Industrial production process of piperacillin-tazobactam spray-dried powder

Abstract

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

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to an industrial production method for piperacillin-tazobactam spray-dried powder. Background Technology

[0002] Piperacillin-tazobactam is a combination drug administered parenterally for the treatment or control of bacterial infections. Its active ingredients include piperacillin or its salts and tazobactam or its salts. Piperacillin is a β-lactam antibiotic, whose β-lactam ring is easily destroyed by β-lactamases, thus losing its antibacterial activity. Tazobactam is a β-lactamase inhibitor, which can reduce the destruction of piperacillin by β-lactamase-producing bacteria and protect the antibacterial activity of piperacillin.

[0003] Piperacillin-tazobactam is indicated for: 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, commercially available piperacillin-tazobactam formulations are mainly of two types: premixed frozen bags stored at -20°C and lyophilized powder injections in vials stored at room temperature. Premixed frozen bags require -20°C low-temperature transportation and storage, increasing drug costs and selling price; they also require pre-thawing at room temperature or under refrigeration, which is time-consuming and labor-intensive. Lyophilized powder injections in vials use a freeze-drying process, resulting in a long production cycle, low capacity, high energy consumption, and significant losses.

[0004] Spray drying is a mature powder production technology. Its principle involves spraying a liquid feedstock into a fine mist through 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 pharmaceutical preparation (Patent Documents 1-3), there are no reports of industrial-scale production of piperacillin-tazobactam using spray drying. Piperacillin-tazobactam is known to be unstable in aqueous solution. On the one hand, piperacillin is a β-lactam antibiotic, which is easily decomposed and destroyed by high temperature, acids, alkalis, oxidants, metal ions, etc. after dissolving in water, generating antigenic degradation products and causing allergic reactions. On the other hand, as piperacillin degrades, the pH value of the solution decreases, and the acid-base balance of piperacillin-tazobactam shifts to acidic form, resulting in the crystallization of piperacillin-tazobactam and the formation of insoluble piperacillin-tazobactam acid particles.

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

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: US6001800

[0009] Patent Document 2: US6479049

[0010] Patent Document 3: WO2014 / 139329 Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide an industrial manufacturing method for producing high-purity and high-stability piperacillin-tazobactam with high efficiency and high yield.

[0012] In order to solve the above-mentioned technical problems, the inventors of the present invention conducted in-depth research and unexpectedly discovered that spray drying can produce high-purity piperacillin-tazobactam powder with high efficiency and high yield, thus completing the present invention.

[0013] Specifically, the present invention provides an industrial method for producing piperacillin-tazobactam spray-dried powder.

[0014] (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; (3) spray-drying the mixed solution obtained in step (2) to obtain piperacillin-tazobactam spray-dried powder.

[0015] (2) An industrial production method of piperacillin-tazobactam spray-dried powder as described in (1), wherein the mixed solution prepared in step (1) contains piperacillin sodium or a pharmaceutically acceptable salt thereof, calculated as free acid of piperacillin, and tazobactam or a pharmaceutically acceptable salt thereof, in a ratio of approximately 8:1, calculated as free acid of tazobactam.

[0016] (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 salted separately under the action of sodium bicarbonate, sodium carbonate or sodium hydroxide to prepare a solution of piperacillin sodium and / or tazobactam sodium, and then a mixed solution is prepared.

[0017] (4) An industrial method for producing 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 of piperacillin.

[0018] (5) An industrial method for producing piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein the concentration of the mixed solution obtained in step (2) is 26-38% by weight, calculated as piperacillin.

[0019] (6) An 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.

[0020] (7) An industrial production method of piperacillin-tazobactam spray-dried powder as described in (6), wherein the stabilizer is polyethylene glycol or glycerol.

[0021] (8) An industrial production method of piperacillin-tazobactam spray-dried powder as described in (6), wherein the stabilizer is polyethylene glycol 200-600.

[0022] (9) An industrial production method of piperacillin-tazobactam spray-dried powder as described in (6), wherein the stabilizer is polyethylene glycol 300-400.

[0023] (10) An industrial method for producing piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein in step (2), 0 to 50 parts by weight of stabilizer are added relative to 100 parts by weight of piperacillin.

[0024] (11) An industrial method for producing piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein in step (2), 0 to 20 parts by weight of stabilizer are added relative to 100 parts by weight of piperacillin.

[0025] (12) An industrial method for producing piperacillin-tazobactam spray-dried powder as described in (1) or (2), wherein in step (2), 2.5 to 15 parts by weight of stabilizer are added relative to 100 parts by weight of piperacillin.

[0026] (13) An 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 added to the solution obtained in step (1).

[0027] (14) An 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.

[0028] (15) An 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.

[0029] (16) An 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.

[0030] (17) An 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.

[0031] (18) An 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.

[0032] (19) An 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 100-115°C.

