Industrial production method of piperacillin tazobactam spray-dried powder

Abstract

The invention relates to an industrial production method of piperacillin and tazobactam powder, which comprises the following steps: 1) preparing a mixed solution of piperacillin or pharmaceutically acceptable salts thereof and tazobactam or pharmaceutically acceptable salts thereof, and maintaining the pH value at 6.0-7.5; (2) a stabilizer is added into the solution obtained in the step (1), a mixed solution is obtained, and the stabilizer is selected from one or more of carbohydrate, amino acid and polyhydric alcohols; and 3) carrying out spray drying on the mixed solution obtained in the step 2) to obtain the piperacillin tazobactam spray-dried powder.

Description

Industrial production method of piperacillin-tazobactam spray-dried powder Technical Field

[0001] The invention belongs to the field of medicine and relates to an industrial production method of piperacillin-tazobactam spray-dried powder. Background Art

[0002] Piperacillin-tazobactam is a parenteral combination drug used to treat or control bacterial infections. Its active ingredients include piperacillin or its salt and tazobactam or its salt. Piperacillin is a β-lactam antibiotic whose β-lactam ring is easily destroyed by β-lactamases, resulting in loss of antibacterial activity. Tazobactam is a β-lactamase inhibitor that reduces the destruction of piperacillin by β-lactamase-producing bacteria, thereby preserving its antibacterial activity.

[0003] Piperacillin-tazobactam is indicated for the following: intra-abdominal infections, such as appendicitis (with perforation or abscess) and peritonitis caused by Escherichia coli; hospitalized pneumonia caused by Staphylococcus aureus; skin and skin tissue infections, such as cellulitis, skin abscesses, and ischemic / diabetic foot infections caused by Staphylococcus aureus; gynecological infections, such as postpartum endometritis or pelvic inflammatory disease caused by Escherichia coli; and community-acquired pneumonia caused by Haemophilus influenzae. Currently, there are two main types of piperacillin-tazobactam formulations available on the market: premixed frozen bags stored at -20°C and lyophilized powder injections in vials stored at room temperature. Premixed frozen bags require low-temperature transportation and storage at -20°C, increasing drug costs and sales prices. They also require pre-thawing at room temperature or refrigeration before use, which is time-consuming and labor-intensive. Lyophilized powder injections in vials utilize a freeze-drying process, which has a long production cycle, low production capacity, high energy consumption, and significant waste.

[0004] Spray drying is a mature technology for producing powders. Its principle is to spray a liquid into a fine mist in a hot air stream to increase the contact area between the liquid and gas phases, directly drying it into a fine powder. Spray drying is widely used in food production, such as milk powder production, but its application in the industrial production of pharmaceuticals is still very limited. One obvious reason is the concern that heat-sensitive materials in pharmaceuticals may be degraded by the high temperatures during the spray drying process. Although a few patents have disclosed the application of spray drying methods in the preparation of pharmaceuticals (Patent Documents 1-3), there are no reports of industrial production of piperacillin-tazobactam using spray drying methods. It is known that piperacillin-tazobactam is unstable in aqueous solution. On the one hand, piperacillin is a β-lactam antibiotic. After being dissolved in water, it is easily decomposed and destroyed by high temperature, acid and alkali, oxidants, metal ions, etc., to generate antigenic degradation products and cause allergic reactions. On the other hand, as piperacillin degrades, the pH value of the solution decreases, and the acid-base equilibrium of piperacillin-tazobactam shifts to the acid form, resulting in the crystallization of piperacillin-tazobactam and the formation of insoluble piperacillin acid-tazobactam particles.

[0005] Therefore, in the existing technology, there is still much room for improvement in the industrial production of piperacillin-tazobactam, and people are eager to develop an industrial manufacturing method that can produce high-purity and high-stability piperacillin-tazobactam with high efficiency and high yield.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: US6001800

[0009] Patent Document 2: US6479049

[0010] Patent Document 3: WO2014 / 139329

[0011] Summary of the Invention

[0012] The technical problem to be solved by the present invention is to provide an industrialized production method capable of producing high-purity and high-stability piperacillin-tazobactam with high efficiency and high yield.

[0013] In order to solve the above technical problems, the inventors of the present invention conducted in-depth research and unexpectedly found that the spray drying method can produce high-purity piperacillin-tazobactam powder with high efficiency and high yield, thereby completing the present invention.

[0014] Specifically, the present invention provides the following industrial production method of piperacillin-tazobactam spray-dried powder.

[0015] (1) An industrial production method of piperacillin-tazobactam spray-dried powder, comprising the following steps: (1) preparing a mixed solution of piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof, and maintaining the pH value at 6.0 to 7.5; (2) adding a stabilizer to the solution obtained in step (1) to obtain a mixed solution, wherein the stabilizer is selected from one or more of carbohydrates, amino acids and polyols; and (3) spray-drying the mixed solution obtained in step (2) to obtain piperacillin-tazobactam spray-dried powder.

[0016] (2) The industrial production method of the piperacillin-tazobactam spray-dried powder as described in (1), wherein the content ratio of piperacillin sodium or its pharmaceutically acceptable salt calculated as piperacillin free acid and tazobactam or its pharmaceutically acceptable salt calculated as tazobactam free acid in the mixed solution prepared in step (1) is approximately 8:1.

