Preparation method and application of cefoperazone sodium and sulbactam sodium for injection

Abstract

The invention discloses a preparation method and application of cefoperazone sodium and sulbactam sodium for injection, and relates to the field of preparation methods of cefoperazone sodium and sulbactam sodium, and the preparation method comprises preparation of cefoperazone sodium and preparation of a mixed solution. The preparation of the mixed solution comprises the following steps: weighing sulbactam sodium and the prepared cefoperazone sodium, adding the sulbactam sodium and the prepared cefoperazone sodium into a sodium chloride injection, dissolving, adding a phosphate buffer solution, filtering, adding valine into the solution, dispersing, and filtering to obtain the mixed solution. Sequentially carrying out freeze-drying treatment, drying, crushing, screening and re-drying on the dispersed mixed solution to obtain the cefoperazone sodium sulbactam sodium for injection. The mass ratio of the cefoperazone sodium to the sulbactam sodium is (1-5): 1. The valine is added into the mixed solution and the process is optimized, so that the valine and the cefoperazone sodium can form hydrogen bonds and electrostatic interaction, and the purpose of improving the stability of the cefoperazone sodium sulbactam sodium for injection with high cefoperazone sodium content is achieved.

Description

Technical Field

[0001] The present invention relates to the field of preparation methods of cefoperazone sodium and sulbactam sodium, and particularly relates to a preparation method and application of cefoperazone sodium and sulbactam sodium for injection. Background Art

[0002] Cefoperazone sodium and sulbactam sodium is a compound antibiotic composed of cefoperazone sodium (a third-generation cephalosporin antibiotic) and sulbactam sodium (a β-lactamase inhibitor). This combination can enhance the antibacterial effect by inhibiting bacterial cell wall synthesis (the function of cefoperazone sodium) and protecting the antibiotic from β-lactamase destruction (the function of sulbactam sodium).

[0003] Traditionally, the combination ratio of cefoperazone sodium and sulbactam sodium is usually 1:1 or 2:1. Because at a ratio of 1:1, sulbactam sodium can effectively inhibit the β-lactamase produced by bacteria, thereby enhancing the antibacterial activity of cefoperazone sodium. However, cefoperazone sodium will cause a decrease in the stability of the solution at higher concentrations, especially when conditions such as pH value, temperature, and light change. Therefore, in the prior art, a mass ratio higher than 2:1 is usually avoided to prevent the concentration of cefoperazone sodium from being too high and affecting the overall stability. However, in some clinical applications, the maximum daily dose of sulbactam sodium is limited to 4 g. Different infection types and patient groups have different drug requirements, and children and patients with renal insufficiency also need to strictly control the dose of sulbactam sodium, resulting in safety problems in effective drug use.

[0004] In view of this, the present application is specifically proposed. Summary of the Invention

[0005] The purpose of the present invention is to provide a preparation method and application of cefoperazone sodium and sulbactam sodium for injection. By adding valine to the mixed solution and optimizing the process, valine can form hydrogen bonds and electrostatic interactions with cefoperazone sodium to solve the problem of poor stability when the ratio of cefoperazone sodium is greater than 2 in the prior art.

[0006] The embodiments of the present invention are implemented through the following technical solutions: The embodiments of the present invention provide a preparation method of cefoperazone sodium and sulbactam sodium for injection, including the preparation of cefoperazone sodium and the preparation of a mixed solution. Among them,

[0007] The preparation of the mixed solution includes weighing sulbactam sodium and the prepared cefoperazone sodium, adding them to sodium chloride injection for dissolution, continuously adding phosphate buffer solution, stirring until completely dissolved, filtering, adding valine to the solution for dispersion, and subjecting the dispersed mixed solution to freeze-drying treatment, first drying, crushing and screening, and second drying in sequence to obtain cefoperazone sodium and sulbactam sodium for injection;

[0008] Among them, the mass ratio of cefoperazone sodium to sulbactam sodium is 1-5:1.

[0009] In the embodiment of the present invention, valine, as a branched-chain amino acid, has the functions of regulating the pH value of the solution and buffering. At the same time, it can form hydrogen bonds and electrostatic interactions with cefoperazone sodium, thereby reducing the degradation risk. The addition of valine can regulate the pH value of the solution and cooperate with the phosphate buffer solution to maintain a stable acid-base environment, reducing drug degradation caused by pH changes. At the same time, the buffering capacity of valine can further optimize the crystallization environment and reduce the mixing of impurities. The mass ratio of cefoperazone sodium to sulbactam sodium in the cefoperazone sodium and sulbactam sodium for injection prepared by this process can reach 5:1, which can provide a stronger antibacterial effect, while reducing the dosage of sulbactam sodium and avoiding potential risks to patients caused by too high a concentration of sulbactam sodium.

[0010] Sodium chloride injection provides an isotonic environment, which helps to maintain the solubility of the drug. Isotonic solutions can reduce precipitation or aggregation of the drug caused by osmotic pressure changes. At the same time, the phosphate ions in PBS can have a weak interaction with drug molecules, further enhancing the solubility of the drug. Valine reduces the possibility of degradation by forming hydrogen bonds and electrostatic interactions with drug molecules, and this effect is more significant in the combination of sodium chloride injection and PBS because they jointly maintain the stability and solubility of the solution.

[0011] Valine has high chemical stability at room temperature, with a decomposition temperature of 315 °C, and is stable to heat, light and air. It also has a certain solubility in water and can form a clear solution, avoiding the appearance of insoluble particles in the injection. Valine is a glucogenic amino acid that can generate glucose in the body through gluconeogenesis to provide energy for patients. At the same time, valine is also a branched-chain amino acid that is mainly metabolized in muscle tissue rather than in the liver, and will not affect the antibacterial activity of cefoperazone sodium, let alone interfere with the pharmacological effect of cefoperazone sodium. If other amino acids are added, the cefoperazone sodium and sulbactam sodium for injection obtained are inferior to the embodiment of the present invention in terms of rapid energy supply, solubility, stability, pharmacological interference, etc.