[0033] Invention Effects

[0034] The industrial 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. Attached Figure Description

[0035] Figure 1 This indicates the morphology of piperacillin sodium / tazobactam sodium spray-dried powder under an optical microscope. Detailed Implementation

[0036] As mentioned above, commercially available piperacillin-tazobactam formulations are mainly divided into two types: premixed frozen bags stored at -20°C and lyophilized powder injections in vials stored at room temperature. However, there are no reports of industrial-scale production using spray drying. Because piperacillin is unstable in aqueous solution and is easily decomposed by high temperatures, acids, alkalis, oxidants, and metal ions after dissolving in water, its stability during aqueous storage is questionable. There are also concerns that piperacillin-tazobactam may be degraded by the high temperatures during spray drying.

[0037] The inventors of this invention attempted to prepare piperacillin-tazobactam powder using a spray-drying method. Through research, they discovered that when using spray drying to prepare piperacillin-tazobactam powder, adding stabilizers (such as carbohydrates, amino acids, and / or polyols) to the formulation can increase the stability of piperacillin-tazobactam, thereby enabling the efficient and high-yield production of high-purity piperacillin-tazobactam powder. Simultaneously, lowering the storage temperature of the piperacillin-tazobactam solution can also significantly improve the stability of the solution and reduce the generation of impurities. Furthermore, using citrate or similar pH buffers to maintain the pH of the piperacillin-tazobactam solution at 6.0–7.5 can further enhance its stability. EDTA, as a metal ion chelating agent, can also further increase the stability of piperacillin-tazobactam.

[0038] Based on the above research, this invention provides an industrial manufacturing method for high-purity, low-impurity, high-efficiency, and high-yield spray-dried piperacillin-tazobactam powder. The method includes preparing a piperacillin-tazobactam solution, adding carbohydrate, amino acid, and / or polyol stabilizers, and adding EDTA and sodium citrate as needed to obtain a mixed solution. This solution is stored under low-temperature conditions to ensure purity and reduce impurities, followed by sterile filtration or non-sterile filtration, and then spray-dried to obtain sterile or non-sterile piperacillin-tazobactam API. The sterile API is then aseptically packaged to obtain the final formulation product.

[0039] The industrial manufacturing method of the present invention specifically includes the following steps:

[0040] (1) Prepare a mixed solution of piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof.

[0041] In this step, the pH value is maintained at 6.0–7.5, for example, 6.0–7.0, 6.1–6.9, 6.2–6.8, 6.3–6.7, 6.4–6.6, preferably around 6.5. By maintaining the pH value within this range, piperacillin-tazobactam exhibits better stability. The pH value can be adjusted using methods known in the art, such as adding citrate.

[0042] In this step, a mixed solution can be prepared by dissolving piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof in water; 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 salted in the presence of sodium bicarbonate, sodium carbonate, or sodium hydroxide to prepare piperacillin sodium and / or tazobactam sodium solutions, and then mixed to prepare a mixed solution. When the method of separately salting piperacillin acid and / or tazobactam acid in the presence of sodium bicarbonate, sodium carbonate, or sodium hydroxide to prepare piperacillin sodium and / or tazobactam sodium solutions, and then preparing a mixed solution, the degradation of piperacillin and tazobactam can be minimized, resulting in a product with better purity.

[0043] The mixing ratio of piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof is approximately 8:1, which may be adjusted as needed. Therefore, in the mixed solution prepared in step (1), the ratio of piperacillin sodium or a pharmaceutically acceptable salt thereof, calculated as free piperacillin acid, to tazobactam or a pharmaceutically acceptable salt thereof, calculated as free tazobactam acid, is approximately 8:1.

[0044] (2) Add a stabilizer to the solution obtained in step (1) to obtain a mixed solution.

[0045] This invention discovers that adding a stabilizer to the formulation when preparing piperacillin-tazobactam powder using a spray drying method can increase the stability of piperacillin-tazobactam. The stabilizer used in this invention is selected from one or more of carbohydrates, amino acids, and polyols, preferably polyols such as polyethylene glycol and glycerol, more preferably polyethylene glycol, and even more preferably polyethylene glycol 200-600 or 300-400. In this step, 0-50 parts by weight of stabilizer are added relative to 100 parts by weight of piperacillin, preferably 0-20 parts by weight, more preferably 2.5-15 parts by weight, and even more preferably 7.5-15 parts by weight.

[0046] The concentration of the mixed solution obtained in this step, calculated as piperacillin, is 1 to 50% by weight, preferably 1 to 42% by weight, and more preferably 26 to 38% by weight.

[0047] If necessary, an aminocarboxylic acid chelating agent, EDTA, can also be added in this step. EDTA, as a metal chelating agent, can increase the stability of piperacillin-tazobactam.

[0048] The mixed solution obtained in this step can be used directly for spray drying or stored at a suitable low temperature, preferably -12 to 8°C, more preferably -10 to 0°C. Storing the piperacillin-tazobactam solution at a suitable low temperature can significantly improve its stability and reduce the generation of impurities.

[0049] Depending on the needs, the mixed solution obtained in this step can be sterilized and filtered before being used for spray drying, or it can be used directly for spray drying without sterilization and filtration.