[0017] (3) An industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein, in step (1), a mixed powder of piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof is dissolved in water to prepare a mixed solution; or, piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof are dissolved in water separately and then mixed to prepare a mixed solution; or, piperacillin acid and / or tazobactam acid are first salified under the action of sodium bicarbonate, sodium carbonate or sodium hydroxide to prepare piperacillin sodium and / or tazobactam sodium solutions, and then the mixed solution is prepared.

[0018] (4) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein the concentration of the mixed solution obtained in step (2) is 1 to 50% by weight based on piperacillin.

[0019] (5) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein the concentration of the mixed solution obtained in step (2) is 26 to 38% by weight based on piperacillin.

[0020] (6) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein the stabilizer added in step (2) is a polyol.

[0021] (7) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (6), wherein the stabilizer is polyethylene glycol or glycerol.

[0022] (8) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (6), wherein the stabilizer is polyethylene glycol 200-600.

[0023] (9) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (6), wherein the stabilizer is polyethylene glycol 300-400.

[0024] (10) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein in step (2), 0 to 50 parts by weight of a stabilizer are added for every 100 parts by weight of piperacillin.

[0025] (11) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein in step (2), 0 to 20 parts by weight of a stabilizer are added for every 100 parts by weight of piperacillin.

[0026] (12) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein in step (2), 2.5 to 15 parts by weight of a stabilizer are added for every 100 parts by weight of piperacillin.

[0027] (13) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein, in step (2), an aminocarboxylic acid chelating agent EDTA is further added to the solution obtained in step (1).

[0028] (14) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein the storage temperature of the mixed solution obtained in step (2) is -12 to 8°C.

[0029] (15) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein the storage temperature of the mixed solution obtained in step (2) is -10 to 0°C.

[0030] (16) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein, in step (3), the inlet air temperature during spray drying is 160 to 240°C.

[0031] (17) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein, in step (3), the inlet air temperature during spray drying is 185-200°C.

[0032] (18) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein, in step (3), the outlet air temperature during spray drying is 80 to 130°C.

[0033] (19) The industrial production method of piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein, in step (3), the air outlet temperature during spray drying is 100-115°C.

[0034] Effects of the Invention

[0035] The industrialized production method of piperacillin-tazobactam spray-dried powder according to the present invention can produce high-purity and high-stability piperacillin-tazobactam powder with high efficiency and high yield, and has high application value in the pharmaceutical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG1 shows the morphology of piperacillin sodium and tazobactam sodium spray-dried powder under an optical microscope. DETAILED DESCRIPTION

[0037] As mentioned above, there are two main types of piperacillin-tazobactam formulations currently available on the market: premixed frozen bags stored at -20°C, and lyophilized powder injections in vials stored at room temperature. However, there have been no reports of industrial production using spray drying. Piperacillin is unstable in aqueous solutions and is easily decomposed and destroyed by heat, acids, bases, oxidants, and metal ions once dissolved in water. This poses stability issues during storage of aqueous solutions, and there are also concerns that piperacillin-tazobactam may be degraded by the high temperatures experienced during the spray drying process.

[0038] The inventors of the present invention attempted to prepare piperacillin-tazobactam powder using a spray drying method. After research, they found that when using the spray drying method to prepare piperacillin-tazobactam powder, the stability of piperacillin-tazobactam can be increased by adding stabilizers (such as carbohydrates, amino acids, and / or polyols) to the formula, thereby enabling the production of high-purity piperacillin-tazobactam powder with high efficiency and high yield. At the same time, by lowering the storage temperature of the piperacillin-tazobactam solution, the stability of the piperacillin-tazobactam solution can also be significantly improved, reducing the generation of impurities. In addition, using citrate or the like as a pH buffer to maintain the pH value of the piperacillin-tazobactam solution between 6.0 and 7.5 can improve the stability of piperacillin-tazobactam. EDTA, as a chelating agent for metal ions, can further increase the stability of piperacillin-tazobactam.

[0039] Based on the above research, the present invention provides an industrialized method for producing a high-purity, low-impurity, high-efficiency, and high-yield piperacillin-tazobactam spray-dried powder. The method comprises preparing a piperacillin-tazobactam solution, adding carbohydrate, amino acid, and / or polyol stabilizers, and optionally adding EDTA and sodium citrate to obtain a mixed solution. The solution is then stored at a low temperature to ensure purity and reduce impurities. The solution is then sterile-filtered or not sterile-filtered, followed by spray drying to obtain a sterile or non-sterile piperacillin-tazobactam API. The sterile API is then packaged under aseptic conditions to obtain the final formulation.

[0040] The industrialized manufacturing method of the present invention specifically comprises the following steps:

[0041] (1) Preparing a mixed solution of piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof.

[0042] In this step, the pH is maintained between 6.0 and 7.5, for example, between 6.0 and 7.0, 6.1 and 6.9, 6.2 and 6.8, 6.3 and 6.7, or 6.4 and 6.6, preferably around 6.5. Maintaining the pH within this range improves the stability of piperacillin-tazobactam. The pH can be adjusted using methods known in the art, such as by adding citrate.

