Sterile cefepime hydrochloride and direct preparation method thereof

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to sterile cefepime hydrochloride and a direct preparation method thereof. The method comprises the following steps: firstly, carrying out condensation reaction on a 7-MPCA solution and an AE active ester solution through a solid base catalyst column at the same time; then, carrying out extraction phase separation, two times of pH regulation crystallization, activated carbon decoloration and sodium sulfite reduction on the condensation liquid to obtain a cefepime hydrochloride liquid to be crystallized; and then taking a part of the cefepime hydrochloride to-be-crystallized liquid to prepare a seed crystal mixed liquid, and adding the rest of the cefepime hydrochloride to-be-crystallized liquid and the crystallization solvent into the seed crystal mixed liquid at a specific speed to obtain the sterile cefepime hydrochloride. According to the method disclosed by the invention, the continuous production of the sterile cefepime hydrochloride is realized, the preparation period of the sterile cefepime hydrochloride is greatly shortened, side reactions and product degradation are reduced, the quality and yield of the obtained cefepime hydrochloride product are relatively high and stable, and industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and particularly relates to sterile cefepime hydrochloride and a direct preparation method thereof. Background Art

[0002] Sterile cefepime hydrochloride is an important fourth-generation cephalosporin antibiotic with broad-spectrum antibacterial activity and good inhibitory effect on a variety of Gram-positive and Gram-negative bacteria. It is widely used in the clinic to treat various serious infections, such as respiratory tract infections, urinary tract infections, skin and soft tissue infections, etc., with significant efficacy and safety.

[0003] The current industrial production process of sterile cefepime hydrochloride is: 7-MPCA ((6R, 7R)-7-amino-3-[(1-methyl-1-pyrrolidine)methyl] cef-3-ene-4-carboxylic acid inner salt) and AE active ester ((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminothioacetic acid-2'-benzothiazole active ester) are mixed and dissolved in dichloromethane in a certain proportion, and triethylamine is added to react to prepare cefepime hydrochloride. According to research, in this process, since it is mainly a tank-type intermittent production process with a long cycle, it leads to an increase in side reactions, product degradation, etc., and the obtained finished product has more impurities. Only crude cefepime hydrochloride can be obtained first, and then recrystallization can be used to obtain high-purity sterile cefepime hydrochloride (such as Chinese patent CN105859747A). In addition, this tank-type intermittent production process has some other defects: the production efficiency is relatively low, and the quality stability between batches is difficult to ensure; the process is relatively complex, involving multiple steps and operation links, and is prone to errors and deviations; the reaction time is long, which leads to an extension of the overall production cycle, increased costs and resource consumption; and in intermittent operations, the residence time of materials is inconsistent, further affecting the purity and consistency of the product. These defects limit the expansion of the production scale and further improvement of the quality of sterile cefepime hydrochloride, and are not conducive to the wider and more efficient application of this drug in the medical field.

[0004] Therefore, in order to overcome the shortcomings of the existing intermittent preparation method, it is urgently necessary to develop a new sterile cefepime hydrochloride production method to improve production efficiency, ensure the stability of product quality, reduce costs and achieve more efficient industrial production. Summary of the invention

[0005] The invention aims to provide a sterile cefepime hydrochloride and a direct preparation method thereof, wherein the method significantly shortens the preparation cycle of the sterile cefepime hydrochloride, greatly reduces side reactions and product degradation, improves production efficiency and product quality, and lays a foundation for directly crystallizing the sterile cefepime hydrochloride.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions: The invention first provides a sterile cefepime hydrochloride, wherein the product particle size D90 is 100-110 μm, the angle of repose is 45-65°, the bulk density is 0.35-0.50 g / ml, the tap density is 0.67-0.78 g / ml, the total impurities are ≤0.17%, and the solution color is ≤1. # .