[0050] (3) The mixed solution obtained in step (2) is spray-dried to obtain piperacillin tazobactam spray-dried powder.

[0051] In this step, the inlet air temperature during spray drying is 160–240°C, preferably 185–200°C. The outlet air temperature during spray drying is 80–130°C, preferably 100–115°C. The heating medium used during spray drying can be compressed air or nitrogen, thereby obtaining piperacillin-tazobactam spray-dried powder.

[0052] The spray-dried powder obtained by the industrial manufacturing method of the piperacillin-tazobactam spray-dried powder of the present invention is a non-sterile or sterile powder spherical particle, which can be filled into non-sterile or sterile bags / vials using a powder filling machine to produce non-sterile or sterile APIs or sterile preparations.

[0053] The results of accelerated and long-term stability studies on the spray-dried powder obtained by the industrial manufacturing method of the present invention show that the key quality properties of the product (such as moisture and impurities) are comparable to those of commercially available reference formulations, and meet the requirements of the Chinese Pharmacopoeia and / or the United States Pharmacopoeia.

[0054] The stabilizer contained in the spray-dried powder obtained by the industrial manufacturing method of the piperacillin-tazobactam spray-dried powder of the present invention has no effect on the biopotency of piperacillin-tazobactam.

[0055] This invention offers the following advantages: Firstly, it utilizes spray drying technology for the production of piperacillin-tazobactam powder. Secondly, by adding a stabilizer to the formulation, the quality of the obtained spray-dried powder can be comparable to that of a commercially available reference formulation. Thirdly, this invention discovers that lowering the storage temperature of the piperacillin-tazobactam solution to below 0°C significantly reduces impurity generation and improves the stability of the piperacillin-tazobactam aqueous solution. Fourthly, this invention confirms that the concentration of piperacillin-tazobactam in the prepared solution can reach up to 42%. Finally, this invention utilizes a high-concentration piperacillin-tazobactam solution for spray drying, developing a highly efficient, high-yield, and low-energy-consumption method for the industrial production of piperacillin-tazobactam.

[0056] Example

[0057] The present invention will be further described in detail below through the following embodiments, but the present invention is not limited to the range of process parameters in the following embodiments.

[0058] Example 1: Experiments on salt formation of piperacillin acid and tazobactam acid using different bases 1.1 Salt formation using sodium bicarbonate

[0059] Weigh 42g of water for injection and cool it to 2-8℃. Weigh 0.86g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to bring the pH of the solution to approximately 6.5. Take 24g of piperacillin and 3g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature between 2-8℃ throughout the entire salt formation reaction. Sample batch number: 200303-2.

[0060] 1.2 Salt formation using sodium carbonate

[0061] Weigh 42g of water for injection and cool it to 2-8℃. Weigh 0.86g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to bring the pH of the solution to approximately 6.5. Take 24g of piperacillin and 3g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium carbonate to raise the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the entire salt formation reaction. Sample batch number: 200303-3.

[0062] The above two batches of piperacillin sodium and tazobactam sodium solutions were tested for related substances and content. The results are shown in Table 1.

[0063] Table 1. Results of the salt formation reaction of piperacillin-tazobactam using different bases.

[0064]

[0065] As shown in Table 1, when using sodium bicarbonate salt formation and sodium carbonate salt formation, the related substances test of the samples met the CP standard (single impurity ≤ 2.0%, total impurity ≤ 4.0%).

[0066] Example 2: Stability test of feed solutions with different concentrations

[0067] 2.1 Stability test of 42% piperacillin sodium / tazobactam sodium solution

[0068] Weigh 244g of water for injection and cool it to 2-8℃. Weigh 6.9g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium carbonate until the pH of the solution reaches approximately 6.5. Take 192g of piperacillin and 24g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium carbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.048g of disodium EDTA and 14.2g of PEG400, stirring until dissolved. Add water to a final total weight of 500g. The concentration of the solution is approximately 42% (based on piperacillin), batch number 200318-1.

[0069] 2.2 Stability test of 38% piperacillin sodium / tazobactam sodium solution

[0070] Weigh 287g of water for injection and cool it to 2-8℃. Weigh 6.9g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium carbonate until the pH of the solution reaches approximately 6.5. Take 192g of piperacillin and 24g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium carbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.048g of disodium EDTA and 14.2g of PEG400, stirring until dissolved. Add water to a final total weight of 550g. The concentration of the solution is approximately 39% (based on piperacillin), batch number 200318-2.

[0071] 2.3 Stability test of 34% piperacillin sodium / tazobactam sodium solution

[0072] Weigh 338g of water for injection and cool it to 2-8℃. Weigh 6.9g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium carbonate until the pH of the solution reaches approximately 6.5. Take 192g of piperacillin and 24g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium carbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.048g of disodium EDTA and 14.2g of PEG400, stirring until dissolved. Add water to a final total weight of 600g. The concentration of the solution is approximately 34% (based on piperacillin), batch number 200318-3.