[0043] In this step, a mixed powder of piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof can be dissolved in water to prepare a mixed solution; alternatively, piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof can be dissolved separately in water and then mixed to prepare a mixed solution; alternatively, piperacillin acid and / or tazobactam acid can be separately salified under the action of sodium bicarbonate, sodium carbonate, or sodium hydroxide to prepare a piperacillin sodium and / or tazobactam sodium solution, and then the mixed solution can be prepared. When the method of separately salifying piperacillin acid and / or tazobactam acid under the action of sodium bicarbonate, sodium carbonate, or sodium hydroxide to prepare a piperacillin sodium and / or tazobactam sodium solution, and then preparing the mixed solution, the degradation of piperacillin and tazobactam can be minimized, and a product with higher purity can be obtained.

[0044] The mixing ratio of piperacillin or a pharmaceutically acceptable salt thereof to tazobactam or a pharmaceutically acceptable salt thereof is approximately 8:1, which can be adjusted appropriately as needed. Thus, in the mixed solution prepared in step (1), the content ratio of piperacillin sodium or a pharmaceutically acceptable salt thereof calculated as piperacillin free acid and tazobactam or a pharmaceutically acceptable salt thereof calculated as tazobactam free acid is approximately 8:1.

[0045] (2) adding a stabilizer to the solution obtained in step (1) to obtain a mixed solution.

[0046] The present invention has discovered that when piperacillin-tazobactam powder is prepared using a spray drying method, adding a stabilizer to the formulation can increase the stability of piperacillin-tazobactam. The stabilizer used in the present invention is selected from one or more of carbohydrates, amino acids, and polyols. Polyols are preferably used as stabilizers, such as polyethylene glycol, glycerol, etc., more preferably polyethylene glycol, and even more preferably polyethylene glycol 200-600 and polyethylene glycol 300-400. In this step, for every 100 parts by weight of piperacillin, 0 to 50 parts by weight of stabilizer are added, preferably 0 to 20 parts by weight of stabilizer are added, more preferably 2.5 to 15 parts by weight of stabilizer are added, and even more preferably 7.5 to 15 parts by weight of stabilizer are added.

[0047] The concentration of the mixed solution obtained in this step is 1 to 50% by weight, preferably 1 to 42% by weight, and more preferably 26 to 38% by weight, based on piperacillin.

[0048] If necessary, an aminocarboxylic acid chelating agent EDTA may be added in this step. EDTA, as a metal chelating agent, can increase the stability of piperacillin-tazobactam.

[0049] The mixed solution obtained in this step can be directly used for spray drying or stored at an appropriate low temperature, preferably at a storage temperature of -12 to 8° C., more preferably -10 to 0° C. By storing the piperacillin-tazobactam solution at an appropriate low temperature, the stability of the piperacillin-tazobactam solution can be significantly improved and the generation of impurities can be reduced.

[0050] If necessary, the mixed solution obtained in this step can be sterilized and filtered before being used for spray drying, or can be directly used for spray drying without being sterilized and filtered.

[0051] (3) spray-drying the mixed solution obtained in step (2) to obtain piperacillin-tazobactam spray-dried powder.

[0052] In this step, the air inlet temperature during spray drying is 160-240° C., preferably 185-200° C. The air outlet temperature during spray drying is 80-130° C., preferably 100-115° C. The heating carrier used during spray drying can be compressed air or nitrogen, thereby obtaining a piperacillin-tazobactam spray-dried powder.

[0053] The spray-dried powder obtained by the industrialized production method of the piperacillin-tazobactam spray-dried powder of the present invention is non-sterile or sterile powder spherical particles, which can be filled into non-sterile or sterile bags / vials using a powder filling machine to prepare non-sterile or sterile APIs, or sterile preparations.

[0054] The results of accelerated and long-term stability studies on the spray-dried powder obtained by the industrialized manufacturing method of the present invention show that the key quality attributes of the product (such as moisture and impurities) are comparable to those of the commercially available reference preparation and meet the requirements of the Chinese Pharmacopoeia and / or the United States Pharmacopoeia.

[0055] The stabilizer contained in the spray-dried powder obtained by the industrialized production method of the piperacillin-tazobactam spray-dried powder of the present invention has no effect on the biological potency of piperacillin-tazobactam.

[0056] The present invention has the following advantages: It is the first to utilize a spray-drying process for the production of piperacillin-tazobactam powder. By adding a stabilizer to the formulation, the resulting spray-dried powder can be made comparable in quality to a commercially available reference preparation. The present invention has discovered that lowering the storage temperature of the piperacillin-tazobactam solution to below 0°C significantly reduces the generation of impurities and improves the stability of the piperacillin-tazobactam aqueous solution. The present invention confirms that the piperacillin-tazobactam solution can be prepared with a concentration of up to 42%. The present invention utilizes a high-concentration piperacillin-tazobactam solution for spray drying, developing a high-efficiency, high-yield, and low-energy industrial production method for piperacillin-tazobactam.

[0057] Example

[0058] The present invention is further described in detail below through the following examples, but the present invention is not limited to the process parameter ranges in the following examples.

[0059] Example 1: Experimental study on the salt formation of piperacillin acid and tazobactam acid using different bases

[0060] 1.1 Using sodium bicarbonate to form salt

[0061] Weigh 42g of water for injection and lower the temperature to 2-8°C. Weigh 0.86g of citric acid, add it to the water for injection, stir until dissolved, add sodium bicarbonate, and make the pH of the solution reach about 6.5. Take 24g of piperacillin and 3g of tazobactam, add them to the above sodium citrate solution, and stir to form a suspension. Slowly add sodium bicarbonate to carry out salt-forming reaction to raise the pH value of the solution to about 6.5. The temperature is maintained at 2-8°C during the entire salt-forming reaction. The sample batch number is 200303-2. 1.2 Use sodium carbonate to form salt

[0062] Weigh 42g of water for injection and cool to 2-8°C. Weigh 0.86g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the solution pH to approximately 6.5. Add 24g of piperacillin and 3g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to raise the solution pH to approximately 6.5. Maintain the temperature between 2-8°C throughout the salt-forming reaction. Sample batch number: 200303-3.

