A continuous preparation method of ceftazidime

Abstract

The invention discloses a ceftazidime continuous preparation method, comprising the following steps: S1, preparing a ceftazidime dihydrochloride solution; S2, preparing a sodium hydroxide solution; S3, preparing a phosphoric acid solution; S4, respectively adding the ceftazidime dihydrochloride solution and the sodium hydroxide solution into a high-speed centrifugal mixer at a certain flow rate for rapid mixing, and then flowing out from the outlet of the high-speed centrifugal mixer to obtain a ceftazidime solution 1; S5, adding a suspension of ceftazidime crystal seeds and water into a crystallizer A, and simultaneously continuously and uniformly adding the ceftazidime solution 1 and the phosphoric acid solution; S6, when the volume of the crystallization liquid in the crystallizer A exceeds 100 ml, the crystallization liquid automatically overflows from the crystallizer A and flows into the crystallizer B, and the crystals are grown in the crystallizer B for a period of time, filtered, washed and dried to obtain a ceftazidime product. The invention can significantly reduce the content of impurities, especially the impurity content of RRT=0.82, improve the purity, and the powder particle size is uniform.

Description

Technical Field

[0001] The invention relates to a continuous preparation method of ceftazidime and belongs to the technical field of medicines. Background Art

[0002] Ceftazidime is a third-generation cephalosporin antibiotic created by GlaxoSmithKline, which has strong effects on both Gram-positive and Gram-negative bacteria. It has strong antibacterial activity against Pseudomonas aeruginosa, Enterococcus, Klebsiella, Escherichia coli, Salmonella, Proteus, Shigella, Neisseria gonorrhoeae, Neisseria meningitidis, Staphylococcus aureus, hemolytic Streptococcus, Pneumococcus and Clostridium difficile, especially against Pseudomonas aeruginosa, where ceftazidime is the most effective antibiotic.

[0003] Ceftazidime injection is a compound preparation of ceftazidime sodium carbonate or ceftazidime arginine, which is obtained by mixing ceftazidime powder with sodium carbonate or arginine powder. In order to improve the mixing uniformity, mixing efficiency and stability, when preparing ceftazidime powder, the particle size of ceftazidime powder needs to be strictly controlled to improve the applicability of the mixed powder.

[0004] When preparing ceftazidime powder, in addition to controlling the particle size of the ceftazidime powder, the content of impurities must also be controlled, especially impurities with RRT=0.82, which are difficult to remove and are brought into the product, affecting the quality of the product.

[0005] The application number is 201510104265.0, and the patent name is A ceftazidime powder injection preparation for injection. It discloses a method for preparing ceftazidime, including the following steps: (1) at 5°C to 10°C, weigh ceftazidime dihydrochloride raw material, add distilled water, stir to dissolve, cool and add alkaline agent to adjust the pH, add activated carbon, filter after decolorization, and wash; (2) at 10°C to 20°C, stir at a speed of 250 to 300 rpm, add acid according to the flow rate table to adjust the pH; (3) filter, wash, and vacuum dry.

[0006] However, the ceftazidime obtained by the above method has a high impurity content, especially the impurity content of RRT=0.82 is also relatively high, and the particle size of the obtained powder is uneven, which is not conducive to subsequent powder mixing.

[0007] Moreover, in the existing knowledge, when ceftazidime dihydrochloride solution is mixed with an alkaline agent, in order to prevent local over-alkalinity and degradation, a dripping method is usually adopted and the dripping speed is controlled. Summary of the invention

[0008] In order to solve the above technical problems, the present invention provides a continuous preparation method of ceftazidime, which can achieve continuous production and significantly reduce the content of impurities, especially the impurity content of RRT=0.82, improve the purity, and make the powder particle size uniform.

