: The sodium-forming agent is selected from one or more of sodium octanoate, sodium acetate, crystalline sodium acetate, sodium bicarbonate, sodium carbonate, and sodium lactate; the molar ratio of the cefoperazone acid to the sodium-forming agent is 1:(0.95-2).

12. The preparation method according to claim 8, characterized in that: The crystallization temperature is controlled to be 0-40°C, and the crystallization time is 0.5-5h; the drying temperature is controlled to be 20-60°C, and the drying time is controlled to be 2-10h.

13. A pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable carrier, characterized in that: The active ingredient comprises the crystalline form of cefoperazone sodium according to any one of claims 1 to 7.

14. The pharmaceutical composition according to claim 13, characterized in that: The pharmaceutical composition also includes a β-lactamase inhibitor.

15. Use of the crystal form of cefoperazone sodium according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 13 or 14 in the preparation of an anti-inflammatory drug.

16. The use according to claim 15, characterized in that: The anti-inflammatory drugs include anti-acute bronchitis drugs and anti-pneumonia drugs.

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