[0073] 2.4 Stability test of 30% piperacillin sodium / tazobactam sodium solution

[0074] Weigh 317g of water for injection and cool it to 2-8℃. Weigh 5.5g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium carbonate until the pH of the solution reaches approximately 6.5. Take 152g of piperacillin and 19g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium carbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.038g of disodium EDTA and 11.4g of PEG400, stirring until dissolved. Add water to a final total weight of 524g. The concentration of the solution is approximately 30% (based on piperacillin), batch number 200319-1.

[0075] 2.5 Stability test of 26% piperacillin sodium / tazobactam sodium solution

[0076] Weigh 358g of water for injection and cool it to 2-8℃. Weigh 5.2g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium carbonate until the solution pH reaches approximately 6.5. Take 144g of piperacillin and 18g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium carbonate to initiate the salt formation reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.036g of disodium EDTA and 10.8g of PEG400, stirring until dissolved. Add water to a final total weight of 554g. The solution concentration is approximately 30% (based on piperacillin), batch number 200319-2.

[0077] The above five batches of piperacillin sodium and tazobactam sodium solutions were filtered using a 0.22 μm microporous membrane. The filtration time was recorded, and the filtration efficiency was calculated. The filtered solutions were then subjected to stability studies at 2–8 °C. Samples were taken at 0 h, 24 h, 48 h, and 72 h to determine the pH, content, and related substances. The results are shown in Table 2.

[0078] Table 2 Results of solution stability study

[0079]

[0080] As can be seen from Table 2:

[0081] 1) As the solution concentration decreases, the filtration efficiency increases; the filtration efficiency of solutions with a concentration below 38% is significantly higher than that of solutions with a concentration above 38%.

[0082] 2) When the five groups of feed solutions with different concentrations (26% to 42%, calculated as piperacillin) were stored at 2 to 8°C for 72 hours, the relevant substances all met the CP standard. Among them, the third group (concentration of about 34%) had the smallest increase in impurities.

[0083] Example 3: Spray drying test of piperacillin sodium and tazobactam sodium (35% solution concentration) with different stabilizers

[0084] 3.1 Spray drying test of piperacillin sodium and tazobactam sodium without stabilizer

[0085] Weigh 225g of water for injection and cool it to 2-8℃. Weigh 4.6g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium carbonate to adjust the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium carbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and stir until dissolved. Add water to a final total weight of 400g. Filter the solution through a 0.22-micron filter and set aside. Batch number: 200424-1.

[0086] 3.2 Spray drying test of piperacillin sodium and tazobactam sodium containing PEG400

[0087] Take 225g of water for injection and cool it to 2-8℃. Weigh 4.6g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium carbonate to bring the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium carbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 9.6g of PEG 400, stirring until dissolved. Add 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), batch number 200424-3.

[0088] 3.3 Spray drying test of piperacillin sodium and tazobactam sodium containing PEG300

[0089] Weigh 162g of water for injection and cool it to 2-8℃. Weigh 3.45g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium carbonate to bring the pH of the solution to approximately 6.5. Take 96g of piperacillin and 12g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium carbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.024g of disodium EDTA and 7.2g of PEG 300, stirring until dissolved. Add 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% PEG300, batch number 200425-4.

[0090] 3.4 Spray drying test of piperacillin sodium and tazobactam sodium containing PEG600

[0091] Weigh 162g of water for injection and cool it to 2-8℃. Weigh 3.45g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium carbonate to adjust the pH of the solution to approximately 6.5. Add 96g of piperacillin and 12g of tazobactam to the above sodium citrate solution and stir to form a suspension. Slowly add sodium carbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.024g of disodium EDTA and 7.2g of PEG 600 and stir until dissolved. Add 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% PEG600, batch number 200425-5.

[0092] The above four batches of liquid feed were spray-dried using a small-scale spray drying tower with the following parameters: inlet air temperature: 185℃; outlet air temperature: 115℃. The obtained spray-dried powder was placed at 80℃ for ultra-accelerated testing, and samples were taken at 0 days, 1 day, and 3 days to detect related substances, moisture, and pH. The test results are shown in Table 3.

[0093] Table 3. Stability Study Results of Piperacillin Sodium / Tazobactam Sodium Spray-Dried Powder with Different Stabilizers

[0094]

[0095] As shown in Table 3, compared with the batches of piperacillin sodium and tazobactam sodium without PEG, the spray-dried powder obtained after spray drying of the feed solution with PEG400, PEG300, and PEG600 had lower moisture content, lower levels of single impurities and total impurities, indicating that the addition of PEG reduced the moisture content and enhanced the stability of the spray-dried powder.

[0096] Example 4: Spray drying test of piperacillin-tazobactam sodium with different concentrations of PEG400

[0097] The experiment used a formulation that combined citric acid and sodium bicarbonate to form a salt / adjust pH level, exploring the effect of different proportions of PEG400 on product quality, and thus determining the optimal proportion of PEG400. A total of 9 sets of experiments were conducted.

