Superfine cefoxitin sodium and method for continuously preparing superfine cefoxitin sodium

Abstract

The invention discloses superfine cefoxitin sodium and a method for continuously preparing the superfine cefoxitin sodium, and belongs to the technical field of pharmacy. Preparing a solution B, namely a cefoxitin acid solution; the solution A and the solution B simultaneously enter a micro-channel reactor I and are uniformly mixed to obtain a solution C; the solution C and acetone enter a microchannel reactor II at the same time, mixed liquid at an outlet of the microchannel reactor II directly enters an ultrasonic pipeline crystallizer I, flowing-out crystallization liquid directly enters a crystallization liquid buffer tank I, and overflowing crystallization liquid of the crystallization buffer tank I enters an efficient filtering device I to be filtered, so that filtrate I is obtained; the filtrate I and acetone enter a micro-channel reactor III at the same time and then enter an ultrasonic pipeline crystallizer II after reaction, flowing-out crystallization liquid directly enters a crystallization liquid buffer tank II, and overflowing crystallization liquid of the crystallization buffer tank II enters a high-efficiency filtering device II; solids obtained in the first efficient filtering device and the second efficient filtering device are washed with acetone respectively and then enter a double cone to be mixed and dried, and the superfine cefoxitin sodium product is obtained.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals, and in particular relates to ultrafine cefoxitin sodium and a method for continuously preparing the ultrafine cefoxitin sodium. Background Art

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

[0003] Currently, cefoxitin sodium is crystallized in a tank batch process, which has problems such as large particle size, uneven particle size, long dissolution time, and discontinuous production. In particular, the existing cefoxitin sodium production process requires the preparation of crude cefoxitin sodium first, and then recrystallization to obtain pure cefoxitin, which has a long process and wastes manpower and material 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 continuously preparing the ultrafine cefoxitin sodium. The cefoxitin sodium product has a small and uniform particle size, and the preparation method can realize continuous production.

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

[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 continuously preparing ultrafine cefoxitin sodium comprises the following steps:

[0008] Step S1, preparing solution A: adding sodium isooctanoate and sodium thiocyanate into an organic mixed solvent, and stirring until completely dissolved;

[0009] Step S2, preparing solution B: adding cefoxitin acid to an organic mixed solvent, stirring until dissolved, adding activated carbon, stirring and filtering;

[0010] Step S3, solution A and solution B enter microchannel reactor 1 simultaneously, and are mixed evenly to prepare solution C;

[0011] Step S4, solution C and acetone enter microchannel reactor 2 simultaneously, the mixed solution at the outlet of microchannel reactor 2 directly enters ultrasonic pipeline crystallizer 1, the outflowing crystal liquid directly enters crystal liquid buffer tank 1, the crystal liquid overflowing from crystallization buffer tank 1 enters high-efficiency filtration device 1 for filtration, and obtains filtrate 1;

[0012] Step S5, the filtrate I and acetone enter the microchannel reactor III at the same time, and then enter the ultrasonic pipeline crystallizer II after the reaction, and the outflowing crystal liquid directly enters the crystal liquid buffer tank II, and the crystal liquid overflowing from the crystal buffer tank II enters the high-efficiency filtration device II;

[0013] Step S6: The solids obtained in the high-efficiency filtration device 1 and the high-efficiency filtration device 2 are washed with acetone respectively, and then enter the double cone mixing and drying to obtain an ultrafine cefoxitin sodium product.

[0014] The technical solution of the present invention is further improved in 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 the organic solvent in step S1 is 100-103:10:1300-1500 in kg / L.

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

[0016] A further improvement of the technical solution of the present invention is that in step S3, the feed volume ratio of solution A to solution B 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 microchannel reactor 2 is 1:1.5, the residence time in microchannel reactor 2 is 0.5-3s, the temperature is 10-20°C, the time in ultrasonic pipeline crystallizer 1 is 1-5s, and the stirring speed in crystallization buffer tank Ⅰ is maintained at 10-25HZ.

[0018] A further improvement of the technical solution of the present invention is that in step S4, the residence time of solution C and acetone in microchannel reactor 2 is 0.5-3s.

[0019] A further improvement of the technical solution of the present invention is that the feed volume ratio of the filtrate I and acetone in the microchannel reactor three in step S5 is 1:0.5-1.0, the time in the microchannel reactor three is 0.5-3s, the time in the ultrasonic pipeline crystallizer two is 1-5s, and the stirring speed in the crystallization buffer tank II is maintained at 10-25HZ.