[0063] The two batches of piperacillin sodium and tazobactam sodium solutions were tested for related substances and their contents. The results are shown in Table 1.

[0064] Table 1 Results of piperacillin-tazobactam salt formation reactions using different bases

[0065]

[0066] As shown in Table 1, when sodium bicarbonate and sodium carbonate are used to form salts, the related substance detection of the samples meets the CP standard (single impurity ≤ 2.0%, total impurity ≤ 4.0%).

[0067] Example 2: Stability test of feed solutions of different concentrations

[0068] 2.1 Stability test of 42% piperacillin sodium and tazobactam sodium solution

[0069] Weigh 244g of water for injection and cool to 2-8°C. Weigh 6.9g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium carbonate and bring the solution pH to approximately 6.5. Add 192g of piperacillin and 24g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.048g of disodium EDTA and 14.2g of PEG400 and stir until dissolved. Add more water to a final total weight of 500g. The concentration of the solution is approximately 42% (based on piperacillin). Batch number: 200318-1.

[0070] 2.2 Stability test of 38% piperacillin sodium and tazobactam sodium solution

[0071] Weigh 287g of water for injection and cool to 2-8°C. Weigh 6.9g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium carbonate and bring the solution pH to approximately 6.5. Add 192g of piperacillin and 24g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.048g of disodium EDTA and 14.2g of PEG400 and stir until dissolved. Add more water to a final total weight of 550g. The solution concentration is approximately 39% (based on piperacillin). Batch number: 200318-2.

[0072] 2.3 Stability test of 34% piperacillin sodium and tazobactam sodium solution

[0073] Weigh 338g of water for injection and cool to 2-8°C. Weigh 6.9g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium carbonate and bring the solution pH to approximately 6.5. Add 192g of piperacillin and 24g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.048g of disodium EDTA and 14.2g of PEG400 and stir until dissolved. Add more water to a final total weight of 600g. The concentration of the solution is approximately 34% (based on piperacillin). Batch number: 200318-3.

[0074] 2.4 Stability test of 30% piperacillin sodium and tazobactam sodium solution

[0075] Weigh 317g of water for injection and cool to 2-8°C. Weigh 5.5g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium carbonate and bring the solution pH to approximately 6.5. Add 152g of piperacillin and 19g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.038g of disodium EDTA and 11.4g of PEG400 and stir until dissolved. Add more water to a final total weight of 524g. The concentration of the solution is approximately 30% (based on piperacillin). Batch number: 200319-1.

[0076] 2.5 Stability test of 26% piperacillin sodium and tazobactam sodium solution

[0077] Weigh 358g of water for injection and cool to 2-8°C. Weigh 5.2g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium carbonate and raise the pH of the solution to approximately 6.5. Add 144g of piperacillin and 18g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate a salt-forming reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.036g of disodium EDTA and 10.8g of PEG400 and stir until dissolved. Add more water to a final total weight of 554g. The concentration of the solution is approximately 30% (based on piperacillin). Batch number: 200319-2.

[0078] The five batches of piperacillin sodium and tazobactam sodium solutions were filtered through a 0.22 μm microporous membrane. The filtration time was recorded and the filtration efficiency was calculated. The filtered solutions were subjected to a stability study at 2-8°C. Samples were collected at 0 h, 24 h, 48 h, and 72 h for pH, content, and related substances. The results are shown in Table 2.

[0079] Table 2 Solution stability study test results

[0080]

[0081] From Table 2 we can see that:

[0082] 1) As the solution concentration decreases, the filtration efficiency increases, and the filtration efficiency of solutions with a concentration below 38% is significantly higher than that above 38%.

[0083] 2) The relevant substances in 5 groups of solutions with different concentrations (26% to 42%, calculated as piperacillin) stored at 2-8°C for 72 hours all met the CP standard, among which the impurity increase in the solution of group 3 (concentration of about 34%) was the smallest.

[0084] Example 3: Spray drying test of piperacillin sodium and tazobactam sodium (solution concentration 35%) with different stabilizers added

[0085] 3.1 Spray Drying Test of Piperacillin Sodium and Tazobactam Sodium without Stabilizer

[0086] Weigh 225g of water for injection and cool to 2-8°C. Weigh 4.6g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium carbonate to bring the solution pH to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22-micron filter and set aside. Batch number 200424-1.

[0087] 3.2 Spray drying test of piperacillin sodium and tazobactam sodium containing PEG400

[0088] Take 225g of water for injection and cool to 2-8°C. Weigh 4.6g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium carbonate to bring the solution pH to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 9.6g of PEG400 and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22 micron filter and set aside. The solution contains 7.5% PEG400 (relative to piperacillin) and is batch number 200424-3.

