Preparation method of piperacillin sodium and tazobactam sodium freeze-dried preparation for injection

Abstract

The invention discloses a preparation method of a piperacillin sodium and tazobactam sodium freeze-dried preparation for injection. The preparation method comprises the following steps: S1, reacting; s2, pre-freezing: enabling the temperature of the product to reach-35 to-45 DEG C within 10-60 minutes, keeping the temperature for 1 hour, returning the temperature to-15 to-5 DEG C within 10-60 minutes, and keeping the temperature for 2 hours; cooling to-35 DEG C to-45 DEG C again for 10-60 minutes, and keeping for 2 hours; s3, sublimation drying: vacuumizing to 0.15 Mbar, maintaining the vacuum degree, raising the temperature to 5-15 DEG C within 1-2 hours, and maintaining the temperature for 30 hours; s4, analyzing and drying, keeping the vacuum at 0.15 Mbar, heating to 45-60 DEG C within 1-2 hours, keeping the temperature for 2 hours, vacuumizing to 0.01 Mbar, and keeping the temperature at 45-60 DEG C for 1 hour; and S5, testing pressure rise, pressing a plug, and finishing freeze-drying when the pressure rises to normal pressure. The problems that in the prior art, a piperacillin sodium and tazobactam sodium freeze-dried preparation for injection is high in water content, so that the product stability is poor, and meanwhile, due to long freeze-drying time, the preparation energy consumption is high, and the product production cost is high are solved.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to a method for preparing a freeze-dried piperacillin sodium and tazobactam sodium preparation for injection. Background Art

[0002] Tazobactam sodium, molecular formula: C 10 H 11 N 4 NaO 5 S, Tazobactam is a new type of penicillin sulfone β-lactamase inhibitor developed by Taiho Pharmaceutical Co., Ltd. of Japan. It is one of the best β-lactamase inhibitors in clinical application, with high stability, low activity, low toxicity, strong enzyme inhibition activity, etc.

[0003] Piperacillin sodium, molecular formula: C 23 H 26 N 5 NaO 7 S is an excellent variety of the second-generation semi-synthetic β-lactam antibiotics. It has the characteristics of a broad antibacterial spectrum, strong antibacterial effect, mild toxic side effects, and is particularly suitable for patients with severe Gram-negative bacterial infection accompanied by renal impairment. It has been widely used in clinical practice.

[0004] The combination of a powerful β-lactamase inhibitor, tazobactam sodium, and a broad-spectrum semisynthetic penicillin, piperacillin sodium, is an ideal choice for solving drug-resistant bacteria. In the compound preparation of piperacillin sodium and tazobactam sodium for injection, the ratio of piperacillin to tazobactam is 8:1 and 4:1. The compound preparation with a ratio of 8:1 was originally studied by Taiho of Japan. Lederle of the United States first obtained the 8:1 license and was first launched in France in 1992. After 1993, it was launched in the United Kingdom, Spain, Germany, the United States and other countries for the treatment of infections caused by enzyme-producing bacteria in adults and children over 12 years old.

[0005] The existing production of piperacillin sodium and tazobactam sodium lyophilized preparations for injection generally uses piperacillin acid, tazobactam acid and sodium bicarbonate as reaction raw materials and auxiliary materials for production. Since the product does not contain scaffolding agents, the original research company's patents and domestic patents have poor molding and appearance. At the same time, the original research patent has a long lyophilization time, resulting in high energy consumption for preparation, increasing product costs, and high moisture content after lyophilization, affecting product stability. Summary of the invention

[0006] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a method for preparing a freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection, which solves the problem that the product moisture content is high when preparing the freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection in the prior art, thereby causing poor product stability. At the same time, due to the long freeze-drying time, the preparation energy consumption is high and the product production cost is high.