[0012] Optionally, the mass ratio of valine to the total mass of cefoperazone sodium and sulbactam sodium is 0.10-0.17:1, and the mass ratio of cefoperazone sodium to sulbactam sodium is 2.5-5:1.

[0013] Specifically, by controlling the precise dosage of valine, the stability of cefoperazone sodium and sulbactam sodium for injection with a mass ratio of cefoperazone sodium to sulbactam sodium of 2.5-5:1 can be significantly improved. If the dosage of valine is too low, its buffering capacity is not sufficient to maintain the stable pH value of the solution, which will lead to the degradation of cefoperazone sodium and sulbactam sodium. If the dosage of valine is too high, the production cost will increase.

[0014] Optionally, the preparation of cefoperazone sodium includes dissolving cefoperazone acid in pure water, then adding sodium hydroxide solution to the solution. After the reaction is completed, crystallization, filtration, washing with a solvent, and drying are carried out in sequence to obtain cefoperazone sodium.

[0015] Specifically, after the reaction is completed, crystallization is carried out by controlling the temperature and stirring speed. The crystallization process can be carried out at 15 - 18 °C, and a solvent (such as ethyl acetate) is added dropwise to promote crystallization. After crystallization is completed, the crystals are washed with a solvent to remove impurities, and then vacuum dried at 40 °C for 10 hours to obtain high-purity cefoperazone sodium.

[0016] Optionally, in the preparation of cefoperazone sodium, after adding sodium hydroxide solution, the pH value is controlled at 6.6 - 6.8. This pH range can ensure that the reaction between cefoperazone acid and sodium hydroxide is complete, and at the same time avoid drug degradation caused by too high a pH value.

[0017] Optionally, the crystallization process includes the following steps:

[0018] In the first stage, the temperature is controlled at 15 - 18 °C, ethyl acetate is added dropwise with stirring, the dropping time is controlled at 10 - 15 minutes, and the dropping amount of ethyl acetate is 10% - 20% of the volume of the reaction solution;

[0019] In the second stage, the temperature is maintained at 15 - 18 °C, and stirring is continued for 30 - 60 minutes until crystals begin to precipitate;

[0020] In the third stage, the temperature is lowered to 10 - 15 °C, and stirring is continued for 30 - 60 minutes to further promote crystal precipitation;

[0021] In the fourth stage, the temperature is lowered to 5 - 10 °C, left standing for 1 hour, and finally the temperature is lowered to 0 - 5 °C and stirred for 30 minutes to ensure complete crystal precipitation.

[0022] Specifically, by sequentially combining the increased low-temperature standing stage (5 - 10 °C, standing for 1 hour) and the final cooling stage (0 - 5 °C, stirring for 30 minutes), solvent residues can be reduced, the purity of the crystals can be further improved, and the mixing of impurities can be reduced.

[0023] Optionally, the mass fraction of the sodium chloride injection is 0.88 - 0.92%, preferably 0.9%, to ensure the stability and safety of the drug.

[0024] Optionally, the pH of the phosphate buffer solution is 6.5 - 6.8, which helps to maintain the chemical stability of the drug and at the same time reduces the introduction of impurities.

[0025] Optionally, the temperature for freeze-drying treatment is -35 °C to -45 °C, and the freeze-drying time is 3 - 5 hours to ensure the stability of the drug and the integrity of the active ingredients.

[0026] Optionally, both the first drying and the second drying are vacuum drying. The temperature of the first drying is 40 - 50°C, and the drying time is 60 - 80 minutes. The temperature of the second drying is 25 - 35°C, and the drying time is 50 - 60 minutes, ensuring that the drug remains stable during the drying process, while removing excess moisture to guarantee the quality of the final product.

[0027] To better solve the above problems, an embodiment of the present invention also provides an application of cefoperazone sodium and sulbactam sodium for injection, specifically using the prepared cefoperazone sodium and sulbactam sodium for injection after dissolution for injection.

[0028] Compared with the prior art, the embodiment of the present invention has the following advantages and beneficial effects:

[0029] 1. In the preparation process of the mixed solution in the embodiment of the present invention, valine is added. As a branched-chain amino acid, valine has the functions of regulating the pH value of the solution and buffering, and can simultaneously form hydrogen bonds and electrostatic interactions with cefoperazone sodium, thereby reducing the degradation risk. The combined action of valine and phosphate buffer solution can more effectively maintain the stability of the solution, reduce the degradation of the drug during storage and use, enabling the mass ratio of cefoperazone sodium to sulbactam sodium in the cefoperazone sodium and sulbactam sodium for injection prepared in the embodiment of the present invention to reach 5:1, and the cefoperazone sodium and sulbactam sodium for injection can maintain good stability during long-term storage.

[0030] 2. The combined use of sodium chloride injection and phosphate buffer solution in the embodiment of the present invention can provide a stable pH environment for cefoperazone sodium and sulbactam sodium. The buffering capacity of PBS can effectively maintain the pH value of the solution within the physiological range, which is crucial for the stability of valine, because as an amino acid, the stability of valine is greatly affected by the pH value. Specifically, sodium chloride injection provides an isotonic environment, which helps to maintain the solubility of the drug. Isotonic solutions can reduce precipitation or aggregation phenomena caused by changes in osmotic pressure of the drug. At the same time, phosphate ions in PBS can have a weak interaction with drug molecules, further enhancing the solubility of the drug. Valine reduces the possibility of degradation by forming hydrogen bonds and electrostatic interactions with drug molecules, and this effect is more significant under the combination of sodium chloride injection and PBS because they jointly maintain the stability and solubility of the solution.