[0020] A further improvement of the technical solution of the present invention is that in step S4, the ultrasonic wave of the ultrasonic pipe crystallizer 1 is controlled at 20-30 Hz, and the ultrasonic wave of the ultrasonic pipe crystallizer 2 is controlled at 40-45 Hz.

[0021] 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°C to 20.0°C, and the temperature of solution B in step S2 is controlled at 10.0°C to 20.0°C during preparation.

[0022] Due to the adoption of the above technical solution, the technical progress achieved by the present invention is:

[0023] The invention discloses a novel method for preparing ultrafine cefoxitin sodium, which changes the traditional tank batch production mode, achieves continuous production, and also omits the recrystallization step, so as to directly obtain a high-quality cefoxitin sodium product with uniform particle size. DETAILED DESCRIPTION

[0024] The present invention is further described in detail below in conjunction with embodiments:

[0025] Example 1

[0026] 1. Preparation of sodium 2-ethylhexanoate solution (Solution A): 800 L methanol, 500 L acetone, stirring at 50 rpm to 120 rpm, 10.0°C to 20.0°C. Add 100 kg sodium 2-ethylhexanoate and 10 kg sodium thiocyanate, and stir until completely dissolved.

[0027] 2. Preparation of cefoxitin acid solution (solution B): 300L methanol, 1300L acetone, stir at 50rpm~120rpm, 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℃, stir for 25min~30min and filter. Wash the decarbonization filter with 250L acetone and combine the filtrate.

[0028] 3. Solution A and solution B enter microchannel reactor 1 at the same time, with a feed ratio of 13:18.5, and are mixed evenly to prepare solution C.

[0029] 4. Solution C and acetone enter microchannel reactor 2 at the same time, with a feed ratio of 1:1.5. The time in microchannel reactor 2 is 0.5s. The mixed liquid at the outlet of microchannel reactor 2 directly enters ultrasonic pipeline crystallizer 1, with ultrasonic wave controlled at 40HZ and ultrasonic pipeline crystallizer 1 staying for 5s. The outflowing crystal liquid directly enters crystal liquid buffer tank Ⅰ, and the crystal liquid overflowing from crystal liquid buffer tank Ⅰ enters high-efficiency filter device 1 for filtration, and is washed with a small amount of (1:1) methanol acetone solution to obtain filtrate Ⅰ. Filtrate Ⅰ and acetone (ratio 1:05) enter microchannel reactor 3 again, and after staying in microchannel reactor 3 for 0.5s, enter ultrasonic pipeline crystallizer 2, with ultrasonic wave controlled at 40HZ and ultrasonic pipeline crystallizer staying for 5s. The outflowing crystal liquid enters crystal liquid buffer tank Ⅱ, and the crystal liquid overflowing from crystal liquid buffer tank Ⅱ enters high-efficiency filter device 2 for filtration. The powders in the high-efficiency filter device 1 and the high-efficiency filter device 2 were washed with 1000L and 400L of acetone respectively, and then entered the double cone mixing and drying to obtain an ultrafine cefoxitin sodium product.

[0030] Example 2

[0031] 1. Preparation of sodium isooctanoate solution (solution A): 800L methanol, 500L acetone, stirring at 50rpm-120rpm, 10.0℃-20.0℃. Add 103Kg sodium isooctanoate and 10Kg sodium thiocyanate, stirring until completely dissolved.

[0032] 2. Preparation of cefoxitin acid solution (solution B): 400L methanol, 1400L acetone, stir at 50rpm~120rpm, 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℃, stir for 25min~30min and filter. Wash the decarbonization filter with 250L acetone and combine the filtrate.

[0033] 3. Solution A and solution B enter microchannel reactor 1 at the same time, with a feed ratio of 13:20.5, and are mixed evenly to prepare solution C.