[0009] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0010] A method for continuously preparing ceftazidime comprises the following steps:

[0011] S1. Preparation of ceftazidime dihydrochloride solution: adding ceftazidime dihydrochloride into purified water, stirring to dissolve; adding a decolorizing agent, stirring, filtering, and obtaining a ceftazidime dihydrochloride solution;

[0012] S2. Preparation of sodium hydroxide solution: adding sodium hydroxide into purified water and stirring to dissolve;

[0013] S3. Preparation of phosphoric acid solution: add phosphoric acid into purified water and stir evenly;

[0014] S4, adding the ceftazidime dihydrochloride solution and the sodium hydroxide solution into a high-speed centrifugal mixer at a certain flow rate, mixing them rapidly, and then flowing out from the outlet of the high-speed centrifugal mixer to obtain a ceftazidime solution 1;

[0015] S5, adding a suspension of ceftazidime seed crystals and water to crystallizer A, stirring rapidly for a period of time, then reducing the stirring speed, and simultaneously continuously and uniformly adding ceftazidime solution 1 and phosphoric acid solution;

[0016] S6. When the volume of the crystallization liquid in crystallizer A exceeds 100 ml, the crystallization liquid automatically overflows from the overflow port of crystallizer A and flows into crystallizer B. The crystals are grown in crystallizer B for a period of time, filtered, washed and dried to obtain ceftazidime product.

[0017] A further improvement of the technical solution of the present invention is that in step S1, the weight ratio of ceftazidime dihydrochloride to purified water is 1:1-2, and the stirring temperature is 0-5°C.

[0018] A further improvement of the technical solution of the present invention is that the decolorizing agent in step S1 is EDTA, sodium tetrathionate and activated carbon, and the added amounts are 1-5%, 1-5% and 2-6% of the weight of ceftazidime dihydrochloride respectively, and the decolorizing time is 30 minutes.

[0019] A further improvement of the technical solution of the present invention is that in step S2, the weight ratio of sodium hydroxide to purified water is 1:6-7, and the stirring temperature is 0-5°C.

[0020] A further improvement of the technical solution of the present invention is that the weight ratio of phosphoric acid to purified water in step S3 is 1:3-4.

[0021] A further improvement of the technical solution of the present invention is that in step S4, the flow ratio of the ceftazidime dihydrochloride solution to the sodium hydroxide solution is 1:0.4-0.7, and the residence time in the high-speed centrifugal mixer is 0.5-2s.

[0022] A further improvement of the technical solution of the present invention is that the temperature of the ceftazidime solution 1 flowing out of the outlet of the high-speed centrifugal mixer is maintained at 0-5°C, and the pH value is maintained at 5.5-6.0.

[0023] A further improvement of the technical solution of the present invention is that: in the step S5, the weight of the ceftazidime seed crystal suspension added is 10% to 20% of the volume of the crystallizer A, wherein the solid content in the suspension is 5 to 15%, and stirring is performed at 800 rpm for 15 to 30 min.

[0024] The further improvement of the technical solution of the present invention is that: in the step S5, the stirring speed is reduced to 200-300 rpm, the flow acceleration ratio of the ceftazidime solution 1 and the phosphoric acid solution is 1:0.20-0.35, and the pH in the crystallizer A is 3.5-4.0.

[0025] A further improvement of the technical solution of the present invention is that: in the S6, the crystallizer B is grown for 30 to 60 minutes, and the pH is kept consistent with that of the crystallizer A, the stirring speed is 100 to 200 rpm, and the temperature is 0 to 5°C.

[0026] Due to the adoption of the above technical solution, the technical progress achieved by the present invention is:

[0027] 1) Product quality is improved, with single impurities and total impurities at RRT = 0.82 significantly reduced and content increased;

[0028] 2) Uniform particle size, moderate density, easy to use in preparation;

[0029] 3) Degradation is reduced and the yield is significantly improved;

[0030] 4) Improved production efficiency and reduced batch-to-batch differences. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is a flow chart of the present invention; DETAILED DESCRIPTION

[0032] The present invention is further described in detail below in conjunction with embodiments:

[0033] A method for continuously preparing ceftazidime comprises the following steps:

[0034] S1. Preparation of ceftazidime dihydrochloride solution: adding ceftazidime dihydrochloride to purified water, the weight ratio of ceftazidime dihydrochloride to purified water is 1:1-2, stirring and dissolving at 0-5°C; adding decolorizing agents respectively, stirring for 30 minutes, filtering, and obtaining ceftazidime dihydrochloride solution; wherein the decolorizing agent is a mixture of EDTA, sodium tetrathionate, and activated carbon, and the added amounts are 1-5%, 1-5%, and 2-6% of the weight of ceftazidime dihydrochloride, respectively;

[0035] S2. Preparation of sodium hydroxide solution: add sodium hydroxide to purified water, the sodium hydroxide: purified water ratio is 1:6-7 (weight ratio), and stir and dissolve at 0-5°C;

[0036] S3. Preparation of phosphoric acid solution: add phosphoric acid to purified water, phosphoric acid: purified water is 1:3-4 (weight ratio), and stir evenly;

[0037] S4, adding ceftazidime dihydrochloride solution and sodium hydroxide solution into a high-speed centrifugal mixer at a flow ratio of 1:0.4-0.7, respectively, for rapid mixing to obtain ceftazidime solution 1, which flows out from the outlet of the high-speed centrifugal mixer after staying for 0.5-2 seconds, with the temperature maintained at 0-5°C and the pH value maintained at 5.5-6.0;

[0038] S5. Add ceftazidime seed suspension and water to crystallizer A, wherein the weight of ceftazidime seed suspension added is 10% to 20% of the volume of crystallizer A, wherein the solid content of the suspension is 5 to 15%, stir at 800 rpm for 15 to 30 min, then reduce the stirring speed to 200-300 rpm, and continuously and uniformly add ceftazidime solution 1 and phosphoric acid solution at the same time, wherein the flow acceleration ratio of ceftazidime solution 1 to phosphoric acid solution is 1:0.20 to 0.35, and maintain the pH in crystallizer A at 3.5 to 4.0;

[0039] S6. When the volume of the crystallization liquid in the crystallizer A exceeds 100 ml, the crystallization liquid automatically overflows from the overflow port of the crystallizer A and flows into the crystallizer B. The crystals are grown in the crystallizer B for 30 minutes and the pH value is kept consistent with that of the crystallizer A. The stirring speed is 100-200 rpm and the temperature is 0-5°C. The product is filtered, washed and dried to obtain the ceftazidime product.

[0040] Embodiment 1:

[0041] S1. Preparation of ceftazidime dihydrochloride solution: Take 400 g of ceftazidime dihydrochloride, add 650 ml of purified water, stir and dissolve at 0-2° C.; add 5 g of EDTA, 5 g of sodium tetrathionate, and 10 g of activated carbon, stir for 30 min, and filter to obtain a ceftazidime dihydrochloride solution;

[0042] S2, preparation of sodium hydroxide solution: 80g sodium hydroxide, add 500ml purified water, stir to dissolve, 0-2℃ for standby use;

[0043] S3. Preparation of phosphoric acid solution: 150 g phosphoric acid (concentration 90-95%), add 600 ml purified water, stir evenly and set aside;

[0044] S4, adding ceftazidime dihydrochloride solution and sodium hydroxide solution into a high-speed centrifugal mixer at a flow ratio of 1:0.4-0.7 for rapid mixing to obtain ceftazidime solution 1, which is retained in the high-speed centrifugal mixer for 0.5-1 s and then flows out from the outlet of the high-speed centrifugal mixer, and the material temperature at the outlet of the high-speed centrifugal mixer is maintained at 0-5°C and the pH value is maintained at 5.5;

[0045] S5. Add 1 g of ceftazidime seed suspension and 25 ml of water to crystallizer A, stir at 800 rpm for 30 min, reduce the stirring speed to 200-300 rpm, and continuously add ceftazidime solution 1 and phosphoric acid solution at a constant speed ratio of 1:0.20-0.35, and keep the pH in crystallizer A at 3.5;

[0046] S6. When the volume of the crystallization liquid in the crystallizer A exceeds 100 ml, the crystallization liquid automatically overflows from the overflow port of the crystallizer A and flows into the crystallizer B. The crystals are grown in the crystallizer B for 30 minutes, and the pH is maintained at 3.5, the stirring speed is 100-200 rpm, and the temperature is 0-5°C. Then, the crystals are filtered, washed, and dried to obtain the ceftazidime product.