[0031] 3. In the embodiments of the present invention, ethyl acetate is preferably used as the solvent. It has moderate polarity and volatility and can be evenly released during the crystallization process, reducing the aggregation of valine. Since the high polarity of ethanol will affect the stability of valine, causing it to be over-dispersed in the solution and reducing its protective effect on the drug, and the high volatility of acetone will cause the rapid precipitation of valine, affecting its uniform distribution.

[0032] 4. The embodiments of the present invention adopt a four-stage crystallization method. By sequentially combining the increased low-temperature static stage (5 - 10°C, static for 1 hour) and the final cooling stage (0 - 5°C, stirring for 30 minutes), it is possible to reduce solvent residues, further improve the purity of the crystals, and reduce the mixing of impurities.

[0033] 5. By controlling the precise dosage of valine in the embodiments of the present invention, the stability of cefoperazone sodium and sulbactam sodium for injection with a mass ratio of cefoperazone sodium to sulbactam sodium of 2.5 - 5:1 can be significantly improved. If the dosage of valine is too low, its buffering capacity is insufficient to maintain the stable pH value of the solution, which will lead to the degradation of cefoperazone sodium and sulbactam sodium. If the dosage of valine is too high, the production cost will increase. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, other related drawings can also be obtained based on these drawings without creative efforts.

[0035] Figure 1 It is a degradation situation diagram of cefoperazone sodium and sulbactam sodium for injection prepared in Example 1;

[0036] Figure 2 It is a degradation situation diagram of cefoperazone sodium and sulbactam sodium for injection prepared in Example 6;

[0037] Figure 3 It is a comparative degradation situation diagram of cefoperazone sodium and sulbactam sodium for injection prepared in Example 1 and Example 8;

[0038] Figure 4 It is a comparative degradation situation diagram of cefoperazone sodium and sulbactam sodium for injection prepared in Example 1 and Comparative Example 1;

[0039] Figure 5 It is a comparative degradation situation diagram of cefoperazone sodium and sulbactam sodium for injection prepared in Example 1 and Comparative Example 3. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0040] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. The components of the embodiments of the present invention described and shown in the accompanying drawings here can be arranged and designed in various different configurations.

[0041] Therefore, the following detailed description of the embodiments of the present invention provided in the accompanying drawings is not intended to limit the scope of the claimed present invention, but merely represents selected embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0042] It should be noted that similar reference numerals and letters denote similar items in the following drawings. Therefore, once an item is defined in one drawing, it does not need to be further defined and explained in subsequent drawings.

[0043] In the description of the present invention, it should be noted that the terms "first", "second", "third", etc. are only used for descriptive distinction and cannot be construed as indicating or implying relative importance.

[0044] Embodiment

[0045] An embodiment of the present invention provides a preparation method of cefoperazone sodium and sulbactam sodium for injection, including the following:

[0046] I. Preparation of cefoperazone sodium

[0047] 1. Dissolve cefoperazone acid: Weigh 100 g of cefoperazone acid and add it to 500 mL of pure water, and stir until completely dissolved.

[0048] 2. Adjust the pH value: Slowly add 0.1 mol / L sodium hydroxide solution, and at the same time monitor the pH value of the solution with a pH meter, and adjust it to 6.6 - 6.8.

[0049] 3. Crystallization process

[0050] The first stage: Control the temperature of the reaction solution at 15 - 18 °C, and dropwise add ethyl acetate with stirring. The dropping time is controlled within 10 - 15 minutes, and the dropping amount of ethyl acetate is 10% - 20% of the volume of the reaction solution;

[0051] The second stage: Keep the temperature at 15 - 18 °C and continue to stir for 30 - 60 minutes to observe the start of crystal precipitation;

[0052] The third stage: Lower the temperature to 10 - 15 °C and continue to stir for 30 - 60 minutes to further promote crystal precipitation;

[0053] Fourth stage: Lower the temperature to 5 - 10 °C, let it stand for 1 hour, and finally cool it down to 0 - 5 °C and stir for 30 minutes to ensure complete precipitation of crystals.

[0054] 4. Filtration and washing: Use filter paper to filter and collect the crystals, and wash the crystals with an appropriate amount of ethyl acetate.

[0055] 5. Drying: Place the washed crystals in a drying oven and dry them to a constant weight at 45 °C.

[0056] II. Preparation of the mixed solution

[0057] 1. Weigh the raw materials: Weigh cefoperazone sodium and sulbactam sodium according to a mass ratio of 1 - 5:1.

[0058] 2. Dissolve the raw materials: Add the weighed cefoperazone sodium and sulbactam sodium into an appropriate amount of sodium chloride injection (mass fraction is 0.88% - 0.92%), and stir until completely dissolved.

[0059] 3. Add phosphate buffer solution: Continue to add phosphate buffer solution with a pH value of 6.5 - 6.8 to the solution, and stir until completely dissolved. The preparation method of the phosphate buffer solution is as follows:

[0060] pH 6.5: Take 0.68 g of potassium dihydrogen phosphate, add 15.2 mL of 0.1 mol / L sodium hydroxide solution, and dilute it to 100 mL with water.

[0061] pH 6.8: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution, add 118 mL of 0.2 mol / L sodium hydroxide solution, and dilute it to 1000 mL with water.

[0062] 4. Add valine: Calculate the dosage of valine so that its total mass ratio with cefoperazone sodium and sulbactam sodium is 0.10 - 0.17:1, add valine to the solution, and stir until completely dispersed.