[0034] 4. Solution C and acetone enter microchannel reactor 2 at the same time, with a feed ratio of 1:1.5. The time in microchannel reactor 2 is 3s. The mixed liquid at the outlet of microchannel reactor 2 directly enters ultrasonic pipeline crystallizer 1, with ultrasonic wave controlled at 30HZ and ultrasonic pipeline crystallizer 1 staying for 1s. The outflowing crystal liquid directly enters crystal liquid buffer tank Ⅰ, and the crystal liquid overflowing from crystal liquid buffer tank Ⅰ enters high-efficiency filter device 1 for filtration, and is washed with a small amount of (1:1) methanol acetone solution to obtain filtrate Ⅰ. Filtrate Ⅰ and acetone (ratio 1:1) enter microchannel reactor 3 again, and after staying in microchannel reactor 3 for 3s, enter ultrasonic pipeline crystallizer 2, with ultrasonic wave controlled at 45HZ and ultrasonic pipeline crystallizer staying for 1s. The outflowing crystal liquid enters crystal liquid buffer tank Ⅱ, and the crystal liquid overflowing from crystal liquid buffer tank Ⅱ enters high-efficiency filter device 2 for filtration. The powders in the high-efficiency filter device 1 and the high-efficiency filter device 2 were washed with 1000L and 400L of acetone respectively, and then entered the double cone mixing and drying to obtain an ultrafine cefoxitin sodium product.

[0035] Example 3

[0036] 1. Preparation of sodium 2-ethylhexanoate solution (Solution A): 800 L methanol, 500 L acetone, stirring at 50 rpm to 120 rpm, 10.0°C to 20.0°C. Add 101 kg sodium 2-ethylhexanoate and 10 kg sodium thiocyanate, and stir until completely dissolved.

[0037] 2. Preparation of cefoxitin acid solution (solution B): 350L methanol, 1350L acetone, stir at 50rpm~120rpm, 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℃, stir for 25min~30min and filter. Wash the decarbonization filter with 250L acetone and combine the filtrate.

[0038] 3. Solution A and solution B enter microchannel reactor 1 at the same time, with a feed ratio of 13:19.5, and are mixed evenly to prepare solution C.

[0039] 4. Solution C and acetone enter microchannel reactor 2 at the same time, with a feed ratio of 1:1.5. The time in microchannel reactor 2 is 2s. The mixed liquid at the outlet of microchannel reactor 2 directly enters ultrasonic pipeline crystallizer 1, with ultrasonic wave controlled at 45HZ and staying in ultrasonic pipeline crystallizer 1 for 3s. The outflowing crystal liquid directly enters crystal liquid buffer tank Ⅰ, and the crystal liquid overflowing from crystal liquid buffer tank Ⅰ enters high-efficiency filter device 1 for filtration, and is washed with a small amount of (1:1) methanol acetone solution to obtain filtrate Ⅰ. Filtrate Ⅰ and acetone (ratio 1:1) enter microchannel reactor 3 again, and after staying in microchannel reactor 3 for 2s, enter ultrasonic pipeline crystallizer 2, with ultrasonic wave controlled at 42HZ and staying in ultrasonic pipeline crystallizer 2 for 3s. The outflowing crystal liquid enters crystal liquid buffer tank Ⅱ, and the crystal liquid overflowing from crystal liquid buffer tank Ⅱ enters high-efficiency filter device 2 for filtration. The powders in the high-efficiency filter device 1 and the high-efficiency filter device 2 were washed with 1000L and 400L of acetone respectively, and then entered the double cone mixing and drying to obtain an ultrafine cefoxitin sodium product.

[0040] Example 4

[0041] 1. Preparation of sodium 2-ethylhexanoate solution (Solution A): 800 L ethanol, 500 L acetone, stirring at 50 rpm to 120 rpm, 10.0°C to 20.0°C. Add 100 kg sodium 2-ethylhexanoate and 10 kg sodium thiocyanate, and stir until completely dissolved.

[0042] 2. Preparation of cefoxitin acid solution (solution B): 300L ethanol, 1300L acetone, stir at 50rpm~120rpm, 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℃, stir for 25min~30min and filter. Wash the decarbonization filter with 250L acetone and combine the filtrate.

[0043] 3. Solution A and solution B enter microchannel reactor 1 at the same time, with a feed ratio of 13:18.5, and are mixed evenly to prepare solution C.