[0047] Embodiments 2 to 4

[0048] The process steps of Examples 2 to 4 are the same as those of Example 1, except that the process parameters are changed. The specific process parameters are shown in Table 1.

[0049] Table 1 Process parameters of Examples 1 to 4

[0050]

[0051]

[0052] Comparative Example 1:

[0053] The difference between Comparative Example 1 and Example 1 is that in step S4, sodium hydroxide solution is slowly added to the ceftazidime dihydrochloride solution without using a high-speed centrifugal mixer until the pH value is 5.5, the feed liquid is clarified, and ceftazidime solution 1 is obtained after filtration. The remaining steps are the same as in Example 1.

[0054] Comparative Example 2:

[0055] The difference between Comparative Example 1 and Example 1 is that: in step S4, sodium hydroxide solution is added to the high-speed stirred ceftazidime dihydrochloride solution at one time in a rapid and quantitative manner without using a high-speed centrifugal mixer, the pH is 5.5 after stirring, the feed liquid is clarified, and ceftazidime solution 1 is obtained after filtering. The remaining steps are the same as in Example 1.

[0056] Comparative Example 3:

[0057] The difference between Comparative Example 3 and Example 1 is that: in steps S5 and S6, ceftazidime solution 1 is added to crystallizer A, phosphoric acid solution is added under stirring at 400-600rpm, and the addition of phosphoric acid solution is stopped until the pH is 4.2-4.4, and then 1g of ceftazidime seed suspension is added, and stirred at 200rpm for 30min. The speed is increased to 400-600rpm again, phosphoric acid solution is added under stirring, the pH value is adjusted to 3.5, crystals are grown for 30min, filtered, washed and dried to obtain a ceftazidime product. The remaining steps are the same as in Example 1.

[0058] Comparative Example 4:

[0059] Comparative Example 4 was prepared according to the preparation method of ceftazidime in Example 1 of application number 201510104265.0.

[0060] Experimental results:

[0061] Take the ceftazidime prepared in Examples 1 to 4 and Comparative Examples 1 to 4, and detect the total impurities, impurities with RRT = 0.82, and the content according to the EP Pharmacopoeia method, and calculate the molar yield according to the following formula: ((mass of ceftazidime / molecular weight of ceftazidime) / (mass of ceftazidime dihydrochloride / molecular weight of ceftazidime dihydrochloride)×100%, and the results are shown in Table 2:

[0062] Table 2 Experimental results test table

[0063] Molar yield Total Miscellaneous RRT=0.82 single impurity Particle size / D80 content density Example 1 83.6％ 0.12％ 0.01％ 50~110 microns 100.2％ 0.25 Example 2 83.4％ 0.13％ 0.01％ 50~110 microns 100.0％ 0.23 Example 3 83.3％ 0.12％ 0.01％ 50~120 microns 100.1％ 0.22 Example 4 82.5％ 0.13％ 0.01％ 50~110 microns 99.8％ 0.23 Comparative Example 1 80.2％ 0.72％ 0.28％ 50~130 microns 98.9％ 0.22 Comparative Example 2 79.5％ 0.89％ 0.32％ 50~130 microns 97.9％ 0.21 Comparative Example 3 81.5％ 0.40％ 0.18％ 40~180 microns 99.2％ 0.16 Comparative Example 4 80.8％ 0.65％ 0.21％ 60~210 microns 99.2％ 0.15