[0063] 5. Filter the mixed solution using a microporous membrane to remove insoluble impurities.

[0064] III. Freeze-drying and drying treatment

[0065] 1. Freeze-drying treatment: Place the filtered mixed solution in a freeze-dryer, set the temperature to -35 °C to -45 °C, and the freeze-drying time to 3 to 5 hours.

[0066] 2. First vacuum drying: Place the freeze-dried solid in a vacuum drying oven, set the temperature to 40 - 50 °C, and the drying time to 60 - 80 minutes.

[0067] 3. Crushing and screening: Screen the crushed powder through a screening device using a sieve with a mesh aperture of 80 meshes to select the powder that meets the particle size requirements. For the larger particles that do not pass through the sieve, they can be crushed again until the particle size requirements are met.

[0068] 4. Second vacuum drying: Place the screened powder in a vacuum drying oven again, set the temperature to 25 - 35 °C, and the drying time to 50 - 60 minutes to obtain the powder of cefoperazone sodium and sulbactam sodium for injection. Finally, aseptically dispense the powder into injection vials and seal for storage.

[0069] Example 1

[0070] The embodiment of the present invention provides a preparation method of cefoperazone sodium and sulbactam sodium for injection, including the following steps:

[0071] I. Preparation of cefoperazone sodium

[0072] 1. Dissolve cefoperazone acid: Weigh 100 g of cefoperazone acid and add it to 500 mL of pure water, stir until completely dissolved.

[0073] 2. Adjust the pH value: Slowly add 0.1 mol / L sodium hydroxide solution while monitoring the pH value of the solution with a pH meter and adjust it to 6.7.

[0074] 3. Crystallization process

[0075] The first stage: Control the temperature of the reaction solution at 16 °C, and add ethyl acetate dropwise with stirring. The dropping time is controlled within 12 minutes, and the dropping amount of ethyl acetate is 15% of the volume of the reaction solution.

[0076] The second stage: Keep the temperature at 16 °C and continue stirring for 45 minutes to observe the start of crystal precipitation.

[0077] The third stage: Lower the temperature to 12 °C and continue stirring for 45 minutes to further promote crystal precipitation.

[0078] The fourth stage: Lower the temperature to 8 °C, let it stand for 1 hour, and finally lower the temperature to 3 °C and stir for 30 minutes to ensure complete crystal precipitation.

[0079] 4. Filtration and washing: Filter and collect the crystals using filter paper, and wash the crystals with an appropriate amount of ethyl acetate.

[0080] 5. Drying: Place the washed crystals in a drying oven and dry them to a constant weight at 45 °C.

[0081] II. Preparation of the mixed solution

[0082] 1. Weigh the raw materials: Weigh cefoperazone sodium and sulbactam sodium according to a mass ratio of 3:1.

[0083] 2. Dissolve the raw materials. Add the weighed cefoperazone sodium and sulbactam sodium into an appropriate amount of sodium chloride injection (mass fraction is 9%), and stir until completely dissolved.

[0084] 3. Add phosphate buffer solution. Continue to add phosphate buffer solution with a pH value of 6.5 to the solution, and stir until completely dissolved. The preparation method of the phosphate buffer solution is as follows:

[0085] pH 6.5: Take 0.68 g of potassium dihydrogen phosphate, add 15.2 mL of 0.1 mol / L sodium hydroxide solution, and dilute with water to 100 mL.

[0086] 4. Add valine. Calculate the dosage of valine so that its total mass ratio with cefoperazone sodium and sulbactam sodium is 0.13:1. Add valine to the solution and stir until completely dispersed.

[0087] 5. Filter the mixed solution using a microporous membrane to remove insoluble impurities.

[0088] III. Freeze-drying and drying treatment

[0089] 1. Freeze-drying treatment. Place the filtered mixed solution in a freeze-dryer, set the temperature to -40 °C, and the freeze-drying time to 4 hours.

[0090] 2. First vacuum drying. Place the freeze-dried solid in a vacuum drying oven, set the temperature to 45 °C, and the drying time to 70 minutes.

[0091] 3. Crushing and screening. Screen the crushed powder through a screening device, use a sieve with a mesh aperture of 80 meshes to screen out the powder that meets the particle size requirements. For the larger particles that do not pass through the sieve, they can be re-crushed until the particle size requirements are met.

[0092] 4. Second vacuum drying. Place the screened powder in a vacuum drying oven again, set the temperature to 30 °C, and the drying time to 55 minutes to obtain the powder of cefoperazone sodium and sulbactam sodium for injection. Finally, aseptically subpackage the powder into injection vials and seal for storage.

[0093] Example 2

[0094] The embodiment of the present invention provides a preparation method of cefoperazone sodium and sulbactam sodium for injection, including the following contents:

[0095] I. Preparation of cefoperazone sodium

[0096] 1. Dissolve cefoperazone acid. Weigh 100 g of cefoperazone acid, add it to 500 mL of pure water, and stir until completely dissolved.

[0097] 2. Adjust the pH value. Slowly add 0.1 mol / L sodium hydroxide solution while monitoring the pH value of the solution with a pH meter and adjust it to 6.6.

[0098] 3. Crystallization process

[0099] First stage: Control the temperature of the reaction solution at 15°C. While stirring, add ethyl acetate dropwise. The dropping time is controlled within 15 minutes, and the addition amount of ethyl acetate is 20% of the volume of the reaction solution.

[0100] Second stage: Keep the temperature at 15°C and continue stirring for 60 minutes. Observe the start of crystal precipitation.

[0101] Third stage: Lower the temperature to 10°C and continue stirring for 60 minutes to further promote crystal precipitation.

[0102] Fourth stage: Lower the temperature to 5°C, let it stand for 1 hour, and finally cool it to 0°C and stir for 30 minutes to ensure complete crystal precipitation.

