Ultrafine cefinetazole sodium and a method for continuously preparing ultrafine cefinetazole sodium

Abstract

The application discloses superfine cefinetazole sodium and a method for continuously preparing superfine cefinetazole sodium, and belongs to the technical field of pharmacy. Solution A, a sodium iso-octanoate solution, is prepared; solution B, a cefinetazole acid solution, is prepared; solution A and B are simultaneously introduced into a micro-channel reactor I to be uniformly mixed to obtain solution C; solution C and acetone are simultaneously introduced into a micro-channel reactor II; the mixed solution at the outlet of the micro-channel reactor II is directly introduced into an ultrasonic wave pipeline crystallizer I; the crystallization solution flowing out of the crystallizer I is directly introduced into a crystallization solution buffer tank I; the crystallization solution overflowing from the crystallization buffer tank I is introduced into a high-efficiency filtering device I to be filtered to obtain filtrate I; the filtrate I and acetone are simultaneously introduced into a micro-channel reactor III; after reaction, the filtrate I is introduced into an ultrasonic wave pipeline crystallizer II; the crystallization solution flowing out of the crystallizer II is directly introduced into a crystallization solution buffer tank II; the crystallization solution overflowing from the crystallization buffer tank II is introduced into a high-efficiency filtering device II; the solid obtained from the high-efficiency filtering device I and the high-efficiency filtering device II is washed by acetone and then introduced into a double-cone mixing and drying device to obtain superfine cefinetazole sodium products.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and particularly relates to an ultrafine cefoxitin sodium and a method for the continuous preparation of ultrafine cefoxitin sodium. Background Technology

[0002] Cefoxitin sodium, chemical formula C 16 H 16 N3NaO7S2 is a cephalosporin antibiotic, often classified as a second-generation cephalosporin. Clinically, this drug is primarily used to treat various infections caused by susceptible bacteria, such as respiratory tract infections, genitourinary tract infections, peritonitis, cholangitis, bone and joint infections, skin and soft tissue infections, and sepsis.

[0003] Currently, cefoxitin sodium is produced through batch crystallization, which suffers from problems such as large particle size, uneven particle size, long dissolution time, and discontinuous production. In particular, the existing cefoxitin sodium production process requires first preparing crude cefoxitin sodium and then recrystallizing it to obtain pure cefoxitin, which is a lengthy process and wastes both manpower and resources. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide an ultrafine cefoxitin sodium and a method for continuous preparation of ultrafine cefoxitin sodium. The cefoxitin sodium product has small and uniform particle size, and the preparation method can achieve continuous production.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A cefoxitin sodium product with a maximum unknown single impurity of less than 0.1% and a powder particle size of 10-90 μm.

[0007] A method for the continuous preparation of ultrafine cefoxitin sodium includes the following steps:

[0008] Step S1, preparing solution A: Add sodium isooctanoate and sodium thiocyanate to the organic mixed solvent and stir until completely dissolved;

[0009] Step S2, Preparation of solution B: Add cefoxitin to the organic mixed solvent, stir until dissolved, add activated carbon, stir and filter;

[0010] Step S3: Solution A and solution B are simultaneously introduced into microchannel reactor one, mixed evenly, and solution C is prepared.

[0011] Step S4: Solution C and acetone enter microchannel reactor two at the same time. The mixture from the outlet of microchannel reactor two directly enters ultrasonic pipeline crystallizer one. The outflowing crystallizer directly enters crystallizer buffer tank I. The overflowing crystallizer from crystallizer buffer tank I enters high-efficiency filter device one for filtration to obtain filtrate I.

[0012] Step S5: Filtrate I and acetone enter microchannel reactor three at the same time. After the reaction, they enter ultrasonic pipeline crystallizer two. The crystallized liquid flows out directly into crystallization buffer tank II. The crystallized liquid overflowing from crystallization buffer tank II enters high-efficiency filtration device two.

[0013] Step S6: The solids obtained in high-efficiency filtration device one and high-efficiency filtration device two are washed with acetone and then dried in a double cone mixing process to obtain ultrafine cefoxitin sodium product.

[0014] A further improvement of the technical solution of the present invention is that the organic mixed solvent in steps S1 and S2 includes methanol, acetone, ethanol and ethyl acetate, and the mass-volume ratio of sodium isooctanoate, sodium thiocyanate and organic mixed solvent in step S1 is 100-103:10:1300-1500 kg / L.

