A method for preparing cefuroxime axetil double-phase crystal

Abstract

The application discloses a preparation method of cefuroxime axetil biphasic crystallization and belongs to the technical field of medicine preparation. The method comprises the following steps: step one, adding purified water into an ethyl acetate solution of cefuroxime axetil and stirring; step two, water-bath heating, vacuum distillation and concentration are continued until the vacuum is stopped after crystals are precipitated, the temperature of the crystallization liquid is controlled to be not higher than 20 DEG C, the crystals are stirred and aged, and the precipitated crystals sink into the water phase; step three, water-bath heating, vacuum distillation are continued until 90% of the ethyl acetate is distilled out, the distillation is stopped, and the aging is continued; step four, the aging is finished, the material is discharged, the material is filtered at the same time, the material is stopped when the material is discharged to the interface between the ethyl acetate phase and the water phase, the cefuroxime axetil solid is obtained, the cefuroxime axetil solid is washed with ethanol, the cefuroxime axetil solid is dried, and the cefuroxime axetil is obtained. The crystallization method of the cefuroxime axetil is environment-friendly and efficient, there is no residual isopropyl ether in the product, and the product quality is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and particularly relates to a method for preparing cefuroxime axetil biphase crystals. Background Technology

[0002] Cefuroxime axetil, chemical formula C 20 H 22 N4O 10 Cefuroxime is a second-generation oral cephalosporin antibiotic. It is quite stable against β-lactamases produced by Staphylococcus aureus and Gram-negative bacilli, exhibiting broad-spectrum antibacterial activity. Clinically, it is mainly used for infections of the lower respiratory tract, urinary tract, skin and soft tissues, bones and joints, and female genitalia caused by susceptible Gram-negative bacteria. It is also effective against sepsis and meningitis. Cefuroxime sodium is available for injection, while cefuroxime axetil, an esterified form, is available orally. Its antibacterial properties and the availability of various routes of administration make cefuroxime widely used in clinical practice.

[0003] Cefuroxime axetil is readily soluble in dioxane, relatively soluble in acetone and ethyl acetate, slightly soluble in ethanol, very slightly soluble in diethyl ether, and practically insoluble in water. Conventional cefuroxime axetil crystallization typically involves vacuum distillation to concentrate the ethyl acetate solution of cefuroxime axetil, followed by the addition of a large amount of the anti-solvent isopropyl ether to reduce the concentration of cefuroxime axetil in the ethyl acetate solution and improve the yield. This process leads to crystal aggregation, easily trapping impurities, and requires a large amount of isopropyl ether, resulting in a large isopropyl ether-ethyl acetate mixture, making the recovery of ethyl acetate and isopropyl ether difficult, and consuming significant amounts of energy. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing cefuroxime axetil biphase crystals that is environmentally friendly, easy to operate, and produces a product with high purity.

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

[0006] A method for preparing cefuroxime axetil biphasic crystals includes the following steps:

[0007] Step 1: Add purified water to the ethyl acetate solution of cefuroxime axetil, stir, and control the stirring method and speed to keep the ethyl acetate phase and the aqueous phase in a separate state;

[0008] Step 2: Heat in a water bath and concentrate by vacuum distillation until crystals precipitate. Stop the vacuum, control the temperature of the crystallization solution to not exceed 20°C, stir to grow crystals, and the larger crystals precipitated will sink into the aqueous phase.

[0009] Step 3: Continue water bath heating and vacuum distillation until 90% ethyl acetate is distilled off. Stop distillation and continue crystal growth.

[0010] Step 4: After crystal growth is complete, discharge the material while filtering. Stop discharging when the material reaches the interface between ethyl acetate and the aqueous phase to obtain solid cefuroxime axetil. Wash with ethanol, then vacuum dry to obtain cefuroxime axetil.

[0011] A further improvement of the technical solution of the present invention is that the concentration of cefuroxime axetil in the ethyl acetate solution of cefuroxime axetil in step one is 100-150 mg / ml.

[0012] A further improvement to the technical solution of the present invention is that the ratio of the amount of purified water added in step one to the mass of cefuroxime axetil (ml / g) is 15-30.

[0013] A further improvement to the technical solution of the present invention is that the temperature of the water bath in steps two and three is 40-70°C.

[0014] A further improvement to the technical solution of the present invention is that: in step three, crystals are grown at 10-20°C for 0.5-1.0 hours.

[0015] A further improvement to the technical solution of the present invention is that: the cefuroxime axetil obtained by filtration in step four is washed 3-5 times with 95% ethanol.

[0016] A further improvement to the technical solution of the present invention is that the residual ethyl acetate phase in step four is recycled into the next batch of extraction processes.