[0044] 4. Solution C and acetone enter microchannel reactor 2 at the same time, with a feed ratio of 1:1.5. The time in microchannel reactor 2 is 0.5s. The mixed liquid at the outlet of microchannel reactor 2 directly enters ultrasonic pipeline crystallizer 1, with ultrasonic wave controlled at 40HZ and ultrasonic pipeline crystallizer 1 staying for 5s. The outflowing crystal liquid directly enters crystal liquid buffer tank Ⅰ, and the crystal liquid overflowing from crystal liquid buffer tank Ⅰ enters high-efficiency filter device 1 for filtration, and is washed with a small amount of (1:1) methanol acetone solution to obtain filtrate Ⅰ. Filtrate Ⅰ and acetone (ratio 1:05) enter microchannel reactor 3 again, and after staying in microchannel reactor 3 for 0.5s, enter ultrasonic pipeline crystallizer 2, with ultrasonic wave controlled at 40HZ and ultrasonic pipeline crystallizer staying for 5s. The outflowing crystal liquid enters crystal liquid buffer tank Ⅱ, and the crystal liquid overflowing from crystal liquid buffer tank Ⅱ enters high-efficiency filter device 2 for filtration. The powders in the high-efficiency filter device 1 and the high-efficiency filter device 2 were washed with 1000L and 400L of acetone respectively, and then entered the double cone mixing and drying to obtain an ultrafine cefoxitin sodium product.

[0045] A high-efficiency filtration device can be a high-speed centrifugal filter.

[0046] Comparative Example 1

[0047] 1. Preparation of sodium 2-ethylhexanoate solution (solution A): 800 L methanol, 550 L acetone, stir at 30 rpm to 100 rpm, and control the temperature in the tank to be 15.0°C to 20.0°C. Add 105 kg sodium 2-ethylhexanoate and 11 kg sodium thiocyanate, and stir until completely dissolved.

[0048] 2. Preparation of cefoxitin acid solution (solution B): 300L methanol, 15000 acetone, stir at 50rpm~120rpm, control 15.0℃~25.0℃. Add 250.0kg cefoxitin acid and stir until dissolved. Add 11.0kg activated carbon and control the tank temperature at 15.0℃~25.0℃, stir for 25min~30min, and filter into the crystallization tank. Wash the carbon filter with 250 acetone and combine the filtrate in the crystallization tank.

[0049] 3. Crystallization: Turn on the crystallization tank and stir at 15 rpm, and control the temperature of the crystallization tank at 10.0°C to 15.0°C. Add solution A to the crystallization tank at a flow rate of 40 L / min, and keep the temperature of the crystallization tank at 10.0°C to 15.0°C.

[0050] 4. Crystal growth: After adding solution A, control the temperature in the crystallization tank to 10.0℃~15.0℃ and grow the crystal for 30 minutes.

[0051] 5. Then add 3500L of acetone into the crystallizer at a flow rate of 100L / min, and keep the temperature of the crystallizer at 10.0℃~15.0℃ during the addition process.

[0052] 6. Crystal growing: After the addition of acetone is completed, the temperature is 10.0℃~15.0℃, and the crystal is grown for 30 minutes.

[0053] 7. Centrifugal filtration, washing twice with 1000+800L acetone, and double cone drying to obtain the cefoxitin product.

[0054] Comparative Example 2

[0055] Take 200 kg of crude cefoxitin sodium, add 400 L of purified water, stir until dissolved, control the temperature at 8±2°C, add activated carbon, stir for 30 minutes, filter; then wash the activated carbon with 40 L of purified water. Combine the carbon washing water and the filtrate to obtain the cefoxitin sodium solution, and control the temperature at 8±2°C.

[0056] The temperature of a mixed solution of acetone, methanol and dichloromethane in a volume ratio of 20:1:1 is controlled at 2±2°C, and the above-mentioned cefoxitin sodium solution and the mixed solvent are simultaneously introduced into a micro-mixer with a flow rate ratio of 1:10, wherein the flow rate of the cefoxitin sodium solution is 20 L / min, and the retention time in the micro-mixer is 2s; a crystallization liquid is obtained at the outlet of the micro-mixer, and the cefoxitin sodium crystallization liquid is sent to a filter for filtration to obtain a cefoxitin sodium wet product 1 and a mother liquor; the mother liquor is collected in a stirring container, and the same amount of a mixed solution of acetone, methanol and dichloromethane in a volume ratio of 20:1:1 is continuously added, the temperature is controlled at 8±2°C, and the mixture is stirred for 15 minutes for crystallization, and then the cefoxitin sodium wet product 2 is obtained after filtration, and the cefoxitin sodium wet product 1 and the cefoxitin sodium wet product 2 are mixed and dried to obtain cefoxitin sodium powder.

[0057] Comparative Example 3

[0058] This comparative example is basically the same as Example 1, the only difference being that in step S4, solution C and acetone enter the microchannel reactor 2 simultaneously, and the feed ratio is 1:1.0.