[0007] The present invention also provides a direct method for preparing the above-mentioned sterile cefepime hydrochloride, comprising the following steps: (1) passing the 7-MPCA solution and the AE active ester solution through a solid base catalyst column simultaneously for condensation reaction to obtain a condensation solution; (2) Controlling the temperature at 0-2°C, passing the condensation liquid, dichloromethane and water through a fast pipeline mixer at the same time, and continuously separating the obtained mixed liquid through an extraction phase separation column to obtain an aqueous phase; (3) adding concentrated hydrochloric acid to the aqueous phase under vacuum and rapid stirring conditions to adjust the pH to 3.5-4.5 to obtain cefepime solution 1; adding activated carbon and sodium sulfite to cefepime solution 1, stirring and filtering to obtain cefepime solution 2; passing cefepime solution 2 and concentrated hydrochloric acid through a microchannel reactor at the same time, adsorbing on granular activated carbon, and fine filtering to obtain cefepime hydrochloride crystallization solution; wherein the pH of the mixed solution at the outlet of the microchannel reactor is 0.8-1.0; (4) A portion of the cefepime hydrochloride crystallization solution is taken out and mixed with water and acetone to prepare a seed crystal mixture; the remaining cefepime hydrochloride crystallization solution and acetone are added to the seed crystal mixture, and the crystals are grown for 30-60 minutes, and then filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0008] Furthermore, the volume ratio of the 7-MPCA solution to the AE active ester solution in step (1) is (100-110):(60-65); and the volume ratio of the condensation solution to dichloromethane and water in step (2) is 120:(60-70):(30-40).

[0009] Furthermore, the pH of the solid base catalyst column in step (1) is constant and is between 7.5 and 10.

[0010] Furthermore, in step (1), the time for the 7-MPCA solution and the AE active ester solution to pass through the solid base catalyst column is 15 to 20 minutes.

[0011] Furthermore, the preparation method of the 7-MPCA solution in step (1) is: 7-MPCA, dichloromethane, methanol, and DMF are mixed, the temperature is controlled at -5 to 0°C, triethylamine is added under rapid stirring conditions, and stirring is continued until it is completely dissolved; wherein the dosage ratio of 7-MPCA, dichloromethane, methanol, DMF, and triethylamine is 100Kg: 300-350L: 250-270L: 400-430L: 30-35Kg.

[0012] Furthermore, the preparation method of the AE active ester solution in step (1) is: mixing the AE active ester with dichloromethane and DMF at -5~0°C and stirring until dissolved; wherein the dosage ratio of the AE active ester to dichloromethane and DMF is 110Kg:250-300L:300-350L.

[0013] Furthermore, in step (3), the mass of the activated carbon is 3%-5% of the mass of 7-MPCA, and the mass of the sodium sulfite is 1%-2% of the mass of 7-MPCA.

[0014] Furthermore, the mass fraction of the concentrated hydrochloric acid in step (3) is 25% to 30%.

[0015] Furthermore, the volume ratio of the remaining cefepime hydrochloride crystallization liquid to acetone in step (4) is 8:(40-45).

[0016] Furthermore, in the seed crystal mixture of step (4), the volume ratio of the cefepime hydrochloride solution to be crystallized to water and acetone is 1:(4-5):(20-25), and the volume of the seed crystal mixture is based on the volume that can be touched by the stirring device.

[0017] The present invention (1) first passes 7-MPCA and AE active ester in the form of a solution through a solid base catalyst column so that they can undergo a condensation reaction under constant alkaline conditions, which not only solves the problem of local over-alkalinity during the reaction process, but also significantly shortens the reaction period of 7-MPCA and AE active ester, and reduces the occurrence of side reactions and product degradation under long-term over-alkalinity conditions; (2) then extracts and separates the condensed liquid, adjusts the pH twice for crystallization, and combines activated carbon decolorization and sodium sulfite reduction to further improve the quality and color of the cefepime hydrochloride crystallization solution and avoid recrystallization; (3) after obtaining the cefepime hydrochloride crystallization solution, first take a portion of the cefepime hydrochloride crystallization solution to prepare a seed mixture, and then add the remaining cefepime hydrochloride crystallization solution and a crystallization solvent to the seed mixture at a specific speed and in a specific manner, so as to better control the quality and quantity of sterile cefepime hydrochloride crystal nuclei, and thus accurately control the crystal growth.