[0089] 3.3 Spray drying test of piperacillin sodium and tazobactam sodium containing PEG300

[0090] Weigh 162g of water for injection and cool to 2-8°C. Weigh 3.45g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium carbonate to bring the solution pH to approximately 6.5. Add 96g of piperacillin and 12g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.024g of disodium EDTA and 7.2g of PEG 300 and stir until dissolved. Add additional water to a final total weight of 300g. Filter the solution through a 0.22-micron filter and set aside. The solution contains 7.5% PEG 300, batch number 200425-4.

[0091] 3.4 Spray drying test of piperacillin sodium and tazobactam sodium containing PEG600

[0092] Weigh 162g of water for injection and cool to 2-8°C. Weigh 3.5g of citric acid to approximately 6.5°C. Maintain the temperature at 45g throughout the salt-forming reaction. Add to the water for injection and stir until dissolved. Add sodium carbonate to bring the solution pH to approximately 6.5. Add 96g of piperacillin and 12g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate the salt-forming reaction, raising the solution pH to 2-8°C. Add 0.024g of disodium EDTA and 7.2g of PEG 600 and stir until dissolved. Add additional water to a final total weight of 300g. Filter the solution through a 0.22 micron filter and set aside. The solution contains 7.5% PEG 600, batch number 200425-5.

[0093] The four batches of liquid were spray-dried using a pilot spray dryer with the following parameters: inlet temperature: 185°C; outlet temperature: 115°C. The resulting spray-dried powder was then subjected to an ultra-accelerated test at 80°C. Samples were collected at 0, 1, and 3 days to analyze relevant substances, moisture, and pH. The test results are shown in Table 3.

[0094] Table 3 Stability test results of piperacillin sodium and tazobactam sodium spray-dried powder with different stabilizers

[0095]

[0096] As can be seen from Table 3: compared with the batch number of piperacillin sodium and tazobactam sodium without PEG, the spray-dried powder obtained after spray drying of the liquid with PEG400, PEG300, and PEG600 has lower moisture content, lower single impurity and total impurity levels, indicating that the moisture content of the spray-dried powder is reduced and the stability is enhanced after the addition of PEG.

[0097] Example 4: Spray drying test of piperacillin-tazobactam sodium with different concentrations of PEG400

[0098] Using a salt / pH adjustment formula with citric acid and sodium bicarbonate, we explored the effects of different PEG400 ratios on product quality and determined the optimal PEG400 ratio. A total of nine sets of experiments were conducted.

[0099] 4.1 Spray Drying Test of Piperacillin Sodium and Tazobactam Sodium without PEG400

[0100] Weigh 225g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the solution pH to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22-micron filter and set aside. This solution does not contain PEG400 and is batch number 200521-1.

[0101] 4.2 Spray drying test of piperacillin sodium and tazobactam sodium containing 2.5% PEG400

[0102] Weigh 225g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the solution pH to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 3.2g of PEG 400 and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22 micron filter and set aside. The solution contains 2.5% PEG 400, batch number 200521-2.

[0103] 4.3 Spray drying test of piperacillin sodium and tazobactam sodium containing 5% PEG400

[0104] Weigh 225g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the pH of the solution to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 6.4g of PEG 400 and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22 micron filter and set aside. The solution contains 5% PEG 400, batch number 200521-3.

[0105] 4.4 Spray Drying Test of Piperacillin Sodium and Tazobactam Sodium Containing 7.5% PEG400

[0106] Weigh 225g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the solution pH to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 9.6g of PEG 400 and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22 micron filter. The solution contains 7.5% PEG 400, batch number 200522-1.

[0107] 4.5 Spray drying test of piperacillin sodium and tazobactam sodium containing 10% PEG400

[0108] Weigh 222g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the solution pH to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 12.8g of PEG 400 and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22 micron filter and set aside. The solution contains 10% PEG 400 and is batch number 200522-2.

[0109] 4.6 Spray Drying Test of Piperacillin Sodium and Tazobactam Sodium Containing 12.5% ​​PEG400

[0110] Weigh 219g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the solution pH to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 16g of PEG 400 and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22 micron filter and set aside. The solution contains 12.5% ​​PEG 400, batch number 200523-1.

[0111] 4.7 Spray Drying Test of Piperacillin Sodium and Tazobactam Sodium Containing 15% PEG400

[0112] Weigh 216g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the solution pH to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 19.2g of PEG 400 and stir until dissolved. Add more water to a final total weight of 400g. Filter the solution through a 0.22-micron filter and set aside. The solution contains 15% PEG 400, batch number 200523-2.

[0113] 4.8 Spray Drying Test of Piperacillin Sodium and Tazobactam Sodium Containing 17.5% PEG400

[0114] Weigh 213g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the pH of the solution to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 22.4g of PEG 400 and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22 micron filter and set aside. The solution contains 17.5% PEG 400 and is batch number 200523-3.

[0115] 4.9 Spray Drying Test of Piperacillin Sodium and Tazobactam Sodium Containing 20% ​​PEG400

[0116] Weigh 210g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate to bring the solution pH to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 25.6g of PEG 400 and stir until dissolved. Add additional water to a final total weight of 400g. Filter the solution through a 0.22 micron filter and set aside. The solution contains 20% PEG 400 and is batch number 200523-4.

[0117] All nine batches of the aforementioned liquids were spray-dried using a pilot spray dryer with the following parameters: inlet temperature: 185°C; outlet temperature: 115°C. The resulting spray-dried powders were then subjected to ultra-accelerated testing at 80°C. Samples were collected at 0, 1, and 3 days to analyze moisture, related substances, pH, and reconstitution time. The test results are shown in Table 4.