[0007] To achieve the above object, the present invention adopts the following technical solution:

[0008] A method for preparing a freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection comprises the following steps:

[0009] S1, preparation of solution, take water, add EDTA and citric acid, stir to dissolve, then add sodium bicarbonate or sodium hydroxide, stir to dissolve, pH control to 5.5-6.5, solution temperature control 5-15 ° C, add piperacillin acid and tazobactam acid, stir to mix evenly, then titrate with 14% sodium bicarbonate solution or 14% sodium hydroxide solution to pH 6.2-6.4, use a vacuum pump to extract carbon dioxide gas generated by the reaction during the titration process, filter the liquid, fill it into a vial, half-stopper it, and then freeze-dry it;

[0010] S2, pre-freezing, adjusting the freeze dryer to make the product reach -35 to -45°C in 10 to 60 minutes, keep it for 1 hour, then return to -15 to -5°C in 10 to 60 minutes, keep it for 2 hours; cool it down to -35 to -45°C in 10 to 60 minutes again, keep it for 2 hours;

[0011] S3, sublimation drying, evacuate to 0.15Mbar and maintain the vacuum, raise the temperature to 5-15°C in 1-2 hours, and maintain for 30 hours;

[0012] S4, analytical drying, vacuum maintained at 0.15Mbar, 1-2 hours to 45-60 ° C for 2 hours, vacuum to 0.01Mbar, 45-60 ° C for 1 hour;

[0013] S5, pressure rise test, plug pressing, pressure rises to normal pressure, and freeze drying is completed.

[0014] Preferably, the mass ratio of piperacillin acid to tazobactam acid is 8:1 or 4:1.

[0015] Preferably, the pre-freezing in step S2 comprises:

[0016] Pre-freeze once, bring the product temperature to -35--45°C in 10-60 minutes, keep it for 1 hour, then return to -15--5°C in 10-60 minutes, keep it for 2 hours;

[0017] Pre-freeze for the second time, cool down to -35 ~ -45℃ again in 10 ~ 60 minutes and keep it for 2 hours.

[0018] Preferably, the preparation process takes no more than 45 hours.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. The present invention can effectively prevent the collapse of the product through one-time pre-freezing and two-time pre-freezing, and can change the properties of the product, so as to avoid the sharp crystal shape of the product caused by direct one-time pre-freezing. The crystal will wrap the water, which is not conducive to the discharge of water during drying, thereby causing the product to have high water content and poor product stability. The product can be formed into a dense granular shape through the two-time pre-freezing, which is convenient for better opening the channel of water vapor during sublimation drying, making it easier to discharge water, reducing the water content of the product, thereby improving the quality of the product, and at the same time making the freeze-drying speed faster and improving the production efficiency;

[0021] 2. The present invention adopts secondary pre-freezing to avoid the phenomenon of product climbing into the bottle;

[0022] 3. The impurities in the products prepared by the present invention are lower than those in existing products, and the product quality is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a physical picture of the preparation prepared by the preparation method of the original patent comparative example 1;

[0024] Figure 2 This is a physical picture of the preparation prepared in Example 1 of the present invention;

[0025] Figure 3 This is a physical picture of the preparation prepared in Example 2 of the present invention;

[0026] Figure 4 This is a physical picture of the preparation prepared in Example 3 of the present invention. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] Example 1

[0029] A method for preparing a freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection comprises the following steps:

[0030] S1, the preparation of the solution, take water, add EDTA and citric acid, stir to dissolve, then add sodium bicarbonate or sodium hydroxide, stir to dissolve, pH control to 5.5 ~ 6.5, the solution temperature control 5 ~ 15 ° C, add piperacillin acid and tazobactam acid and stir to mix evenly, then titrate with 14% sodium bicarbonate solution or 14% sodium hydroxide solution to pH 6.2 ~ 6.4, during the titration process, use a vacuum pump to extract the carbon dioxide gas produced by the reaction, filter the liquid, pour it into the vial and add a half stopper, and then freeze-dry. This reaction step is similar to the steps in the prior art, and will not be introduced in detail again.

[0031] S2. Prefreezing includes primary prefreezing and secondary prefreezing. For primary prefreezing, the freeze dryer is adjusted to make the product reach -40°C in 60 minutes, maintained for 1 hour, and then returned to -5°C in 60 minutes and maintained for 2 hours. For secondary prefreezing, the temperature is lowered to -45°C in 60 minutes again and maintained for 2 hours. Secondary prefreezing can effectively prevent the collapse of the product and change the properties of the product, avoiding the sharp crystal shape of the product caused by direct primary prefreezing. The crystal will wrap the water, which is not conducive to the discharge of water during drying, and then cause the moisture content of the product to be high and the product stability to be poor. Through secondary prefreezing, the product can be formed into dense granules, which is convenient for better opening the channel of water vapor during sublimation drying, making it easier to discharge water, reducing the moisture content of the product, and thus improving the quality of the product. At the same time, it can make the freeze-drying speed faster and improve production efficiency. At the same time, secondary prefreezing can avoid the phenomenon of product climbing into the bottle.