[0064] Take the ceftazidime prepared in Examples 1 to 4 and Comparative Examples 1 to 4, mix with sodium carbonate to prepare a commercially available ceftazidime (sodium carbonate) powder injection of 1.0 g / piece, and test the uniformity of the mixed powder. Take the above samples and mix with the same sodium carbonate, and use the same mixing method. Take 5 samples of each sample for content and calculate the RSD value. The results are as follows:

[0065] Serial number Content RSD value Example 1 0.38％ Example 2 0.39％ Example 3 0.35％ Example 4 0.36％ Comparative Example 1 0.65％ Comparative Example 2 0.68％ Comparative Example 3 2.2％ Comparative Example 4 2.6％

Claims

1. A continuous preparation method of ceftazidime, characterized in that: The steps include: S1. Preparation of ceftazidime dihydrochloride solution: adding ceftazidime dihydrochloride into purified water, stirring to dissolve; adding a decolorizing agent, stirring, filtering, and obtaining a ceftazidime dihydrochloride solution; S2. Preparation of sodium hydroxide solution: adding sodium hydroxide into purified water and stirring to dissolve; S3. Preparation of phosphoric acid solution: add phosphoric acid into purified water and stir evenly; S4, adding the ceftazidime dihydrochloride solution and the sodium hydroxide solution into a high-speed centrifugal mixer at a certain flow rate, mixing them rapidly, and then flowing out from the outlet of the high-speed centrifugal mixer to obtain a ceftazidime solution 1; In step S4, the flow ratio of ceftazidime dihydrochloride solution to sodium hydroxide solution is 1:0.4-0.7, and the residence time in the high-speed centrifugal mixer is 0.5-2s; The temperature of the ceftazidime solution 1 flowing out of the high-speed centrifugal mixer outlet is maintained at 0-5°C, and the pH value is maintained at 5.5-6.0; S5, adding a suspension of ceftazidime seed crystals and water to crystallizer A, stirring rapidly for a period of time, then reducing the stirring speed, and simultaneously continuously and uniformly adding ceftazidime solution 1 and phosphoric acid solution; In the step S5, the weight of the ceftazidime seed suspension added is 10% to 20% of the volume of the crystallizer A, wherein the solid content in the suspension is 5 to 15%, and the mixture is stirred at 800 rpm for 15 to 30 min; In step S5, the stirring speed is reduced to 200-300 rpm, the flow acceleration ratio of the ceftazidime solution 1 and the phosphoric acid solution is 1:0.20-0.35, and the pH in the crystallizer A is 3.5-4.0; S6. When the volume of the crystallization liquid in the crystallizer A exceeds 100 ml, the crystallization liquid automatically overflows from the overflow port of the crystallizer A and flows into the crystallizer B, and grows crystals in the crystallizer B for a period of time, and is filtered, washed and dried to obtain the ceftazidime product; in the S6, the crystallizer B is grown for 30 to 60 minutes, and the pH is kept consistent with that of the crystallizer A, the stirring speed is 100 to 200 rpm, and the temperature is 0 to 5°C.

2. A method for continuously preparing ceftazidime according to claim 1, characterized in that: In the step S1, the weight ratio of ceftazidime dihydrochloride to purified water is 1:1-2, and the stirring temperature is 0-5°C.

3. A method for continuously preparing ceftazidime according to claim 1, characterized in that: The decolorizing agents in step S1 are EDTA, sodium tetrathionate and activated carbon, and the added amounts are 1-5%, 1-5% and 2-6% of the weight of ceftazidime dihydrochloride, respectively, and the decolorizing time is 30 minutes.

4. A method for continuously preparing ceftazidime according to claim 1, characterized in that: In step S2, the weight ratio of sodium hydroxide to purified water is 1:6-7, and the stirring temperature is 0-5°C.

5. A method for continuously preparing ceftazidime according to claim 1, characterized in that: The weight ratio of phosphoric acid to purified water in step S3 is 1:3-4.

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