[0098] 4.1 Spray drying test of piperacillin sodium and tazobactam sodium without PEG400

[0099] Weigh 225g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to adjust the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and stir until dissolved. Add water to a final total weight of 400g. Filter the solution through a 0.22-micron filter and set aside. The solution is PEG-free and batch number 200521-1.

[0100] 4.2 Spray-drying test of piperacillin sodium and tazobactam sodium containing 2.5% PEG400

[0101] Weigh 225g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to adjust the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 3.2g of PEG 400, stirring until dissolved. Add 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% PEG400, batch number 200521-2.

[0102] 4.3 Spray-drying test of piperacillin sodium and tazobactam sodium containing 5% PEG400

[0103] Weigh 225g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to adjust the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring 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℃ throughout the salt-forming reaction. Add 0.032g of disodium EDTA and 6.4g of PEG 400, stirring until dissolved. Add water to a final total weight of 400g. Filter the solution through a 0.22-micron filter and set aside. The solution contains 5% PEG400, batch number 200521-3.

[0104] 4.4 Spray-drying test of piperacillin sodium and tazobactam sodium containing 7.5% PEG400

[0105] Weigh 225g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to bring the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 9.6g of PEG 400, stirring until dissolved. Add water to a final total weight of 400g. Filter the solution through a 0.22-micron filter. The solution contains 7.5% PEG400, batch number 200522-1. 4.5 Spray drying test of piperacillin sodium and tazobactam sodium containing 10% PEG400.

[0106] Weigh 222g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to adjust the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate a salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 12.8g of PEG 400, stirring until dissolved. Add water to a final total weight of 400g. Filter the solution through a 0.22-micron filter and set aside. The solution contains 10% PEG400, batch number 200522-2.

[0107] 4.6 Spray-drying test of piperacillin sodium and tazobactam sodium containing 12.5% ​​PEG400

[0108] Weigh 219g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to adjust the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 16g of PEG 400, stirring until dissolved. Add 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% ​​PEG400, batch number 200523-1.

[0109] 4.7 Spray-drying test of piperacillin sodium and tazobactam sodium containing 15% PEG400

[0110] Weigh 216g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to adjust the pH of the solution to approximately 6.5. Add 128g of piperacillin and 16g of tazobactam to the above sodium citrate solution and stir to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 19.2g of PEG 400 and stir until dissolved. Add water to a final total weight of 400g. Filter the solution through a 0.22-micron filter and set aside. The solution contains 15% PEG400, batch number 200523-2.

[0111] 4.8 Spray-drying test of piperacillin sodium and tazobactam sodium containing 17.5% PEG400

[0112] Weigh 213g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to adjust the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 22.4g of PEG 400, stirring until dissolved. Add 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% PEG400, batch number 200523-3.

[0113] 4.9 Spray-drying test of piperacillin sodium and tazobactam sodium containing 20% ​​PEG400

[0114] Weigh 210g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate to adjust the pH of the solution to approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 25.6g of PEG 400, stirring until dissolved. Add water to a final total weight of 400g. Filter the solution through a 0.22-micron filter and set aside. The solution contains 20% PEG400, batch number 200523-4.

[0115] All nine batches of the above-mentioned liquid materials were spray-dried using a small-scale spray drying tower with the following parameters: inlet air temperature: 185℃; outlet air temperature: 115℃. The obtained spray-dried powder was placed at 80℃ for ultra-accelerated testing, and samples were taken at 0 days, 1 day, and 3 days to test moisture, related substances, pH, and reconstitution time. The test results are shown in Table 4.

[0116]

[0117] As can be seen from Table 4:

[0118] (1) Adding PEG400 can effectively reduce the moisture content of the spray-dried powder from 0% to 20%. The higher the proportion of PEG400, the lower the moisture content, which meets the requirements of the Chinese Pharmacopoeia (moisture content ≤ 2.5%).

[0119] (2) From 0% to 20%, as the proportion of PEG400 increases, after being placed at 80℃ for 3 days, the increase in single impurities and total impurities shows a trend of first decreasing and then increasing. When the proportion of PEG400 is 2.5% to 15%, the increase in impurities (single impurities and total impurities) after 3 days is less than that of the sample without PEG400, which meets the requirements of the Chinese Pharmacopoeia (single impurities ≤ 2.0%, total impurities ≤ 4.0%).

[0120] (3) The reconstitution time of the spray-dried PEG400 powder has been increased to about 2 to 3 minutes.

[0121] Example 5: Stability test of piperacillin sodium / tazobactam sodium solution stored at different temperatures

[0122] 5.1 The stability of piperacillin sodium / tazobactam sodium solution was investigated during storage at 2–8°C.

[0123] Weigh 225g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate until the solution pH reaches approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate a salt formation reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 10.24g of PEG400, stirring until dissolved. Add water to a final total weight of 400g. The solution batch number is 200617-2. The piperacillin sodium tazobactam sodium solution was placed in a 2-8℃ refrigerator for solution stability studies. Samples were taken at 0h, 24h, 48h, and 72h to detect related substances. The results are shown in Table 5.