[0032] S3, sublimation drying, evacuate to 0.15Mbar and maintain the vacuum, heat to 15°C in 2 hours, and keep for 30 hours;

[0033] S4, analytical drying, vacuum maintained at 0.15Mbar, heated to 50°C for 2 hours, maintained at 45°C for 1 hour;

[0034] S5, pressure rise test, plug pressing, pressure rises to normal pressure, and freeze drying is completed.

[0035] Example 2

[0036] A method for preparing a freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection comprises the following steps:

[0037] S1, the preparation of the solution, take water, add EDTA and citric acid, stir to dissolve, then add sodium bicarbonate or sodium hydroxide, stir to dissolve, pH control to 5.5 ~ 6.5, the solution temperature control 5 ~ 15 ° C, add piperacillin acid and tazobactam acid and stir to mix evenly, then titrate with 14% sodium bicarbonate solution or 14% sodium hydroxide solution to pH 6.2 ~ 6.4, during the titration process, use a vacuum pump to extract the carbon dioxide gas produced by the reaction, filter the liquid, pour it into the vial and add a half stopper, and then freeze-dry. This reaction step is similar to the steps in the prior art, and will not be introduced in detail again.

[0038] S2, pre-freezing, including primary pre-freezing and secondary pre-freezing, primary pre-freezing, product temperature reaches -35°C in 10 minutes, keeps for 1 hour, then returns to -15°C in 10 minutes, keeps for 2 hours, secondary pre-freezing, again cools to -35°C in 10 minutes, keeps for 2 hours;

[0039] S3, sublimation drying, evacuate to 0.15Mbar and maintain the vacuum, raise the temperature to 5°C in 1 hour, and maintain for 30 hours;

[0040] S4, analytical drying, vacuum maintained at 0.15Mbar, heated to 45°C for 1 hour and maintained for 2 hours, evacuated to 0.01Mbar, and maintained at 60°C for 1 hour;

[0041] S5, pressure rise test, plug pressing, pressure rises to normal pressure, and freeze drying is completed.

[0042] Example 3

[0043] A method for preparing a freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection comprises the following steps:

[0044] S1, the preparation of the solution, take water, add EDTA and citric acid, stir to dissolve, then add sodium bicarbonate or sodium hydroxide, stir to dissolve, pH control to 5.5 ~ 6.5, the solution temperature control 5 ~ 15 ° C, add piperacillin acid and tazobactam acid and stir to mix evenly, then titrate with 14% sodium bicarbonate solution or 14% sodium hydroxide solution to pH 6.2 ~ 6.4, during the titration process, use a vacuum pump to extract the carbon dioxide gas produced by the reaction, filter the liquid, pour it into the vial and add a half stopper, and then freeze-dry. This reaction step is similar to the steps in the prior art, and will not be introduced in detail again.

[0045] S2, pre-freezing, including primary pre-freezing and secondary pre-freezing, primary pre-freezing, product temperature reaches -45°C in 40 minutes, maintained for 1 hour, then returns to -10°C in 40 minutes, maintained for 2 hours, secondary pre-freezing, again cools to -40°C in 40 minutes, maintained for 2 hours;

[0046] S3, sublimation drying, evacuate to 0.15Mbar and maintain the vacuum, heat to 10°C in 1.5 hours, and maintain for 30 hours;

[0047] S4, analytical drying, vacuum maintained at 0.15Mbar, heated to 60°C for 1.5 hours and maintained for 2 hours, evacuated to 0.01Mbar, and maintained at 50°C for 1 hour;

[0048] S5, pressure rise test, plug pressing, pressure rises to normal pressure, and freeze drying is completed.