[0017] The technological advancements achieved by this invention due to the adoption of the above technical solutions are as follows:

[0018] This invention employs a two-phase (aqueous and ethyl acetate) crystallization process, allowing the resulting cefuroxime axetil crystals to grow to a certain size and then sink into the aqueous phase. This ensures both crystal homogeneity and prevents crystal aggregation. The presence of the aqueous phase enables low-supersaturation crystallization while maintaining a low and relatively stable solid content in ethyl acetate, which is beneficial for crystal growth and results in more uniform crystal particles. Simultaneously, ethyl acetate forms an azeotrope with water at a boiling point of 70–71°C, lower than the boiling point of ethyl acetate (77°C), saving energy and reducing the crystallization temperature, thus effectively guaranteeing the quality of cefuroxime axetil.

[0019] The crystallization method for cefuroxime axetil described in this application is environmentally friendly and efficient, and the product contains no isopropyl ether residue, thus improving product quality. It also reduces the volume of the crystallization system, lowers the crystallization capacity, shortens processing time, increases production efficiency, and reduces production costs. Attached Figure Description

[0020] Figure 1 This is the liquid chromatography chromatogram of cefuroxime axetil prepared in Example 1. Detailed Implementation

[0021] The present invention will be further described in detail below with reference to specific embodiments:

[0022] Example 1:

[0023] Add 300 ml of cefuroxime axetil crystallization solution, with ethyl acetate (concentration 110 mg / ml) as solvent, to 500 ml of water. Adjust the stirring speed to 150–250 rpm to maintain the ethyl acetate phase and aqueous phase in a separate phase.

[0024] Concentrate the crystals under vacuum distillation in a water bath at 50-60°C for about 20-30 minutes. Once crystals are formed, stop the vacuum process. During the process, control the temperature of the crystallization solution to not exceed 30°C. Stir and grow the crystals for 30 minutes. As the grown crystals grow, most of them sink into the aqueous phase.

[0025] Continue vacuum distillation in a water bath at 50–60°C for 90–150 minutes until 90% ethyl acetate is obtained. The temperature of the liquid should be controlled to not exceed 35°C during the process. Stop distillation and allow crystals to grow at 10–20°C for 30 minutes.

[0026] The material is discharged, with the lower layer being the aqueous phase. The discharged aqueous phase is filtered while being discharged. Discharge is stopped at the interface between the aqueous phase and the ethyl acetate phase to obtain cefuroxime axetil solid. It is washed four times with 200 ml of 95% ethanol, dried under vacuum, and then dried to obtain cefuroxime axetil.

[0027] The residual ethyl acetate phase is recycled and reused in the next extraction process.

[0028] The crystallization yield of cefuroxime axetil was 97.2%, and the product purity was 99.6%.

[0029] Example 2

[0030] Add 300 ml of cefuroxime axetil crystallization solution (ethyl acetate, concentration 150 mg / ml) to 900 ml of water. Adjust the stirring speed to 150–250 rpm to maintain the ethyl acetate phase and aqueous phase in a separate phase.

[0031] Concentrate the crystals under vacuum distillation in a water bath at 60–70°C for about 40–60 minutes. Stop the vacuum process and control the temperature of the crystallization solution to not exceed 30°C. Stir and grow the crystals for 30 minutes. As the grown crystals grow, most of them sink into the aqueous phase.

[0032] Continue vacuum distillation in a water bath at 60–70°C for 60–120 minutes until 90% ethyl acetate is obtained. The temperature of the liquid should be controlled to not exceed 35°C during the process. Stop distillation and allow crystals to grow at 10–20°C for 30 minutes.

[0033] The material is discharged, with the lower layer being the aqueous phase. The discharged aqueous phase is filtered while being discharged. Discharge is stopped at the interface between the aqueous phase and the ethyl acetate phase to obtain cefuroxime axetil solid. It is washed four times with 200 ml of 95% ethanol, dried under vacuum, and then dried to obtain cefuroxime axetil.

[0034] The residual ethyl acetate phase is recycled and reused in the next extraction process.

[0035] The crystallization yield of cefuroxime axetil was 96.2%, and the product purity was 99.2%.

[0036] Example 3

[0037] Add 300 ml of cefuroxime axetil crystallization solution, with ethyl acetate (concentration 120 mg / ml) as solvent, to 1080 ml of water. Adjust the stirring speed to 150–250 rpm to maintain the ethyl acetate phase and aqueous phase in a separate phase.

[0038] Concentrate the crystals under vacuum distillation in a water bath at 55–70°C for about 40–60 minutes. Stop the vacuum process and control the temperature of the crystallization solution to not exceed 30°C. Stir and grow the crystals for 30 minutes. As the grown crystals grow, most of them sink into the aqueous phase.

[0039] Continue vacuum distillation at 55–70°C for 60–100 minutes until 90% ethyl acetate is obtained. The temperature of the liquid should be controlled to not exceed 35°C during the process. Stop distillation and allow crystals to grow at 10–20°C for 30 minutes.