[0124] 5.2 The stability of piperacillin sodium / tazobactam sodium solution was investigated when stored at -5°C.

[0125] Weigh 225g of water for injection and cool it to 2-8℃. Weigh 6.4g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate until the solution pH reaches approximately 6.5. Take 128g of piperacillin and 16g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate a salt formation reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.032g of disodium EDTA and 10.24g of PEG400, stirring until dissolved. Add water to a final total weight of 400g. The solution batch number is 200729. The piperacillin sodium tazobactam sodium solution was placed at -5℃ for solution stability studies. Samples were taken at 0h, 24h, 48h, and 72h to detect related substances. The results are shown in Table 5.

[0126] Table 5. Results of stability studies of piperacillin sodium / tazobactam sodium solutions at different storage temperatures.

[0127]

[0128] As shown in Table 5, compared to storage conditions of 2–8℃, the increase in impurities slows down under storage conditions of -5℃, with the increase in impurities decreasing by about half within 72 hours. Therefore, in commercial production, lowering the storage temperature (e.g., -12–0℃) for solution preparation, sterilization filtration, and feed storage can be considered to reduce the generation of degradation impurities.

[0129] Example 6: Study on the process parameters (outlet air temperature) of spray drying of piperacillin sodium and tazobactam sodium

[0130] Weigh 450g of water for injection and cool it to 2-8℃. Weigh 12.8g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate until the solution pH reaches approximately 6.5. Take 256g of piperacillin and 32g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.064g of disodium EDTA and 20.48g of PEG400, stirring until dissolved. Add water to a final total weight of 800g. 6.1 Spray drying test with inlet air temperature of 185℃ and outlet air temperature of 115℃.

[0131] Take 200 ml of the above piperacillin sodium / tazobactam sodium solution and spray dry it using a small-scale spray drying tower with the following parameters set: inlet air temperature: 185℃; outlet air temperature: 115℃. The batch number of the obtained spray-dried powder is 200710-1.

[0132] 6.2 Spray drying test with inlet air temperature of 185℃ and outlet air temperature of 110℃

[0133] Take 200 ml of the above piperacillin sodium / tazobactam sodium solution and spray dry it using a small-scale spray drying tower with the following parameters set: inlet air temperature: 185℃; outlet air temperature: 110℃. The batch number of the obtained spray-dried powder is 200710-2.

[0134] 6.3 Spray drying test with inlet air temperature of 185℃ and outlet air temperature of 105℃

[0135] Take 200 ml of the above piperacillin sodium / tazobactam sodium solution and spray dry it using a small-scale spray drying tower with the following parameters set: inlet air temperature: 185℃; outlet air temperature: 105℃. The batch number of the obtained spray-dried powder is 200710-3.

[0136] 6.4 Spray drying test with inlet air temperature of 185℃ and outlet air temperature of 100℃

[0137] Take 200 ml of the above piperacillin sodium / tazobactam sodium solution and spray dry it using a small-scale spray drying tower with the following parameters set: inlet air temperature: 185℃; outlet air temperature: 100℃. The batch number of the obtained spray-dried powder is 200710-4.

[0138] The moisture and related substances of the above four batches of piperacillin sodium and tazobactam sodium spray-dried powder were tested, and the results are shown in Table 6.

[0139] Table 6. Results of quality study of piperacillin sodium and tazobactam sodium spray-dried powder under different outlet air temperatures.

[0140]

[0141] As shown in Table 6, when the inlet air temperature is 185℃ and the outlet air temperature is 100-115℃, the quality of the sprayed dry powder meets the requirements of the Chinese Pharmacopoeia (moisture ≤ 2.5%, single impurity ≤ 2.0%, total impurity ≤ 4.0%).

[0142] Example 7: Study and Experiment on Spray Drying Process Parameters (Inlet Air Temperature) of Piperacillin Sodium and Tazobactam Sodium

[0143] Weigh 450g of water for injection and cool it to 2-8℃. Weigh 12.8g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate until the solution pH reaches approximately 6.5. Take 256g of piperacillin and 32g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.064g of disodium EDTA and 20.48g of PEG400, stirring until dissolved. Add water to bring the final total weight of the solution to 800g. 7.1 Spray drying test with inlet air temperature of 185℃ and outlet air temperature of 115℃.

[0144] Take 200 ml of the above piperacillin sodium / tazobactam sodium solution and spray dry it using a small-scale spray drying tower with the following parameters set: inlet air temperature: 185℃; outlet air temperature: 115℃. The batch number of the obtained spray-dried powder is 200713-1.

[0145] 7.2 Spray drying test with inlet air temperature of 190℃ and outlet air temperature of 115℃

[0146] Take 200 ml of the above piperacillin sodium / tazobactam sodium solution and spray dry it using a small-scale spray drying tower with the following parameters set: inlet air temperature: 190℃; outlet air temperature: 115℃. The batch number of the obtained spray-dried powder is 200713-2.