[0118]

[0119] From Table 4 we can see that:

[0120] (1) Adding PEG400 can effectively reduce the moisture content of spray-dried powder from 0% to 20%. The higher the proportion of PEG400, the lower the moisture content, meeting the requirements of the Chinese Pharmacopoeia (moisture ≤ 2.5%).

[0121] (2) From 0% to 20%, as the proportion of PEG400 increased, the increments of single and total impurities showed a trend of first decreasing and then increasing when placed at 80°C for 3 days. When the proportion of PEG400 was 2.5% to 15%, the increments of impurities (single and total impurities) in 3 days were less than those of samples without PEG400 addition, meeting the requirements of the Chinese Pharmacopoeia (single impurity ≤ 2.0%, total impurity ≤ 4.0%).

[0122] (3) The reconstitution time of PEG400 spray-dried powder was increased to approximately 2 to 3 minutes.

[0123] Example 5: Stability test of piperacillin sodium and tazobactam sodium solution stored at different temperatures

[0124] 5.1 Study on the stability of piperacillin sodium and tazobactam sodium solution stored at 2-8°C

[0125] Weigh 225g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate until the pH of the solution reaches approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 10.24g of PEG400, stir until dissolved, and add water to a final total weight of 400g. The batch number of the solution is 200617-2. The piperacillin sodium and tazobactam sodium solution was placed in a refrigerator at 2-8°C for solution stability testing. Samples were collected at 0h, 24h, 48h, and 72h for analysis of related substances. The results are shown in Table 5.

[0126] 5.2 Study on the stability of piperacillin sodium and tazobactam sodium solution stored at -5°C

[0127] Weigh 225g of water for injection and cool to 2-8°C. Weigh 6.4g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate until the pH of the solution reaches approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 10.24g of PEG400, stir until dissolved, and add water to a final total weight of 400g. The batch number of the solution is 200729. The piperacillin sodium and tazobactam sodium solution was stored at -5°C for solution stability testing. Samples were collected at 0, 24, 48, and 72 hours for analysis of related substances. The results are shown in Table 5.

[0128] Table 5 Results of stability study of piperacillin sodium and tazobactam sodium solutions at different storage temperatures

[0129]

[0130] Table 5 shows that compared to storage at 2-8°C, the impurity increase slowed down at -5°C, with the impurity increment reduced by approximately half within 72 hours. Therefore, in commercial production, lower storage temperatures (e.g., -12-0°C) may be considered for liquid preparation, sterilization filtration, and liquid storage to reduce the generation of degradation impurities.

[0131] Example 6: Research on piperacillin sodium and tazobactam sodium spray drying process parameters (air outlet temperature)

[0132] Weigh 450g of water for injection and cool to 2-8°C. Weigh 12.8g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate and raise the pH of the solution to approximately 6.5. Add 256g of piperacillin and 32g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.064g of disodium EDTA and 20.48g of PEG400 and stir until dissolved. Add more water to a final total weight of 800g.

[0133] 6.1 Spray drying test with an inlet air temperature of 185°C and an outlet air temperature of 115°C

[0134] 200 ml of the piperacillin sodium and tazobactam sodium solution was spray-dried using a pilot spray drying tower with the following parameters: inlet air temperature: 185° C.; outlet air temperature: 115° C. The resulting spray-dried powder was batch number 200710-1.

[0135] 6.2 Spray drying test with air inlet temperature of 185°C and air outlet temperature of 110°C

[0136] 200 ml of the piperacillin sodium and tazobactam sodium solution was spray-dried using a pilot spray drying tower with the following parameters set: inlet air temperature: 185° C.; outlet air temperature: 110° C. The resulting spray-dried powder was batch number 200710-2.

[0137] 6.3 Spray drying test with inlet air temperature of 185°C and outlet air temperature of 105°C

[0138] 200 ml of the piperacillin sodium and tazobactam sodium solution was spray-dried using a pilot spray drying tower with the following parameters set: inlet air temperature: 185° C.; outlet air temperature: 105° C. The resulting spray-dried powder was batch number 200710-3.

[0139] 6.4 Spray drying test with inlet air temperature of 185°C and outlet air temperature of 100°C

[0140] 200 ml of the piperacillin sodium and tazobactam sodium solution was spray-dried using a pilot spray drying tower with the following parameters set: inlet air temperature: 185° C.; outlet air temperature: 100° C. The resulting spray-dried powder was batch number 200710-4.

[0141] The above four batches of piperacillin sodium and tazobactam sodium spray-dried powder were tested for moisture and related substances. The results are shown in Table 6.

[0142] Table 6 Study results of piperacillin sodium and tazobactam sodium spray-dried powder quality under different air outlet temperatures

[0143]

[0144] From Table 6, it can be seen that when the air inlet temperature is 185°C and the air outlet temperature is 100-115°C, the quality of the spray-dried powder meets the requirements of the Chinese Pharmacopoeia (moisture ≤ 2.5%, single impurity ≤ 2.0%, total impurities ≤ 4.0%).