[0103] 4. Filtration and washing. Use filter paper to filter and collect the crystals, and wash the crystals with an appropriate amount of ethyl acetate.

[0104] 5. Drying. Place the washed crystals in an oven and dry them to a constant weight at 45°C.

[0105] II. Preparation of the mixed solution

[0106] 1. Weigh the raw materials. Weigh cefoperazone sodium and sulbactam sodium according to a mass ratio of 1:1.

[0107] 2. Dissolve the raw materials. Add the weighed cefoperazone sodium and sulbactam sodium into an appropriate amount of sodium chloride injection (mass fraction is 9%) and stir until completely dissolved.

[0108] 3. Add phosphate buffer solution. Continue to add phosphate buffer solution with a pH value of 6.8 to the solution and stir until completely dissolved. The preparation method of the phosphate buffer solution is as follows:

[0109] pH 6.8: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution, add 118 mL of 0.2 mol / L sodium hydroxide solution, and dilute it to 1000 mL with water.

[0110] 4. Add valine. Calculate the dosage of valine so that its total mass ratio with cefoperazone sodium and sulbactam sodium is 0.10:1. Add valine to the solution and stir until completely dispersed.

[0111] 5. Filter the mixed solution using a microporous membrane to remove insoluble impurities.

[0112] III. Freeze-drying and drying treatment

[0113] 1. Freeze-drying treatment: Place the filtered mixed solution in a freeze-dryer, set the temperature to -35°C, and the freeze-drying time to 5 hours.

[0114] 2. First vacuum drying: Place the freeze-dried solid in a vacuum drying oven, set the temperature to 40°C, and the drying time to 80 minutes.

[0115] 3. Crushing and screening: Screen the crushed powder through a screening device using a sieve with a mesh aperture of 80 mesh to select the powder that meets the particle size requirements. For the larger particles that do not pass through the sieve, they can be re-crushed until the particle size requirements are met.

[0116] 4. Second vacuum drying: Place the screened powder in the vacuum drying oven again, set the temperature to 25°C, and the drying time to 60 minutes to obtain the powder of cefoperazone sodium and sulbactam sodium for injection. Finally, aseptically subpackage the powder into injection vials and seal for storage.

[0117] Example 3

[0118] The embodiment of the present invention provides a preparation method of cefoperazone sodium and sulbactam sodium for injection, including the following:

[0119] I. Preparation of cefoperazone sodium

[0120] 1. Dissolve cefoperazone acid: Weigh 100 g of cefoperazone acid and add it to 500 mL of pure water, stir until completely dissolved.

[0121] 2. Adjust the pH value: Slowly add 0.1 mol / L sodium hydroxide solution while monitoring the pH value of the solution with a pH meter and adjust it to 6.8.

[0122] 3. Crystallization process

[0123] First stage: Control the temperature of the reaction solution at 18°C, dropwise add ethyl acetate under stirring, control the dropping time within 10 minutes, and the dropping amount of ethyl acetate is 10% of the volume of the reaction solution;

[0124] Second stage: Keep the temperature at 18°C and continue stirring for 30 minutes to observe the start of crystal precipitation;

[0125] Third stage: Lower the temperature to 15°C and continue stirring for 30 minutes to further promote crystal precipitation;

[0126] Fourth stage: Lower the temperature to 10°C, let it stand for 1 hour, and finally lower the temperature to 5°C and stir for 30 minutes to ensure complete crystal precipitation.

[0127] 4. Filtration and washing: Filter and collect the crystals using filter paper and wash the crystals with an appropriate amount of ethyl acetate.

[0128] 5. Drying: Place the washed crystals in an oven and dry them at 45°C until a constant weight is achieved.

[0129] II. Preparation of the Mixed Solution

[0130] 1. Weigh the raw materials: Weigh cefoperazone sodium and sulbactam sodium in a mass ratio of 5:1.

[0131] 2. Dissolve the raw materials: Add the weighed cefoperazone sodium and sulbactam sodium into an appropriate amount of sodium chloride injection (mass fraction 9%) and stir until completely dissolved.

[0132] 3. Add phosphate buffer solution: Continuously add phosphate buffer solution with a pH of 6.8 to the solution and stir until completely dissolved. The preparation method of the phosphate buffer solution is as follows:

[0133] pH 6.8: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution, add 118 mL of 0.2 mol / L sodium hydroxide solution, and dilute with water to 1000 mL.

[0134] 4. Add valine: Calculate the amount of valine to be added so that its total mass ratio to cefoperazone sodium and sulbactam sodium is 0.17:1. Add valine to the solution and stir until completely dispersed.

[0135] 5. Filter the mixed solution using a microporous membrane to remove insoluble impurities.

[0136] III. Freeze-drying and Drying Treatment

[0137] 1. Freeze-drying treatment: Place the filtered mixed solution in a freeze-dryer, set the temperature to -45°C, and the freeze-drying time to 3 hours.

[0138] 2. First vacuum drying: Place the freeze-dried solid in a vacuum drying oven, set the temperature to 50°C, and the drying time to 60 minutes.

[0139] 3. Crushing and screening: Screen the crushed powder through a screening device using a sieve with a mesh aperture of 80 meshes to select the powder that meets the particle size requirements. For the larger particles that do not pass through the sieve, they can be re-crushed until the particle size requirements are met.

[0140] 4. Second vacuum drying: Place the screened powder in a vacuum drying oven again, set the temperature to 35°C, and the drying time to 50 minutes to obtain the powder of cefoperazone sodium and sulbactam sodium for injection. Finally, aseptically subpackage the powder into injection vials and seal for storage.