[0147] 7.3 Spray drying test with inlet air temperature of 195℃ and outlet air temperature of 115℃

[0148] Take 200 ml of the above piperacillin sodium / tazobactam sodium solution and spray dry it using a small-scale spray drying tower with the following parameters set: inlet air temperature: 195℃; outlet air temperature: 115℃. The batch number of the obtained spray-dried powder is 200713-3.

[0149] 7.4 Spray drying test with inlet air temperature of 200℃ and outlet air temperature of 115℃

[0150] Take 200 ml of the above piperacillin sodium / tazobactam sodium solution and spray dry it using a small-scale spray drying tower with the following parameters set: inlet air temperature: 200℃; outlet air temperature: 115℃. The batch number of the obtained spray-dried powder is 200713-4.

[0151] The moisture and related substances of the above four batches of piperacillin sodium and tazobactam sodium spray-dried powder were tested, and the results are shown in Table 7.

[0152] Table 7 Results of quality study of piperacillin sodium and tazobactam sodium spray-dried powder under different inlet air temperatures.

[0153]

[0154] As shown in Table 7, there is no significant difference in the quality of the sprayed dry powder when the outlet air temperature is 115℃ or 185-200℃, and it meets the requirements of the Chinese Pharmacopoeia (moisture ≤2.5%, single impurity ≤2.0%, total impurity ≤4.0%).

[0155] Example 8: Pilot-scale scale-up and stability study of piperacillin sodium and tazobactam sodium spray drying

[0156] Piperacillin sodium tazobactam sodium without stabilizers and containing PEG400 was formulated and spray-dried on a pilot-scale spray drying tower. Accelerated and long-term stability studies were conducted according to USP methods, comparing it with a commercially available reference formulation (Wyeth RLD).

[0157] 8.1 Pilot-scale and stability study of spray-dried piperacillin sodium and tazobactam sodium without PEG400

[0158] Weigh 1410g of water for injection and cool it to 2-8℃. Weigh 40g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate until the solution pH reaches approximately 6.5. Take 800g of piperacillin and 100g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the solution pH to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.2g of disodium EDTA and stir until dissolved. Add water to a final total weight of 2600g. Filter the solution through a 0.22-micron filter and set aside. Batch number: 200808-1.

[0159] 8.2 Pilot-scale and stability study of spray-dried piperacillin sodium and tazobactam sodium containing PEG400

[0160] Weigh 1410g of water for injection and cool it to 2-8℃. Weigh 40g of citric acid and add it to the water for injection, stirring until dissolved. Add sodium bicarbonate until the pH of the solution reaches approximately 6.5. Take 800g of piperacillin and 100g of tazobactam and add them to the above sodium citrate solution, stirring to form a suspension. Slowly add sodium bicarbonate to initiate the salt formation reaction, raising the pH of the solution to approximately 6.5. Maintain the temperature at 2-8℃ throughout the salt formation reaction. Add 0.2g of disodium EDTA and 64g of PEG400, stirring until dissolved. Add water to a final total weight of 2600g. Filter the solution through a 0.22-micron filter and set aside. Batch number: 200808-2.

[0161] Both batches of the above-mentioned liquid feed were spray-dried using a pilot-scale spray drying tower with the following parameters: inlet air temperature: 195℃; outlet air temperature: 110℃. The obtained spray-dried powder was then packaged into formulations and subjected to stability studies under accelerated testing conditions (40±2℃ / 75±5%RH) and long-term testing conditions (25℃ / 60%RH). The sampling time points for the accelerated testing were 0, 2, 3, and 6 months; the sampling time points for the long-term testing were 0, 3, 6, and 9 months. The pH value, moisture content, related substances, and content of the samples were determined according to the USP method. The results are shown in Table 8.

[0162] Table 8 Results of accelerated stability study of piperacillin sodium and tazobactam sodium spray-dried powder at 40±2℃ / 75±5%RH

[0163]

[0164] Table 9. Results of long-term stability study of piperacillin sodium and tazobactam sodium spray-dried powder at 25±2℃ / 60±5%.

[0165]

[0166] Note: Piperacillin and ampicillin are process impurities introduced into the API, not degradation impurities, and their stability or decreasing trend was observed during stability studies.

[0167] From Tables 8 and 9, we can see that: (1) Compared with the spray-dried powder without stabilizer, the spray-dried powder of piperacillin sodium and tazobactam sodium with PEG has lower moisture content, fewer impurities, and is more stable. (2) Compared with RLD lyophilized powder, due to different processes, the spray-dried powder of piperacillin sodium and tazobactam sodium with PEG has slightly higher moisture content than the RLD lyophilized powder, but the stability is comparable.