[0018] The method of the invention realizes the continuous production of sterile cefepime hydrochloride, greatly shortens the preparation cycle of sterile cefepime hydrochloride, reduces the occurrence of side reactions and product degradation, and the obtained cefepime hydrochloride product has high and stable quality, and the molar yield can reach more than 91.5% and the purity is more than 99.9%. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The present invention is a schematic flow diagram of a direct-through method for preparing sterile cefepime hydrochloride. DETAILED DESCRIPTION

[0020] like Figure 1 The schematic diagram of the process of the direct-through method for preparing sterile cefepime hydrochloride of the present invention is shown. The technical scheme of the present invention is further described below in conjunction with the accompanying drawings and specific embodiments.

[0021] In the following examples, various processes and methods not described in detail are conventional methods known in the art, and reagents used without indicating the source and specifications are commercially available in analytical grade or chromatographic grade.

[0022] Example 1 (1) Mix 100 kg 7-MPCA, 300 L dichloromethane, 250 L methanol and 400 L DMF, control the temperature at -5~0°C, add 30 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions, and continue stirring until it is completely dissolved to obtain a 7-MPCA solution; (2) Add 110 kg AE active ester and 250 L dichloromethane into 300 L DMF at the same time, stir until dissolved at -5 to 0 °C to obtain AE active ester solution; (3) 7-MPCA solution and AE active ester solution enter the solid base catalyst column at a volume ratio of 100:60 for condensation reaction and flow out after 15 minutes to obtain a condensation liquid; (4) The condensation liquid, dichloromethane and water are mixed in a volume ratio of 120:64:30 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained; (5) Controlling the temperature at 0-2°C, adding 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, controlling the pH to 3.5-4.5, to obtain cefepime solution 1; adding 3 kg of activated carbon and 1 kg of sodium sulfite to cefepime solution 1, stirring for 30 min and filtering, to obtain cefepime solution 2; (6) After passing the cefepime solution 2 and 30% hydrochloric acid with a mass fraction in a volume ratio of 7:9 through a microchannel reactor, the mixture is adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor is 0.8-1.0; (7) Take 20 L of cefepime hydrochloride crystallization liquid and mix it with 80 L of water. After stirring evenly, add 400 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture; (8) The remaining cefepime hydrochloride crystals and acetone are added to the seed mixture at a volume ratio of 800:4000. After the addition, the crystals are grown for 60 minutes, filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0023] Example 2 (1) Mix 100 kg 7-MPCA, 350 L dichloromethane, 270 L methanol and 430 L DMF, control the temperature at -5~0°C, add 35 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions, and continue stirring until it is completely dissolved to obtain a 7-MPCA solution; (2) Add 110 kg AE active ester and 300 L dichloromethane into 350 L DMF at the same time, stir until dissolved at -5 to 0 °C to obtain AE active ester solution; (3) The 7-MPCA solution and the AE active ester solution were introduced into the solid base catalyst column at a volume ratio of 110:65 for condensation reaction and then flowed out after 15 minutes to obtain a condensation liquid; (4) The condensation liquid is mixed with dichloromethane and water in a volume ratio of 120:70:40 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained; (5) Controlling the temperature at 0-2°C, adding 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, controlling the pH to 3.5-4.5, to obtain cefepime solution 1; adding 5 kg of activated carbon and 2 kg of sodium sulfite to cefepime solution 1, stirring for 30 min and filtering to obtain cefepime solution 2; (6) After passing the cefepime solution 2 and 30% hydrochloric acid with a mass fraction in a volume ratio of 7:12 through a microchannel reactor, the mixture is adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor is 0.8-1.0; (7) Take 20 L of cefepime hydrochloride to be crystallized solution and mix it with 100 L of water. After stirring evenly, add 500 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture; (8) The remaining cefepime hydrochloride crystals and acetone are added to the seed mixture at a volume ratio of 800:4500. After the addition, the crystals are grown for 60 minutes, filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0024] Example 3 (1) Mix 100 kg 7-MPCA, 320 L dichloromethane, 270 L methanol and 410 L DMF, control the temperature at -5~0°C, add 31 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions, and continue stirring until it is completely dissolved to obtain a 7-MPCA solution; (2) Add 110 kg AE active ester and 265 L dichloromethane into 320 L DMF at the same time, stir until dissolved at -5 to 0 °C to obtain AE active ester solution; (3) The 7-MPCA solution and the AE active ester solution were introduced into the solid base catalyst column at a volume ratio of 105:62 for condensation reaction and then flowed out after 15 minutes to obtain a condensation liquid; (4) The condensation liquid, dichloromethane and water are mixed in a volume ratio of 120:65:35 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained; (5) Controlling the temperature at 0-2°C, adding 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, controlling the pH to 3.5-4.5, to obtain cefepime solution 1; adding 4 kg of activated carbon and 1.5 kg of sodium sulfite to cefepime solution 1, stirring for 30 min and filtering, to obtain cefepime solution 2; (6) After passing the cefepime solution 2 and 30% hydrochloric acid with a volume ratio of 7:10 through a microchannel reactor, the mixture is adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor is 0.8-1.0; (7) Take 20 L of cefepime hydrochloride to be crystallized solution and mix it with 85 L of water. After stirring evenly, add 500 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture; (8) The remaining cefepime hydrochloride crystals and acetone are added to the seed mixture at a volume ratio of 800:4300. After the addition, the crystals are grown for 60 minutes, filtered, washed and dried to obtain sterile cefepime hydrochloride.