[0141] Example 4

[0142] The embodiment of the present invention provides a preparation method of cefoperazone sodium and sulbactam sodium for injection, including the following:

[0143] I. Preparation of Cefoperazone Sodium

[0144] 1. Dissolve cefoperazone acid: Weigh 100 g of cefoperazone acid and add it to 500 mL of pure water, stirring until completely dissolved.

[0145] 2. Adjust the pH value: Slowly add 0.1 mol / L sodium hydroxide solution while monitoring the pH value of the solution with a pH meter and adjust it to 6.7.

[0146] 3. Crystallization process

[0147] First stage: Control the temperature of the reaction solution at 16°C, and slowly add ethyl acetate dropwise with stirring. The dropping time is controlled within 12 minutes, and the dropping amount of ethyl acetate is 15% of the volume of the reaction solution.

[0148] Second stage: Keep the temperature at 16°C and continue stirring for 45 minutes, observing the start of crystal precipitation.

[0149] Third stage: Lower the temperature to 12°C and continue stirring for 45 minutes to further promote crystal precipitation.

[0150] Fourth stage: Finally, lower the temperature to 3°C and stir for 30 minutes to ensure complete crystal precipitation.

[0151] 4. Filtration and washing: Use filter paper to filter and collect the crystals, and wash the crystals with an appropriate amount of ethyl acetate.

[0152] 5. Drying: Place the washed crystals in a drying oven and dry them at 45°C until a constant weight is achieved.

[0153] II. Preparation of the mixed solution

[0154] 1. Weigh the raw materials: Weigh cefoperazone sodium and sulbactam sodium according to a mass ratio of 3:1.

[0155] 2. Dissolve the raw materials: Add the weighed cefoperazone sodium and sulbactam sodium to an appropriate amount of sodium chloride injection (mass fraction 9%) and stir until completely dissolved.

[0156] 3. Add phosphate buffer solution: Continue to add phosphate buffer solution with a pH value of 6.5 to the solution and stir until completely dissolved. The preparation method of the phosphate buffer solution is as follows:

[0157] pH 6.5: Take 0.68 g of potassium dihydrogen phosphate, add 15.2 mL of 0.1 mol / L sodium hydroxide solution, and dilute it to 100 mL with water.

[0158] 4. Add valine: Calculate the dosage of valine to make its total mass ratio with cefoperazone sodium and sulbactam sodium 0.13:1, add valine to the solution, and stir until completely dispersed.

[0159] 5. Filter the mixed solution using a microporous membrane to remove insoluble impurities.

[0160] III. Freeze-drying and drying treatment

[0161] 1. Freeze-drying treatment: Place the filtered mixed solution in a freeze-dryer, set the temperature to -40 °C, and the freeze-drying time to 4 hours.

[0162] 2. First vacuum drying: Place the freeze-dried solid in a vacuum drying oven, set the temperature to 45 °C, and the drying time to 70 minutes.

[0163] 3. Crushing and screening: Screen the crushed powder through a screening device using a sieve with a mesh aperture of 80 meshes to select the powder that meets the particle size requirements. For the larger particles that do not pass through the sieve, they can be re-crushed until the particle size requirements are met.

[0164] 4. Second vacuum drying: Place the screened powder in the vacuum drying oven again, set the temperature to 30 °C, and the drying time to 55 minutes to obtain the powder of cefoperazone sodium and sulbactam sodium for injection. Finally, aseptically dispense the powder into injection vials and seal for storage.

[0165] Example 5

[0166] The embodiment of the present invention provides a preparation method of cefoperazone sodium and sulbactam sodium for injection. The difference from Example 1 is that the mass ratio of cefoperazone sodium to sulbactam sodium weighed is 2.5:1, and the remaining steps are the same.

[0167] Example 6

[0168] The embodiment of the present invention provides a preparation method of cefoperazone sodium and sulbactam sodium for injection. The difference from Example 1 is that the total mass ratio of valine to cefoperazone sodium and sulbactam sodium is 0.08:1, and the remaining steps are the same.

[0169] Example 7

[0170] The embodiment of the present invention provides a preparation method of cefoperazone sodium and sulbactam sodium for injection. The difference from Example 1 is that the total mass ratio of valine to cefoperazone sodium and sulbactam sodium is 0.18:1, and the remaining steps are the same.

[0171] Comparative Example 1

[0172] A preparation method of cefoperazone sodium and sulbactam sodium for injection is provided. The difference from Example 1 is that the sodium chloride injection with a mass fraction of 9% is replaced with a glucose injection with a mass fraction of 5%, and the remaining steps are the same.

[0173] Example 8

[0174] An embodiment of the present invention provides a preparation method of cefoperazone sodium and sulbactam sodium for injection, which is different from Example 1 in that ethyl acetate is replaced by acetone, and the remaining steps are the same.

[0175] Comparative Example 2

[0176] A preparation method of cefoperazone sodium and sulbactam sodium for injection is provided, including the following:

[0177] I. Preparation of cefoperazone sodium

[0178] 1. Dissolve cefoperazone acid. Weigh 100 g of cefoperazone acid and add it to 500 mL of pure water, and stir until completely dissolved.

[0179] 2. Adjust the pH value. Slowly add 0.1 mol / L sodium hydroxide solution, and at the same time monitor the pH value of the solution with a pH meter and adjust it to 6.7.

[0180] 3. Crystallization process

[0181] The first stage: Control the temperature of the reaction solution at 16 °C, and dropwise add ethyl acetate under stirring. The dropping time is controlled within 12 minutes, and the dropping amount of ethyl acetate is 15% of the volume of the reaction solution;

[0182] The second stage: Keep the temperature at 16 °C and continue to stir for 45 minutes, and observe that crystals begin to precipitate;

[0183] The third stage: Lower the temperature to 12 °C and continue to stir for 45 minutes to further promote crystal precipitation;

[0184] The fourth stage: Lower the temperature to 8 °C, stand still for 1 hour, and finally lower the temperature to 3 °C and stir for 30 minutes to ensure complete crystal precipitation.