[0015] A further improvement to the technical solution of the present invention is that the mass-volume ratio of cefoxitin acid and organic mixed solvent in step S2 is 25:160 kg / L.

[0016] A further improvement of the technical solution of the present invention is that the feed volume ratio of solution A to solution B in step S3 is 13:18.5-20.5.

[0017] A further improvement of the technical solution of the present invention is that: in step S4, the feed volume ratio of solution C to acetone in the microchannel reactor II is 1:1.5, the residence time in the microchannel reactor II is 0.5-3s, the temperature is 10-20℃, the residence time in the ultrasonic pipeline crystallizer I is 1-5s, and the stirring speed in the crystallization buffer tank I is maintained at 10-25HZ.

[0018] A further improvement to the technical solution of the present invention is that: in step S5, the feed volume ratio of filtrate I to acetone in microchannel reactor III is 1:0.5-1.0, the time in microchannel reactor III is 0.5-3s, the time in ultrasonic pipeline crystallizer II is 1-5s, and the stirring speed in crystallization buffer tank II is maintained at 10-25HZ.

[0019] A further improvement to the technical solution of the present invention is that: in step S4, the ultrasonic wave of the first ultrasonic pipe crystallizer is controlled at 20-30 Hz, and the ultrasonic wave of the second ultrasonic pipe crystallizer is controlled at 40-45 Hz.

[0020] A further improvement of the technical solution of the present invention is that: the preparation temperature of solution A in step S1 is 10.0℃~20.0℃, and the temperature of solution B in step S2 is controlled at 10.0℃~20.0℃.

[0021] The technological advancements achieved by this invention due to the adoption of the above technical solutions are as follows:

[0022] This invention discloses a novel method for preparing ultrafine cefoxitin sodium, which changes the traditional batch production method, enables continuous production, eliminates the recrystallization step, and directly obtains high-quality cefoxitin sodium product with uniform particle size. Detailed Implementation

[0023] The present invention will be further described in detail below with reference to embodiments:

[0024] Example 1

[0025] 1. Preparation of sodium isooctanoate solution (solution A): 800L methanol, 500L acetone, stir at 50rpm~120rpm, 10.0℃~20.0℃. Add 100Kg sodium isooctanoate and 10Kg sodium thiocyanate, and stir until completely dissolved.

[0026] 2. Preparation of cefoxitin acid solution (Solution B): 300L methanol, 1300L acetone, stirring at 50-120 rpm and 10.0℃-20.0℃. Add 250Kg cefoxitin acid and stir until dissolved. Add 10Kg activated carbon and control the tank temperature at 10.0℃-20.0℃, stirring for 25-30 minutes, then filter. Wash the decarbonized filter with 250L acetone and combine the filtrates.

[0027] 3. Solution A and solution B are simultaneously introduced into microchannel reactor one at a feed ratio of 13:18.5. After being mixed evenly, solution C is prepared.

[0028] 4. Solution C and acetone simultaneously enter microchannel reactor II at a feed ratio of 1:1.5. The mixture remains in microchannel reactor II for 0.5 seconds. The outlet of microchannel reactor II directly enters ultrasonic pipeline crystallizer I, where the ultrasonic waves are controlled at 40 Hz. The residence time in ultrasonic pipeline crystallizer I is 5 seconds. The outflowing crystallizer directly enters crystallization buffer tank I. The overflow from crystallization buffer tank I enters high-efficiency filter I for filtration, and is simultaneously washed with a small amount of (1:1) methanol-acetone solution to obtain filtrate I. Filtrate I and acetone (ratio 1:0.5) then enter microchannel reactor III. After a residence time of 0.5 seconds in microchannel reactor III, it enters ultrasonic pipeline crystallizer II, where the ultrasonic waves are controlled at 40 Hz. The residence time in ultrasonic pipeline crystallizer II is 5 seconds. The outflowing crystallizer enters crystallization buffer tank II. The overflow from crystallization buffer tank II enters high-efficiency filter II for filtration. The powders in high-efficiency filtration devices one and two were washed with 1000L and 400L of acetone, respectively, and then dried in a double-cone mixing dryer to obtain ultrafine cefoxitin sodium product.

[0029] Example 2

[0030] 1. Preparation of sodium isooctanoate solution (solution A): 800L methanol, 500L acetone, stir at 50rpm~120rpm, 10.0℃~20.0℃. Add 103Kg sodium isooctanoate and 10Kg sodium thiocyanate, and stir until completely dissolved.