[0025] Comparative Example 1 (1) Mix 100 kg 7-MPCA, 110 kg AE active ester, 550 L dichloromethane, 250 L methanol and 700 L DMF, control the temperature at -5 to 0 °C, and slowly add triethylamine for about 60 to 120 min; then continue the reaction until 7-MPCA reacts completely to obtain a condensation solution; (2) The condensation liquid, dichloromethane and water are mixed in a volume ratio of 120:64:30 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained; (3) Control the temperature at 0-2°C, add 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 3.5-4.5 to obtain cefepime solution 1; add 3 kg of activated carbon and 1 kg of sodium sulfite to cefepime solution 1, stir for 30 min and filter to obtain cefepime solution 2; (4) After the cefepime solution 2 and 30% hydrochloric acid with a mass fraction of 7:9 are passed through a microchannel reactor, the mixture is adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor is 0.8-1.0; (5) Take 20 L of cefepime hydrochloride to be crystallized solution and mix it with 80 L of water. After stirring evenly, add 400 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture; (6) The remaining cefepime hydrochloride crystals and acetone are added to the seed mixture at a volume ratio of 800:4000. After the addition, the crystals are grown for 60 minutes, filtered, washed and dried to obtain sterile cefepime hydrochloride.

[0026] Comparative Example 2 (1) Mix 100 kg 7-MPCA, 300 L dichloromethane, 250 L methanol and 400 L DMF, control the temperature at -5~0°C, add 30 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions, and continue stirring until it is completely dissolved to obtain a 7-MPCA solution; (2) Add 110 kg AE active ester and 250 L dichloromethane into 300 L DMF at the same time, stir until dissolved at -5 to 0 °C to obtain AE active ester solution; (3) The 7-MPCA solution and the AE active ester solution enter the solid base catalyst column at a flow rate of 100:60 for condensation reaction and flow out after 15 minutes to obtain a condensation liquid; (4) The condensation liquid, dichloromethane and water are mixed in a volume ratio of 120:64:30 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained; (5) Control the temperature at 0-2°C, add 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 3.5-4.5 to obtain cefepime solution 1; add 3 kg of activated carbon and 1 kg of sodium sulfite to cefepime solution 1, stir for 30 min and filter to obtain cefepime solution 2; (6) After passing the cefepime solution 2 and 30% hydrochloric acid with a mass fraction in a volume ratio of 7:9 through a microchannel reactor, the mixture is adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor is 0.8-1.0; (7) Acetone is added to the cefepime hydrochloride crystallization solution at a volume ratio of 5:1, and then the crystals are grown for 60 minutes, filtered, washed, and dried to obtain sterile cefepime hydrochloride.