[0145] Example 7: Research on the spray drying process parameters (inlet air temperature) of piperacillin sodium and tazobactam sodium

[0146] Weigh 450g of water for injection and cool to 2-8°C. Weigh 12.8g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate and raise the pH of the solution to approximately 6.5. Add 256g of piperacillin and 32g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.064g of disodium EDTA and 20.48g of PEG400 and stir until dissolved. Add more water to a final total weight of 800g.

[0147] 7.1 Spray drying test with air inlet temperature of 185°C and air outlet temperature of 115°C

[0148] 200 ml of the piperacillin sodium and tazobactam sodium solution was spray-dried using a pilot spray drying tower with the following parameters set: inlet air temperature: 185° C.; outlet air temperature: 115° C. The resulting spray-dried powder was batch number 200713-1.

[0149] 7.2 Spray drying test with inlet air temperature of 190°C and outlet air temperature of 115°C

[0150] 200 ml of the piperacillin sodium and tazobactam sodium solution was spray-dried using a pilot spray drying tower with the following parameters: inlet air temperature: 190° C.; outlet air temperature: 115° C. The resulting spray-dried powder was batch number 200713-2.

[0151] 7.3 Spray drying test with air inlet temperature of 195°C and air outlet temperature of 115°C

[0152] 200 ml of the piperacillin sodium and tazobactam sodium solution was spray-dried using a pilot spray drying tower with the following parameters: inlet air temperature: 195° C.; outlet air temperature: 115° C. The resulting spray-dried powder was batch number 200713-3.

[0153] 7.4 Spray drying test with air inlet temperature 200°C and air outlet temperature 115°C

[0154] 200 ml of the piperacillin sodium and tazobactam sodium solution was spray-dried using a pilot spray drying tower with the following parameters set: inlet air temperature: 200° C.; outlet air temperature: 115° C. The resulting spray-dried powder was batch number 200713-4.

[0155] The above four batches of piperacillin sodium and tazobactam sodium spray-dried powder were tested for moisture and related substances. The results are shown in Table 7.

[0156] Table 7 Study results of piperacillin sodium and tazobactam sodium spray-dried powder quality under different inlet air temperatures

[0157]

[0158] It can be seen from Table 7 that when the outlet air temperature is 115°C and the outlet air temperature is 185-200°C, there is no significant difference in the quality of the spray-dried powder, and it meets the requirements of the Chinese Pharmacopoeia (moisture ≤ 2.5%, single impurity ≤ 2.0%, total impurities ≤ 4.0%).

[0159] Example 8: Pilot scale-up and stability study of piperacillin sodium and tazobactam sodium spray drying

[0160] Piperacillin sodium and tazobactam sodium formulations without stabilizer and with PEG400 were formulated and spray-dried on a pilot-scale spray dryer. Accelerated and long-term stability studies were conducted using USP methods for comparison with the commercially available reference formulation (Wyeth RLD).

[0161] 8.1 Pilot Scale-up and Stability Study of Spray Drying of Piperacillin Sodium and Tazobactam Sodium without PEG400

[0162] Weigh 1410g of water for injection and cool to 2-8°C. Weigh 40g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate and raise the pH of the solution to approximately 6.5. Add 800g of piperacillin and 100g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.2g of disodium EDTA and stir until dissolved. Add more water to a final total weight of 2600g. Filter the solution through a 0.22-micron filter and set aside. Batch number 200808-1.

[0163] 8.2 Pilot Scale-up and Stability Study of Spray Drying of Piperacillin Sodium and Tazobactam Sodium Containing PEG400

[0164] Weigh 1410g of water for injection and cool to 2-8°C. Weigh 40g of citric acid and add it to the water for injection. Stir until dissolved. Add sodium bicarbonate until the pH of the solution reaches approximately 6.5. Add 800g of piperacillin and 100g of tazobactam to the sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate a salt-forming reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8°C throughout the salt-forming reaction. Add 0.2g of disodium EDTA and 64g of PEG400, stir until dissolved, and add more water to a final total weight of 2600g. Filter the solution through a 0.22-micron filter and set aside. Batch number 200808-2.

[0165] Both batches were spray-dried using a pilot-scale spray dryer with the following parameters: inlet temperature: 195°C; outlet temperature: 110°C. The resulting spray-dried powder was packaged into formulations and subjected to stability studies under accelerated conditions (40±2°C / 75±5% RH) and long-term conditions (25°C / 60% RH). Sampling was performed at 0, 2, 3, and 6 months for the accelerated test and at 0, 3, 6, and 9 months for the long-term test. Samples were tested for pH, moisture, related substances, and content according to USP methods. The results are shown in Table 8.

[0166] Table 8 Results of accelerated stability study of piperacillin sodium and tazobactam sodium spray-dried powder at 40 ± 2 ° C / 75 ± 5% RH

[0167]

[0168] Table 9 Long-term stability study results of piperacillin sodium and tazobactam sodium spray-dried powder at 25±2°C / 60±5%

[0169]

[0170] Note: Piperacillin and ampicillin are process impurities introduced into the API, non-degradation impurities, and are in a stable or decreasing trend during the stability study.

[0171] Tables 8 and 9 show that: (1) Compared with the spray-dried powder without stabilizer, the piperacillin sodium and tazobactam sodium spray-dried powder with PEG has lower moisture content, fewer impurities, and is more stable. (2) Compared with the RLD freeze-dried powder, due to different processes, the moisture content of the piperacillin sodium and tazobactam sodium spray-dried powder with PEG is slightly higher than that of the RLD freeze-dried powder, but the stability is comparable.