[0040] The material is discharged, with the lower layer being the aqueous phase. The discharged aqueous phase is filtered while being discharged. Discharge is stopped at the interface between the aqueous phase and the ethyl acetate phase to obtain cefuroxime axetil solid. It is washed four times with 200 ml of 95% ethanol, dried under vacuum, and then dried to obtain cefuroxime axetil.

[0041] The residual ethyl acetate phase is recycled and reused in the next extraction process.

[0042] The crystallization yield of cefuroxime axetil was 97.0%, and the product purity was 99.4%.

[0043] Comparative Example 1

[0044] 300 ml of cefuroxime axetil crystallization solution was prepared in ethyl acetate at a concentration of 100–150 mg / ml.

[0045] Concentrate the solution under vacuum distillation in a water bath at 40–70°C until crystals are formed. Stop the vacuum process and control the temperature of the crystallization solution to not exceed 30°C. Stir and grow crystals for 30 minutes.

[0046] Continue vacuum distillation in a water bath at 40–70°C for 90–150 minutes until 70% ethyl acetate is obtained. The temperature of the liquid solution should be controlled to not exceed 40°C during the process. Stop distillation and allow crystals to grow at 10–20°C for 30 minutes.

[0047] Slowly add 800-1000 ml of isopropyl ether over 60-120 minutes, then stop adding the isopropyl ether and stir for 30 minutes.

[0048] The sample was filtered and washed four times with a 3:1 mixture of isopropyl ether and ethyl acetate in 600 ml of water, with the final wash being with isopropyl ether. The sample was then dried to obtain the cefuroxime axetil product.

[0049] Crystallization yield was 94.2%, and product purity was 98.9%.

[0050] Comparative Example 2

[0051] 300 ml of cefuroxime axetil crystallization solution was prepared in ethyl acetate (110 mg / ml) and 500 ml of water was added. The stirring speed was adjusted to 350 rpm, and the ethyl acetate phase and water phase were stirred until they did not separate into layers.

[0052] Concentrate the solution under vacuum distillation in a water bath at 40–70°C for about 20–30 minutes. Once crystals are formed, stop the vacuum process. During the process, control the temperature of the crystallization solution to not exceed 30°C. Stir and grow the crystals for 30 minutes until crystals precipitate.

[0053] Continue vacuum distillation in a water bath at 40–70°C for 90–150 minutes until 90% ethyl acetate is obtained. The temperature of the liquid should be controlled to not exceed 35°C during the process. Stop distillation, reduce the stirring speed to 100 rpm, and culture crystals at 10–20°C for 30 minutes.

[0054] The material is discharged, with the lower layer being the aqueous phase. The discharged aqueous phase is filtered while being discharged. Discharge is stopped at the interface between the aqueous phase and the ethyl acetate phase to obtain cefuroxime axetil solid. It is washed four times with 200 ml of 95% ethanol, dried under vacuum, and then dried to obtain cefuroxime axetil.

[0055] The residual ethyl acetate phase is recycled and reused in the next extraction process.

[0056] The crystallization yield of cefuroxime axetil was 93.1%, and the product purity was 98.6%.

[0057] The cefuroxime axetil products obtained in the embodiments and comparative examples of this application were tested, and the test results are as follows:

Claims

1. A method for preparing cefuroxime axetil biphase crystals, characterized in that... Includes the following steps: Step 1: Add purified water to the ethyl acetate solution of cefuroxime axetil, stir, and control the stirring method and speed to keep the ethyl acetate phase and the aqueous phase in a separate state; Step 2: Heat in a water bath and concentrate by vacuum distillation until crystals precipitate. Stop the vacuum and control the temperature of the crystallization solution to not exceed 20°C. Stir to grow crystals, and larger crystals will sink into the aqueous phase. Step 3: Continue water bath heating and vacuum distillation until 90% ethyl acetate is distilled off. Stop distillation and continue crystal growth. Step 4: After crystal growth is complete, discharge the material while filtering. Stop discharging when the material reaches the interface between ethyl acetate and the aqueous phase to obtain solid cefuroxime axetil. Wash with ethanol, dry under vacuum, and dry to obtain cefuroxime axetil. In step one, the concentration of cefuroxime axetil in the ethyl acetate solution is 100–150 mg / ml; In step one, the ratio of purified water added to cefuroxime axetine mass (ml / g) is 15–30. In step one, adjust the stirring speed to 150-250 rpm; The water bath temperature in steps two and three is 40–70°C; In step three, crystals are grown at 10–20°C for 0.5–1.0 hours. The cefuroxime axetil obtained from filtration in step four is washed 3-5 times with 95% ethanol; The residual ethyl acetate phase from step four is recycled into the next batch of extraction processes.

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