[0185] 4. Filtration and washing. Use filter paper to filter and collect the crystals, and wash the crystals with an appropriate amount of ethyl acetate.

[0186] 5. Drying. Place the washed crystals in a drying oven and dry them to constant weight at 45 °C.

[0187] II. Preparation of the mixed solution

[0188] 1. Weigh the raw materials. Weigh cefoperazone sodium and sulbactam sodium according to a mass ratio of 3:1.

[0189] 2. Dissolve the raw materials. Add the weighed cefoperazone sodium and sulbactam sodium to an appropriate amount of sodium chloride injection (mass fraction of 9%) and stir until completely dissolved.

[0190] 3. Add phosphate buffer solution. Continue to add phosphate buffer solution with a pH value of 6.5 to the solution and stir until completely dissolved. The preparation method of the phosphate buffer solution is as follows:

[0191] pH 6.5: Take 0.68 g of potassium dihydrogen phosphate, add 15.2 mL of 0.1 mol / L sodium hydroxide solution, and dilute to 100 mL with water.

[0192] 4. Filter the mixed solution using a microporous membrane to remove insoluble impurities.

[0193] III. Freeze-drying and drying treatment

[0194] 1. Freeze-drying treatment: Place the filtered mixed solution in a freeze-dryer, set the temperature to -40°C, and the freeze-drying time to 4 hours.

[0195] 2. First vacuum drying: Place the freeze-dried solid in a vacuum drying oven, set the temperature to 45°C, and the drying time to 70 minutes.

[0196] 3. Crushing and screening: Screen the crushed powder through a screening device using a sieve with a mesh aperture of 80 meshes to select the powder that meets the particle size requirements. For the larger particles that do not pass through the sieve, they can be crushed again until the particle size requirements are met.

[0197] 4. Second vacuum drying: Place the screened powder in a vacuum drying oven again, set the temperature to 30°C, and the drying time to 55 minutes to obtain the powder of cefoperazone sodium and sulbactam sodium for injection. Finally, aseptically subpackage the powder into injection vials and seal for storage.

[0198] Comparative Example 3

[0199] Provide a preparation method of cefoperazone sodium and sulbactam sodium for injection. The difference from Example 1 is that the mass ratio of cefoperazone sodium to sulbactam sodium is 6:1, and the other steps are the same.

[0200] Perform performance tests on the cefoperazone sodium and sulbactam sodium for injection prepared in Examples 1 - 8 and Comparative Examples 1 - 3. According to the Chinese Pharmacopoeia, after testing for 18 months under the conditions of 25°C and relative humidity of 60%, and after testing for 6 months under the conditions of high temperature of 40°C and relative humidity of 75%, the performance tests are carried out. The test indicators include content 1 Refers to the content of cefoperazone sodium, and the content 2 Refers to the content of sulbactam sodium, and the related substances refer to the total impurity content (including valine). The test results are shown in Table 1 and Table 2 as follows:

[0201] Table 1

[0202]

[0203]

[0204] Table 2

[0205]

[0206] The contents of the newly added impurities (excluding valine) in Table 1 and Table 2 were statistically analyzed. The content of the newly added impurities (excluding valine) = the content of related substances (%) - the content of valine (%). The statistical results are shown in Table 3 below:

[0207] Table 3

[0208]

[0209]

[0210] Referring to Table 3, it can be seen from Examples 1 to 5 that for the cefoperazone sodium and sulbactam sodium for injection prepared by the embodiments of the present invention, the impurity content of the original sample is small, and the impurity content reaches less than 1 after being placed at room temperature for 18 months. Even in Example 3, when the mass ratio of cefoperazone sodium to sulbactam sodium is 5:1, the impurity content is still less than 1.5% after being placed at room temperature for 18 months, and the impurity content is less than 2% after being placed in a high-temperature environment for 6 months. Thus, it can be seen that the cefoperazone sodium and sulbactam sodium for injection prepared by the embodiments of the present invention can achieve high stability within the range of the mass ratio of cefoperazone sodium to sulbactam sodium of 1 to 5:1, is suitable for long-term storage, and the specific ratio can be adjusted according to the needs of different infection types and patient groups for the drug, and has high therapeutic effects and safety.

[0211] Comparing Example 1 with Example 4, it can be seen that under the condition that other conditions remain unchanged, the combination of the increased low-temperature standing stage (5 - 10°C, standing for 1 hour) and the final cooling stage (0 - 5°C, stirring for 30 minutes) in sequence can further improve the purity of the crystal and reduce the mixing of impurities.

[0212] Figure 1 is the column chart of impurity detection of cefoperazone sodium and sulbactam sodium for injection prepared in Example 1 of the present invention. Figure 2 is the column chart of impurity detection of cefoperazone sodium and sulbactam sodium for injection prepared in Example 6 of the present invention. From Figure 1 and Figure 2 comparison shows that when the content of valine is too small, the buffering capacity is not enough to maintain the stable pH value of the solution, which will cause the degradation of cefoperazone sodium and sulbactam sodium, resulting in an increase in their impurity content. Referring to Table 3, comparing Example 7 with Example 1, it can be seen that when the content ratio of valine is higher than 0.17, the stability of the prepared cefoperazone sodium and sulbactam sodium for injection will hardly increase anymore, and excessive valine will affect the therapeutic effect of the drug and increase the cost at the same time.