[0059] Comparative Example 4

[0060] This comparative example is basically the same as Example 1, the only difference being that in step S4, solution C and acetone enter the microchannel reactor 2 simultaneously, and the feed ratio is 1:2.

[0061] The products obtained in the embodiments and comparative examples were tested, and the test results are as follows:

[0062]

Claims

1. An ultrafine cefoxitin sodium, characterized in that: The maximum unknown single impurity of the cefoxitin sodium is less than 0.1%, and the powder particle size is 10-90 μm.

2. A method for continuously preparing ultrafine cefoxitin sodium, characterized in that The following steps are involved: Step S1, preparing solution A: adding sodium isooctanoate and sodium thiocyanate into an organic mixed solvent, and stirring until completely dissolved; Step S2, preparing solution B: adding cefoxitin acid to an organic mixed solvent, stirring until dissolved, adding activated carbon, stirring and filtering; Step S3, solution A and solution B enter microchannel reactor 1 simultaneously, and are mixed evenly to prepare solution C; Step S4, solution C and acetone enter microchannel reactor 2 simultaneously, the mixed solution at the outlet of microchannel reactor 2 directly enters ultrasonic pipeline crystallizer 1, the outflowing crystal liquid directly enters crystal liquid buffer tank 1, the crystal liquid overflowing from crystallization buffer tank 1 enters high-efficiency filtration device 1 for filtration, and obtains filtrate 1; Step S5, the filtrate I and acetone enter the microchannel reactor III at the same time, and then enter the ultrasonic pipeline crystallizer II after the reaction, and the outflowing crystal liquid directly enters the crystal liquid buffer tank II, and the crystal liquid overflowing from the crystal buffer tank II enters the high-efficiency filtration device II; Step S6: The solids obtained in the high-efficiency filter device 1 and the high-efficiency filter device 2 are washed with acetone respectively, and then enter the double cone mixing and drying to obtain an ultrafine cefoxitin sodium product.

3. A method for continuously preparing ultrafine cefoxitin sodium according to claim 2, characterized in that: The organic mixed solvent in steps S1 and S2 includes methanol, acetone, ethanol and ethyl acetate. The mass volume ratio of sodium isooctanoate, sodium thiocyanate and organic solvent in step S1 is 100-103:10:1300-1500 in kg / L.

4. The method for continuously preparing ultrafine cefoxitin sodium according to claim 2, characterized in that: The mass volume ratio of cefoxitin acid to the organic solvent in step S2 is 25:160 in kg / L.

5. The method for continuously preparing ultrafine cefoxitin sodium according to claim 2, characterized in that: In step S3, the feed volume ratio of solution A to solution B is 13: 18.5-20.

5.

6. The method for continuously preparing ultrafine cefoxitin sodium according to claim 2, characterized in that: In step S4, the feed volume ratio of solution C and acetone in microchannel reactor 2 is 1:1.5, the residence time in microchannel reactor 2 is 0.5-3s, the temperature is 10-20°C, the time in ultrasonic pipeline crystallizer 1 is 1-5s, and the stirring speed in crystallization buffer tank Ⅰ is maintained at 10-25HZ.

7. The method for continuously preparing ultrafine cefoxitin sodium according to claim 6, characterized in that: In step S4, the residence time of solution C and acetone in microchannel reactor 2 is 0.5-3s.

8. The method for continuously preparing ultrafine cefoxitin sodium according to claim 2, characterized in that: In step S5, the feed volume ratio of filtrate I to acetone in microchannel reactor three is 1:0.5-1.0, the time in microchannel reactor three is 0.5-3s, the time in ultrasonic pipeline crystallizer two is 1-5s, and the stirring speed in crystallization buffer tank II is maintained at 10-25HZ.

9. The method for continuously preparing ultrafine cefoxitin sodium according to claim 2, characterized in that: In step S4, the ultrasonic wave of the ultrasonic pipe crystallizer 1 is controlled at 20-30 Hz, and the ultrasonic wave of the ultrasonic pipe crystallizer 2 is controlled at 40-45 Hz.

10. The method for continuously preparing ultrafine cefoxitin sodium according to claim 2, characterized in that: The preparation temperature of solution A in step S1 is 10.0°C to 20.0°C, and the temperature of solution B in step S2 is controlled at 10.0°C to 20.0°C during preparation.

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