[0031] 2. Preparation of cefoxitin acid solution (Solution B): 400L methanol, 1400L acetone, stirring at 50-120 rpm and 10.0℃-20.0℃. Add 250Kg cefoxitin acid and stir until dissolved. Add 10Kg activated carbon and control the tank temperature at 10.0℃-20.0℃, stirring for 25-30 minutes, then filter. Wash the decarbonized filter with 250L acetone and combine the filtrates.

[0032] 3. Solution A and solution B are simultaneously introduced into microchannel reactor one at a feed ratio of 13:20.5. After being mixed evenly, solution C is prepared.

[0033] 4. Solution C and acetone simultaneously enter microchannel reactor II at a feed ratio of 1:1.5. After 3 seconds in microchannel reactor II, the mixture exiting microchannel reactor II directly enters ultrasonic pipeline crystallizer I. The ultrasonic waves are controlled at 30 Hz. The residence time in ultrasonic pipeline crystallizer I is 1 second, and the outflowing crystallizer directly enters crystallization buffer tank I. The overflow from crystallization buffer tank I enters high-efficiency filter I for filtration, and is simultaneously washed with a small amount of (1:1) methanol-acetone solution to obtain filtrate I. Filtrate I and acetone (ratio 1:1) then enter microchannel reactor III. After a 3-second residence time in microchannel reactor III, it enters ultrasonic pipeline crystallizer II. The ultrasonic waves are controlled at 45 Hz. The residence time in ultrasonic pipeline crystallizer II is 1 second, and the outflowing crystallizer enters crystallization buffer tank II. The overflow from crystallization buffer tank II enters high-efficiency filter II for filtration. The powders in high-efficiency filtration devices one and two were washed with 1000L and 400L of acetone, respectively, and then dried in a double-cone mixing dryer to obtain ultrafine cefoxitin sodium product.

[0034] Example 3

[0035] 1. Preparation of sodium isooctanoate solution (solution A): 800L methanol, 500L acetone, stir at 50rpm~120rpm, 10.0℃~20.0℃. Add 101Kg sodium isooctanoate and 10Kg sodium thiocyanate, and stir until completely dissolved.

[0036] 2. Preparation of cefoxitin acid solution (Solution B): 350L methanol, 1350L acetone, stirring at 50-120 rpm and 10.0℃-20.0℃. Add 250Kg cefoxitin acid and stir until dissolved. Add 10Kg activated carbon and control the tank temperature at 10.0℃-20.0℃, stirring for 25-30 minutes, then filter. Wash the decarbonized filter with 250L acetone and combine the filtrates.

[0037] 3. Solution A and solution B are simultaneously introduced into microchannel reactor one at a feed ratio of 13:19.5. After being mixed evenly, solution C is prepared.

[0038] 4. Solution C and acetone simultaneously enter microchannel reactor II at a feed ratio of 1:1.5. After 2 seconds in microchannel reactor II, the mixture exiting microchannel reactor II directly enters ultrasonic pipeline crystallizer I. The ultrasonic waves are controlled at 45 Hz. The crystallizer resides in ultrasonic pipeline crystallizer I for 3 seconds, and the outflowing crystallizer directly enters crystallization buffer tank I. The overflow from crystallization buffer tank I enters high-efficiency filter I for filtration, and is simultaneously washed with a small amount of (1:1) methanol-acetone solution to obtain filtrate I. Filtrate I and acetone (1:1 ratio) then enter microchannel reactor III. After 2 seconds in microchannel reactor III, it enters ultrasonic pipeline crystallizer II. The ultrasonic waves are controlled at 42 Hz. The crystallizer resides in ultrasonic pipeline crystallizer II for 3 seconds, and the outflowing crystallizer enters crystallization buffer tank II. The overflow from crystallization buffer tank II enters high-efficiency filter II for filtration. The powders in high-efficiency filtration devices one and two were washed with 1000L and 400L of acetone, respectively, and then dried in a double-cone mixing dryer to obtain ultrafine cefoxitin sodium product.

[0039] Example 4

[0040] 1. Preparation of sodium isooctanoate solution (solution A): 800L ethanol, 500L acetone, stir at 50rpm~120rpm, 10.0℃~20.0℃. Add 100Kg sodium isooctanoate and 10Kg sodium thiocyanate, and stir until completely dissolved.

[0041] 2. Preparation of cefoxitin acid solution (Solution B): 300L ethanol, 1300L acetone, stirring at 50-120 rpm and 10.0℃-20.0℃. Add 250Kg cefoxitin acid and stir until dissolved. Add 10Kg activated carbon and control the tank temperature at 10.0℃-20.0℃, stirring for 25-30 minutes, then filter. Wash the decarbonized filter with 250L acetone and combine the filtrates.