[0027] Comparative Example 3 (1) Mix 100 kg 7-MPCA, 300 L dichloromethane, 250 L methanol and 400 L DMF, control the temperature at -5~0°C, add 30 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions, and continue stirring until it is completely dissolved to obtain a 7-MPCA solution; (2) Add 110 kg AE active ester and 250 L dichloromethane into 300 L DMF at the same time, stir until dissolved at -5 to 0 °C to obtain AE active ester solution; (3) 7-MPCA solution and AE active ester solution enter the solid base catalyst column at a volume ratio of 100:60 for condensation reaction and flow out after 15 minutes to obtain a condensation liquid; (4) The condensation liquid, dichloromethane and water are mixed at a flow rate of 120:64:30 at 0-2°C through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained; (5) Controlling the temperature at 0-2°C, adding 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, and controlling the pH to 3.5-4.5 to obtain cefepime solution 1; adding 3 kg of activated carbon and 1 kg of sodium sulfite to cefepime solution 1, stirring for 30 min and filtering to obtain cefepime solution 2; (6) After passing the cefepime solution 2 and 30% hydrochloric acid with a mass fraction in a volume ratio of 7:9 through a microchannel reactor, the mixture is adsorbed on activated carbon and finely filtered to obtain a cefepime hydrochloride solution to be crystallized; the pH of the mixed solution flowing out of the outlet of the microchannel reactor is 0.8-1.0; (7) Take 20 L of cefepime hydrochloride crystallization liquid and mix it with 80 L of water. After stirring evenly, add 400 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture; (8) Add 1-2 times the amount of acetone to the remaining cefepime hydrochloride crystallization solution, stir evenly, then add the same volume of acetone and seed crystal mixture as in Example 1, grow the crystals for 30 minutes, add 3-4 times the amount of acetone as the remaining crystallization solution again, grow the crystals for 30 minutes, filter, wash and dry to obtain sterile cefepime hydrochloride.

[0028] Comparative Example 4 (1) Mix 100 kg 7-MPCA, 300 L dichloromethane, 250 L methanol and 400 L DMF, control the temperature at -5~0°C, add 30 kg triethylamine to the mixed solution at a rate greater than 0.5 kg / min under rapid stirring conditions, and continue stirring until it is completely dissolved to obtain a 7-MPCA solution; (2) Add 110 kg AE active ester and 250 L dichloromethane into 300 L DMF at the same time, stir until dissolved at -5 to 0 °C to obtain AE active ester solution; (3) 7-MPCA solution and AE active ester solution enter the solid base catalyst column at a volume ratio of 100:60 for condensation reaction and flow out after 15 minutes to obtain a condensation liquid; (4) The condensation liquid, dichloromethane and water are mixed in a volume ratio of 120:64:30 at 0-2°C and passed through a rapid pipeline mixer to obtain a mixed liquid; the mixed liquid enters an extraction phase separation column for continuous phase separation, and the aqueous phase is retained; (5) Control the temperature at 0-2°C, add 30% hydrochloric acid by mass to the aqueous phase under vacuum and rapid stirring conditions, and control the pH to 0.8-1.0 to obtain a cefepime hydrochloride crystallization solution; add 3 kg of activated carbon and 1 kg of sodium sulfite to the cefepime hydrochloride crystallization solution, stir for 30 min and filter; (6) Take 20 L of the cefepime hydrochloride solution to be crystallized obtained in step (5) and mix it with 80 L of water. After stirring evenly, add 400 L of acetone under rapid stirring conditions and stir until the mixture is evenly mixed to obtain a seed crystal mixture; (7) The remaining cefepime hydrochloride crystallization liquid and acetone are added to the seed crystal mixture at a volume ratio of 800:4000. After the addition, the crystals are grown for 60 minutes, and then filtered, washed and dried to obtain sterile cefepime hydrochloride.

[0029] The test results of the sterile cefepime hydrochloride products prepared in Examples 1-3 and Comparative Examples 1-4 are shown in Table 1: Table 1 .