[0213] Figure 3It is a column chart for comparing the impurity detection of cefoperazone sodium and sulbactam sodium for injection prepared in Example 1 and Example 8 of the present invention. It can be seen from Figure 3 that although replacing ethyl acetate with acetone can still solve the technical problems of the embodiments of the present invention, the stability of cefoperazone sodium and sulbactam sodium for injection obtained in Example 8 is weaker than that in Example 1. Because the high volatility of acetone will cause the rapid precipitation of valine, affecting its uniform distribution and thus the stability of the drug.

[0214] Figure 4 It is a column chart for comparing the impurity detection of cefoperazone sodium and sulbactam sodium for injection prepared in Comparative Example 1 and Example 1 of the present invention. It can be seen from Figure 4 that after replacing the 9% sodium chloride injection with a 5% glucose injection, the buffering capacity of the glucose injection is weak, lacking the ionic strength provided by sodium chloride. At high concentrations, it leads to an increase in the aggregation between drug molecules, reducing the stability of the drug. Thus, it can be seen that by using a combination of sodium chloride injection and phosphate buffer solution in the embodiments of the present invention, a stable environment is provided for the addition of valine, enhancing the solubility and stability of the drug and reducing the degradation risk.

[0215] Referring to Table 3, it can be seen from the comparison between Example 1 and Comparative Example 2 that when valine is not added and the mass ratio of cefoperazone sodium to sulbactam sodium is 3:1, cefoperazone sodium and sulbactam sodium not only have poor stability and fast degradation during the mixing and preparation process, but also have poor stability during storage, making it unable to be used for injection treatment.

[0216] Figure 5 It is a column chart for comparing the impurity detection of cefoperazone sodium and sulbactam sodium for injection prepared in Comparative Example 3 and Example 1 of the present invention. It can be seen from Figure 5 that by adopting the preparation method of the embodiments of the present invention, in cefoperazone sodium and sulbactam sodium for injection, when the content ratio of cefoperazone sodium exceeds 5, the stability of the drug will be significantly reduced. When the mass ratio of cefoperazone sodium to sulbactam sodium is in the range of 1-5:1, it is more appropriate.

[0217] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention. It should be noted that the structures or components illustrated in the drawings are not necessarily drawn to scale, and the present invention omits the description of well-known components and processing technologies and processes to avoid unnecessarily limiting the present invention.

Claims

1. A preparation method of cefoperazone sodium and sulbactam sodium for injection, characterized in that, It includes the preparation of cefoperazone sodium and the preparation of a mixed solution. Among them, the preparation of the mixed solution includes weighing sulbactam sodium and the prepared cefoperazone sodium, adding them to sodium chloride injection for dissolution, then adding phosphate buffer solution, stirring until completely dissolved and then filtering, adding valine to the solution for dispersion, and subjecting the dispersed mixed solution to freeze-drying treatment, first drying, crushing and screening, and second drying in sequence to obtain cefoperazone sodium and sulbactam sodium for injection; wherein the mass ratio of cefoperazone sodium to sulbactam sodium is 1-5:

1.

2. The preparation method of cefoperazone sodium and sulbactam sodium for injection according to claim 1, characterized in that, The mass ratio of the valine to the total mass of cefoperazone sodium and sulbactam sodium is 0.10-0.17:1, and the mass ratio of cefoperazone sodium to sulbactam sodium is 2.5-5:

1.

3. The preparation method of cefoperazone sodium and sulbactam sodium for injection according to claim 1, wherein, The preparation of the cefoperazone sodium includes dissolving cefoperazone acid in pure water, then adding sodium hydroxide solution to the solution, and after the reaction is completed, carrying out crystallization, filtration, washing with a solvent, and drying in sequence to obtain cefoperazone sodium.

4. The preparation method of cefoperazone sodium and sulbactam sodium for injection according to claim 3, characterized in that, In the preparation of cefoperazone sodium, after adding sodium hydroxide solution, the pH value is controlled at 6.6-6.

8.

5. The preparation method of cefoperazone sodium and sulbactam sodium for injection according to claim 4, wherein, The crystallization process includes the following steps: In the first stage, the temperature is controlled at 15-18°C, ethyl acetate is added dropwise with stirring, the dropping time is controlled at 10-15 minutes, and the dropping amount of ethyl acetate is 10%-20% of the volume of the reaction solution; In the second stage, the temperature is maintained at 15-18°C, and stirring is continued for 30-60 minutes until crystals begin to precipitate; In the third stage, the temperature is lowered to 10-15°C, and stirring is continued for 30-60 minutes to further promote crystal precipitation; In the fourth stage, the temperature is lowered to 5-10°C, left standing for 1 hour, and finally the temperature is lowered to 0-5°C, and stirring is carried out for 30 minutes to ensure complete crystal precipitation.

6. The preparation method of cefoperazone sodium and sulbactam sodium for injection according to claim 1, characterized in that, The mass fraction of the sodium chloride injection is 0.88-0.92%.

7. The preparation method of cefoperazone sodium and sulbactam sodium for injection according to claim 1, characterized in that, The pH of the phosphate buffer solution is 6.5-6.

8.

8. The preparation method of cefoperazone sodium and sulbactam sodium for injection according to claim 1, characterized in that, The temperature of the freeze-drying treatment is -35°C to -45°C, and the freeze-drying time is 3-5 hours.

9. The preparation method of cefoperazone sodium and sulbactam sodium for injection according to claim 1, wherein Both the first drying and the second drying are vacuum drying. The temperature of the first drying is 40-50°C, and the drying time is 60-80 minutes. The temperature of the second drying is 25-35°C, and the drying time is 50-60 minutes.

10. Use of cefoperazone sodium and sulbactam sodium for injection prepared by the preparation method according to any one of claims 1-9, characterized in that, It is used for injection after dissolution.

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