[0042] 3. Solution A and solution B are simultaneously introduced into microchannel reactor one at a feed ratio of 13:18.5. After being mixed evenly, solution C is prepared.

[0043] 4. Solution C and acetone simultaneously enter microchannel reactor II at a feed ratio of 1:1.5. The mixture remains in microchannel reactor II for 0.5 seconds. The outlet of microchannel reactor II directly enters ultrasonic pipeline crystallizer I, where the ultrasonic waves are controlled at 40 Hz. The residence time in ultrasonic pipeline crystallizer I is 5 seconds. The outflowing crystallizer directly enters crystallization buffer tank I. The overflow from crystallization buffer tank I enters high-efficiency filter I for filtration, and is simultaneously washed with a small amount of (1:1) methanol-acetone solution to obtain filtrate I. Filtrate I and acetone (ratio 1:0.5) then enter microchannel reactor III. After a residence time of 0.5 seconds in microchannel reactor III, it enters ultrasonic pipeline crystallizer II, where the ultrasonic waves are controlled at 40 Hz. The residence time in ultrasonic pipeline crystallizer II is 5 seconds. The outflowing crystallizer enters crystallization buffer tank II. The overflow from crystallization buffer tank II enters high-efficiency filter II for filtration. The powders in high-efficiency filtration devices one and two were washed with 1000L and 400L of acetone, respectively, and then dried in a double-cone mixing dryer to obtain ultrafine cefoxitin sodium product.

[0044] High-efficiency filtration devices can be selected from high-speed centrifugal filters.

[0045] Comparative Example 1

[0046] 1. Preparation of sodium isooctanoate solution (solution A): 800L methanol, 550L acetone, stir at 30rpm~100rpm, maintain the temperature in the container at 15.0℃~20.0℃. Add 105kg sodium isooctanoate and 11kg sodium thiocyanate, and stir until completely dissolved.

[0047] 2. Preparation of cefoxitin acid solution (Solution B): 300L methanol, 15000L acetone, start stirring at 50-120rpm, maintaining a temperature of 15.0℃-25.0℃. Add 250.0kg cefoxitin acid and stir until dissolved. Add 11.0kg activated carbon, maintaining the tank temperature at 15.0℃-25.0℃, and stir for 25-30 minutes. Filter into a crystallization tank. Wash the activated carbon filter with 250ml acetone and combine the filtrates in the crystallization tank.

[0048] 3. Crystallization: Turn on the crystallizer and stir at 15 rpm, and control the crystallizer temperature at 10.0℃~15.0℃. Add solution A to the crystallizer at a flow rate of 40 L / min, and maintain the crystallizer temperature at 10.0℃~15.0℃ throughout the process.

[0049] 4. Crystal growth: After adding solution A, control the temperature inside the crystallizer to 10.0℃~15.0℃ and grow crystals for 30 minutes.

[0050] 5. Add 3500L of acetone to the crystallizer at a flow rate of 100L / min, and maintain the crystallizer temperature at 10.0℃~15.0℃ during the addition process.

[0051] 6. Crystal growth: After the addition of acetone is completed, maintain the temperature at 10.0℃~15.0℃ for 30 minutes to grow crystals.

[0052] 7. After centrifugation and filtration, wash twice with 1000+800L of acetone, and dry with a double cone to obtain the cefoxitin product.

[0053] Comparative Example 2

[0054] Take 200 kg of crude cefoxitin sodium, add 400 L of purified water, stir until dissolved, control the temperature at 8±2℃, add activated carbon and stir for 30 min, then filter; wash the activated carbon with 40 L of purified water. Combine the carbon washing water and filtrate to obtain a cefoxitin sodium solution, and control the temperature at 8±2℃.

[0055] A mixture of acetone, methanol, and dichloromethane (volume ratio 20:1:1) was heated to 2±2℃. The cefoxitin sodium solution and the mixed solvent were simultaneously introduced into a micromixer at a flow rate ratio of 1:10, with the cefoxitin sodium solution flowing at 20 L / min and remaining in the micromixer for 2 seconds. Crystallization solution was obtained from the micromixer outlet and filtered to obtain cefoxitin sodium wet product 1 and mother liquor. The mother liquor was collected in a stirred container, and the same volume ratio of acetone, methanol, and dichloromethane (volume ratio 20:1:1) was added. The mixture was heated to 8±2℃ and stirred for 15 minutes to crystallize. After filtration, cefoxitin sodium wet product 2 was obtained. Cefoxitin sodium wet product 1 and cefoxitin sodium wet product 2 were mixed and dried to obtain cefoxitin sodium powder.