Claims

1. Sterile cefepime hydrochloride, characterized in that, Product particle size D90: 100-110μm, repose angle: 45-65°, bulk density: 0.35-0.50g / ml, tap density: 0.67-0.78g / ml, total impurities: ≤0.17%, solution color: ≤1 # .

2. A direct method for preparing the sterile cefepime hydrochloride according to claim 1, characterized in that: The steps include: (1) passing the 7-MPCA solution and the AE active ester solution through a solid base catalyst column simultaneously for condensation reaction to obtain a condensation solution; (2) Controlling the temperature at 0-2°C, passing the condensation liquid, dichloromethane and water through a fast pipeline mixer at the same time, and continuously separating the obtained mixed liquid through an extraction phase separation column to obtain an aqueous phase; (3) adding concentrated hydrochloric acid to the aqueous phase under vacuum and rapid stirring conditions to adjust the pH to 3.5-4.5 to obtain cefepime solution 1; adding activated carbon and sodium sulfite to cefepime solution 1, stirring and filtering to obtain cefepime solution 2; After the cefepime solution 2 and concentrated hydrochloric acid are simultaneously passed through a microchannel reactor, adsorbed by granular activated carbon and finely filtered, a cefepime hydrochloride solution to be crystallized is obtained; wherein the pH of the mixed solution at the outlet of the microchannel reactor is 0.8-1.0; (4) A portion of the cefepime hydrochloride crystallization solution is taken out and mixed with water and acetone to prepare a seed crystal mixture; the remaining cefepime hydrochloride crystallization solution and acetone are added to the seed crystal mixture, and the crystals are grown for 30-60 minutes, and then filtered, washed, and dried to obtain sterile cefepime hydrochloride.

3. The continuous production method of sterile cefepime hydrochloride according to claim 2, characterized in that: The volume ratio of the 7-MPCA solution to the AE active ester solution in step (1) is (100-110):(60-65); the volume ratio of the condensation solution to dichloromethane and water in step (2) is 120:(60-70):(30-40).

4. The continuous production method of sterile cefepime hydrochloride according to claim 2, characterized in that: The time for the 7-MPCA solution and the AE active ester solution in step (1) to pass through the solid base catalyst column is 15 to 20 minutes.

5. The continuous production method of sterile cefepime hydrochloride according to claim 2, characterized in that: The preparation method of the 7-MPCA solution in step (1) is as follows: 7-MPCA, dichloromethane, methanol and DMF are mixed, the temperature is controlled at -5 to 0°C, triethylamine is added under rapid stirring, and stirring is continued until completely dissolved; wherein the dosage ratio of 7-MPCA, dichloromethane, methanol, DMF and triethylamine is 100Kg: 300-350L: 250-270L: 400-430L: 30-35Kg.

6. The continuous production method of sterile cefepime hydrochloride according to claim 2, characterized in that: The preparation method of the AE active ester solution in step (1) is as follows: AE active ester is mixed with dichloromethane and DMF at -5 to 0°C and stirred until dissolved; wherein the dosage ratio of AE active ester to dichloromethane and DMF is 110Kg: 250-300L: 300-350L.

7. The continuous production method of sterile cefepime hydrochloride according to claim 2, characterized in that: The mass of the activated carbon in step (3) is 3%-5% of the mass of 7-MPCA, and the mass of the sodium sulfite is 1%-2% of the mass of 7-MPCA.

8. The continuous production method of sterile cefepime hydrochloride according to claim 2, characterized in that: The mass fraction of the concentrated hydrochloric acid in step (3) is 25% to 30%.

9. The continuous production method of sterile cefepime hydrochloride according to claim 2, characterized in that: The volume ratio of the remaining cefepime hydrochloride solution to be crystallized in step (4) to acetone is 8:(40-45).

10. The continuous production method of sterile cefepime hydrochloride according to claim 2, characterized in that: In the seed crystal mixture of step (4), the volume ratio of the cefepime hydrochloride solution to be crystallized to water and acetone is 1:(4-5):(20-25), and the volume of the seed crystal mixture is based on the volume that can be touched by the stirring device.

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