[0049] Comparative Example 1

[0050] Prepared according to the original patented method steps:

[0051] S1, reaction, same as the prior art;

[0052] S2, pre-freezing: the product temperature reaches -35°C in 1 hour and is maintained for 4 hours;

[0053] S3, sublimation drying: evacuate to 40Pa and maintain the vacuum, raise the temperature to 5°C in 1 hour, and maintain for 30 hours;

[0054] S4, analytical drying: vacuum maintained at 40Pa, temperature raised to 45°C for 18 hours, maintained for 10 hours, temperature lowered to 30°C, maintained for 1 hour;

[0055] S5. Pressure rise test: Press the plug, the pressure rises to normal pressure, and the freeze-drying is completed.

[0056] The total preparation time of Examples 1 to 3 is 45 hours, and the preparation time of Comparative Example 1 is 60 hours.

[0057] The moisture and impurity contents of the products prepared according to the above different embodiments are shown in the following table:

[0058]

[0059] From the above table and Figures 1 to 4 It can be known that the product prepared by the preparation method of the present invention can effectively prevent the product from collapsing through reasonable pre-freezing and sublimation temperatures, and can change the product properties by pre-freezing once and pre-freezing twice, avoiding the sharp crystal shape of the product caused by direct pre-freezing once. The crystal will wrap the water, which is not conducive to the discharge of water during drying, thereby causing the product to have high moisture content and poor product stability. In the present invention, the product can be formed into a dense granular shape through secondary pre-freezing, which is convenient for better opening the channel of water vapor during sublimation drying, making it easier to discharge water, reducing the moisture content of the product, and thus improving the product quality. At the same time, the freeze-drying speed can be faster and the production efficiency can be improved; at the same time, the secondary pre-freezing can avoid the phenomenon of product climbing the bottle, in which the obvious climbing of the bottle occurred in Comparative Example 1.

[0060] According to the disclosure and teaching of the above description, those skilled in the art to which the present invention belongs may also make changes and modifications to the above embodiments. Therefore, the present invention is not limited to the specific embodiments disclosed and described above, and some modifications and changes to the present invention should also fall within the scope of protection of the claims of the present invention. In addition, although some specific terms are used in this specification, these terms are only for the convenience of description and do not constitute any limitation to the present invention.

Claims

1. A method for preparing a freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection, characterized in that: The steps include: S1, preparation of solution, take water, add EDTA and citric acid, stir to dissolve, then add sodium bicarbonate or sodium hydroxide, stir to dissolve, pH control to 5.5-6.5, solution temperature control 5-15 ° C, add piperacillin acid and tazobactam acid, stir to mix evenly, then titrate with 14% sodium bicarbonate solution or 14% sodium hydroxide solution to pH 6.2-6.4, use a vacuum pump to extract carbon dioxide gas generated by the reaction during the titration process, filter the liquid, fill it into a vial, half-stopper it, and then freeze-dry it; S2, pre-freezing, adjusting the freeze dryer to make the product reach -35 to -45°C in 10 to 60 minutes, keep it for 1 hour, then return to -15 to -5°C in 10 to 60 minutes, keep it for 2 hours; cool it down to -35 to -45°C in 10 to 60 minutes again, keep it for 2 hours; S3, sublimation drying, evacuate to 0.15Mbar and maintain the vacuum, raise the temperature to 5-15°C in 1-2 hours, and maintain for 30 hours; S4, analytical drying, vacuum maintained at 0.15Mbar, 1-2 hours to 45-60 ° C for 2 hours, vacuum to 0.01Mbar, 45-60 ° C for 1 hour; S5, pressure rise test, plug pressing, pressure rises to normal pressure, and freeze drying is completed.

2. The method for preparing the freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection as claimed in claim 1, characterized in that: The mass ratio of the piperacillin acid to tazobactam acid is 8:1 or 4:

1.

3. The method for preparing the freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection as claimed in claim 1, characterized in that: The pre-freezing of step S2 comprises: Pre-freeze once, bring the product temperature to -35--45°C in 10-60 minutes, keep it for 1 hour, then return to -15--5°C in 10-60 minutes, keep it for 2 hours; Pre-freeze for the second time, cool down to -35 ~ -45℃ again in 10 ~ 60 minutes and keep it for 2 hours.

4. The method for preparing the freeze-dried preparation of piperacillin sodium and tazobactam sodium for injection according to any one of claims 1 to 4, characterized in that: The preparation process takes no more than 45 hours.

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