[0172] Example 9: Effect of PEG400 on the bioavailability of piperacillin sodium and tazobactam sodium

[0173] The instructions for use of piperacillin sodium and tazobactam sodium for injection state that in vitro studies and clinical infections have demonstrated antibacterial activity against the following bacteria:

[0174]

[0175] The potency of piperacillin sodium and tazobactam sodium spray-dried powder (Batch No. 200808-2) containing PEG 400 was tested using Wyeth RLD (Batch No. ALM9 / 11) as a control. The effect of PEG 400 on the potency of piperacillin sodium and tazobactam sodium spray-dried powder was investigated using Escherichia coli and Staphylococcus aureus as test bacteria.

[0176] 9.1 Using Escherichia coli as a test bacterium for titer testing

[0177] Method: Butterfly tube method.

[0178] Using the two-dose method, at a concentration of 100U:200U, and using Escherichia coli as the test bacteria, the inhibition zone was between 18-22cm, and the confidence line rate and P value were qualified.

[0179] 9.2 Using Staphylococcus aureus as a test bacteria for potency testing

[0180] Method: Turbidimetric method.

[0181] Wyeth RLD uses Staphylococcus aureus to perform a turbidimetric standard curve test at different gradient concentration units. The standard curve is based on a concentration ratio of 1.6, 2.0, 2.5, 3.125, and 3.906 units. 2 =0.9908, the result is linear.

[0182] Therefore, the potency of piperacillin sodium and tazobactam sodium can be tested using turbidity within a concentration range of 1.6-3.9. Using Wyeth's RLD as the standard and Staphylococcus aureus as the test bacteria, the biopotency of piperacillin sodium and tazobactam sodium spray-dried powder containing PEG400 (Batch No. 200808-2) was determined by diluting the mixture to high and low doses of 3.2U and 1.6U, respectively.

[0183] The above biological potency test results are shown in Table 10.

[0184] Table 10 Bioavailability relative to Wyeth RLD piperacillin sodium tazobactam sodium spray-dried powder

[0185]

[0186] As shown in Table 10, the bioavailability of piperacillin sodium and tazobactam sodium spray-dried powder containing PEG400 is comparable to that of Wyeth RLD, indicating that PEG400 has no effect on the bioavailability of piperacillin sodium and tazobactam sodium. Industrial Applicability

[0187] The industrialized production method of the piperacillin-tazobactam spray-dried powder of the present invention can produce high-purity piperacillin-tazobactam powder with high efficiency and high yield, and has high application value in the pharmaceutical field.

Claims

1. An industrial production method of piperacillin-tazobactam spray-dried powder, characterized in that: The following steps are involved: (1) preparing a mixed solution of piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof, and maintaining the pH value at 6.0 to 7.5; (2) adding a stabilizer to the solution obtained in step (1) to obtain a mixed solution, wherein the stabilizer is selected from one or more of carbohydrates, amino acids, and polyols; and (3) spray-drying the mixed solution obtained in step (2) to obtain piperacillin-tazobactam spray-dried powder.

2. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1, characterized in that: In the mixed solution prepared in step (1), the content ratio of piperacillin sodium or its pharmaceutically acceptable salt calculated as piperacillin free acid and tazobactam or its pharmaceutically acceptable salt calculated as tazobactam free acid is 8:

1.

3. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: In the step (1), a mixed powder of piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof is dissolved in water to prepare a mixed solution; or, piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof are dissolved in water separately and then mixed to prepare a mixed solution; or, piperacillin acid and / or tazobactam acid are first salified under the action of sodium bicarbonate, sodium carbonate or sodium hydroxide to prepare piperacillin sodium and / or tazobactam sodium solutions, and then the mixed solution is prepared.

4. The industrial production method of the piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: The concentration of the mixed solution obtained in the step (2) is 1 to 50% by weight based on piperacillin.

5. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: The concentration of the mixed solution obtained in the step (2) is 26 to 38% by weight based on piperacillin.

6. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: The stabilizer added in step (2) is a polyol.

7. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 6, characterized in that: The stabilizer is polyethylene glycol or glycerol.

8. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 6, characterized in that: The stabilizer is polyethylene glycol 200-600.

9. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 6, characterized in that: The stabilizer is polyethylene glycol 300-400.

10. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: In the step (2), 0 to 50 parts by weight of a stabilizer is added for every 100 parts by weight of piperacillin.

11. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: In the step (2), 0 to 20 parts by weight of a stabilizer is added for every 100 parts by weight of piperacillin.

12. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: In the step (2), 2.5 to 15 parts by weight of a stabilizer is added per 100 parts by weight of piperacillin.

13. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: In the step (2), an aminocarboxylic acid chelating agent EDTA is also added to the solution obtained in the step (1).

14. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: The storage temperature of the mixed solution obtained in step (2) is -12 to 8°C.

15. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: The storage temperature of the mixed solution obtained in step (2) is -10 to 0°C.

16. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: In the step (3), the air inlet temperature during spray drying is 160-240°C.

17. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: In the step (3), the air inlet temperature during spray drying is 185-200°C.

18. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: In the step (3), the outlet air temperature during spray drying is 80-130°C.

19. The industrial production method of piperacillin-tazobactam spray-dried powder according to claim 1 or 2, characterized in that: In the step (3), the air outlet temperature during spray drying is 100-115°C.

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