[0056] Comparative Example 3

[0057] This comparative example is basically the same as Example 1, except that in step S4, solution C and acetone enter the microchannel reactor 2 at the same time, with a feed ratio of 1:1.0.

[0058] Comparative Example 4

[0059] This comparative example is basically the same as Example 1, except that in step S4, solution C and acetone enter the microchannel reactor 2 at the same time, with a feed ratio of 1:2.

[0060] The products obtained from the examples and comparative examples were tested, and the test results are as follows:

[0061]

[0062]

Claims

1. A method for the continuous preparation of cefoxitin sodium, characterized in that: The cefoxitin sodium has a maximum unknown single impurity content of less than 0.1% and a powder particle size of 10-90 μm. The continuous preparation method of the cefoxitin sodium includes the following steps: Step S1: Prepare solution A: Add sodium isooctanoate and sodium thiocyanate to the organic mixed solvent and stir until completely dissolved. Step S2: Prepare solution B: Add cefoxitin acid to the organic mixed solvent and stir until dissolved. Add activated carbon, stir, and then filter. Step S3: Solution A and solution B are simultaneously introduced into microchannel reactor one and mixed evenly to prepare solution C. Step S4: Solution C and acetone are simultaneously introduced into microchannel reactor two. The mixture from the outlet of microchannel reactor two directly enters ultrasonic pipeline crystallizer one. The crystallized liquid flowing out directly enters crystallization buffer tank I. The crystallized liquid overflowing from crystallization buffer tank I enters high-efficiency filtration device one for filtration to obtain filtrate I. Step S5: Filtrate I and acetone are simultaneously introduced into microchannel reactor three. After reaction, it enters ultrasonic pipeline crystallizer two. The crystallized liquid flowing out directly enters crystallization buffer tank II. The crystallized liquid overflowing from crystallization buffer tank II enters high-efficiency filtration device two. Step S6: The solids obtained in high-efficiency filtration device one and high-efficiency filtration device two are washed with acetone and then dried in a double-cone mixing process to obtain ultrafine cefoxitin sodium product.

2. The method for continuous preparation of cefoxitin sodium according to claim 1, characterized in that: The organic mixed solvents in steps S1 and S2 include methanol, acetone, ethanol, and ethyl acetate. The mass-volume ratio (kg / L) of sodium isooctanoate, sodium thiocyanate, and organic mixed solvent in step S1 is 100-103:10:1300-1500.

3. The method for continuous preparation of cefoxitin sodium according to claim 1, characterized in that: In step S2, the mass-to-volume ratio of cefoxitin and the organic mixed solvent is 25:160 (kg / L).

4. The method for continuous preparation of cefoxitin sodium according to claim 1, characterized in that: In step S3, the feed volume ratio of solution A to solution B is 13:18.5-20.

5.

5. The method for continuous preparation of cefoxitin sodium according to claim 1, characterized in that: In step S4, the feed volume ratio of solution C to acetone in microchannel reactor II is 1:1.5, the residence time in microchannel reactor II is 0.5-3s, the temperature is 10-20℃, the residence time in ultrasonic pipeline crystallizer I is 1-5s, and the stirring speed in crystallization buffer tank I is maintained at 10-25HZ.

6. The method for continuous preparation of cefoxitin sodium according to claim 1, characterized in that: In step S5, the feed volume ratio of filtrate I to acetone in microchannel reactor III is 1:0.5-1.0, the time in microchannel reactor III is 0.5-3s, the time in ultrasonic pipeline crystallizer II is 1-5s, and the stirring speed in crystallization buffer tank II is maintained at 10-25HZ.

7. The method for continuous preparation of cefoxitin sodium according to claim 1, characterized in that: In step S4, the ultrasonic frequency of ultrasonic pipe crystallizer one is controlled at 20~30HZ, and the ultrasonic frequency of ultrasonic pipe crystallizer two is controlled at 40~45HZ.

8. The method for continuous preparation of cefoxitin sodium according to claim 1, characterized in that: In step S1, the preparation temperature of solution A is 10.0℃~20.0℃, and in step S2, the preparation temperature of solution B is controlled at 10.0℃~20.0℃.

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