[0168] Example 9: Effect of PEG400 on the biopotency of piperacillin sodium and tazobactam sodium

[0169] The package insert for piperacillin sodium and tazobactam sodium for injection states that in vitro studies and clinical infection studies have demonstrated antibacterial activity against the following bacteria:

[0170]

[0171] Using Wyeth RLD (lot number ALM9 / 11) as a control, the potency of piperacillin sodium tazobactam sodium spray-dried powder (lot number 200808-2) containing PEG400 was tested. *Escherichia coli* and *Staphylococcus aureus* were used as test bacteria to investigate the effect of PEG400 on the potency of piperacillin sodium tazobactam sodium spray-dried powder.

[0172] 9.1 Using Escherichia coli as the test bacterium for titer determination

[0173] Method: Tube butterfly method.

[0174] Using the two-dose method, at a concentration of 100U:200U, with Escherichia coli as the test bacterium, the inhibition zone was between 18-22 cm, and the confidence level and P-value were acceptable.

[0175] 9.2 Using Staphylococcus aureus as the test bacterium for titer determination

[0176] Method: Turbidity method.

[0177] Wyeth RLD used Staphylococcus aureus to conduct turbidimetric standard curve experiments at different concentration gradients. The standard curves were prepared with concentration ratios of 1.6, 2.0, 2.5, 3.125, and 3.906 units, with R² = 0.9908, indicating linearity.

[0178] Therefore, the potency of piperacillin sodium / tazobactam sodium can be determined by turbidimetric assay within the concentration range of 1.6-3.9. Using Wyeth RLD as the standard and Staphylococcus aureus as the test bacterium, the solution was diluted to high and low doses of 3.2U and 1.6U, respectively, to determine the biopotency of piperacillin sodium / tazobactam sodium spray-dried powder (batch number 200808-2) containing PEG400.

[0179] The results of the above biopotency tests are shown in Table 10.

[0180] Table 10 Biopotency relative to Wyeth RLD piperacillin sodium tazobactam sodium spray powder

[0181]

[0182] As shown in Table 10, the biopotency of piperacillin sodium tazobactam sodium spray-dried powder containing PEG400 is comparable to that of Wyeth RLD, indicating that PEG400 has no effect on the biopotency of piperacillin sodium tazobactam sodium.

[0183] Industrial applicability

[0184] The industrial production method of 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 method for producing piperacillin-tazobactam spray-dried powder, characterized in that, Includes the following steps: (1) Prepare a mixed solution of piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof, and maintain the pH value at 6.0 to 7.5; (2) Add a stabilizer to the solution obtained in step (1) to obtain a mixed solution; and (3) The mixed solution obtained in step (2) is spray-dried to obtain piperacillin-tazobactam spray-dried powder. In step (2), the added stabilizer is polyethylene glycol 200-600, which is 2.5-15 parts by weight of stabilizer per 100 parts by weight of piperacillin. In step (2), an aminocarboxylic acid chelating agent, EDTA, is also added to the solution obtained in step (1). The storage temperature of the mixed solution obtained in step (2) is -10~0℃. In step (3), the inlet air temperature during spray drying is 185~200℃, and the outlet air temperature during spray drying is 100~115℃.

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

1.

3. The industrial production method of piperacillin-tazobactam spray-dried powder as described in claim 1 or 2, characterized in that: 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 separately in water and then mixed to prepare a mixed solution; or, piperacillin acid and / or tazobactam acid are first salted separately in the presence of sodium bicarbonate, sodium carbonate or sodium hydroxide to prepare a solution of piperacillin sodium and / or tazobactam sodium, and then a mixed solution is prepared.

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

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

6. The industrial production method of piperacillin-tazobactam spray-dried powder as described in claim 1 or 2, characterized in that: The stabilizer is polyethylene glycol 300-400.

7. A piperacillin-tazobactam spray-dried powder, characterized in that: It is a powder-like granule obtained by the industrial production method of the spray-dried powder of piperacillin-tazobactam according to any one of claims 1 to 6. The piperacillin-tazobactam spray-dried powder comprises piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof, and also contains a stabilizer. The stabilizer is polyethylene glycol 200-600. For every 100 parts by weight of piperacillin, there are 2.5 to 15 parts by weight of stabilizer. The spray-dried powder of piperacillin-tazobactam also contains EDTA, an aminocarboxylic acid chelating agent.

8. The piperacillin-tazobactam spray-dried powder according to claim 7, characterized in that: The piperacillin or a pharmaceutically acceptable salt thereof and tazobactam or a pharmaceutically acceptable salt thereof are piperacillin sodium and tazobactam sodium.

9. The piperacillin-tazobactam spray-dried powder according to claim 7, characterized in that: The ratio of piperacillin sodium or a pharmaceutically acceptable salt thereof, calculated as piperacillin free acid, to tazobactam or a pharmaceutically acceptable salt thereof, calculated as tazobactam free acid, is 8:

1.

10. The piperacillin-tazobactam spray-dried powder according to claim 7, characterized in that: The stabilizer is polyethylene glycol 300-400.

11. The piperacillin-tazobactam spray-dried powder according to any one of claims 7 to 10, characterized in that: It also contains citrate.

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