Method for purifying cefradine

Abstract

The invention discloses a method for purifying cefradine, and belongs to the technical field of medicine purification. The method comprises the following steps: (1) suspending to-be-purified cefradine in a mixed solution of purified water and petroleum ether, dropwise adding an acidic reagent under a temperature-controlled stirring condition to adjust the pH value of a system, stirring until the solution is clear, standing for phase splitting, and reserving a water phase and a filtering membrane to obtain a filtrate; (2) adding a dispersing agent into the filtrate obtained in the step (1) to obtain feed liquid, and sequentially crystallizing and growing the feed liquid in four stages of connected crystallization production tanks by simultaneously adjusting the temperature and pH of each stage of crystallization production tank in a gradient manner; and (3) after crystal growing is finished, filtering, washing, vacuum drying and discharging to obtain a white solid of cefradine. The method is simple, energy-saving and environment-friendly, and the obtained cefradine product has the advantages of high content, few impurities and good stability, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical purification, and in particular relates to a method for purifying cefuroxime. Background Art

[0002] Cefuroxime is the first generation of oral cephalosporin antibiotics. In recent years, due to its broad antibacterial spectrum, weak antigenicity, good efficacy, low toxicity, good oral absorption and safe use, cephalosporin has been ranked among the top ten cephalosporin antibiotics in terms of market sales. At present, cephalosporin products on the market are generally cephalosporin monohydrate, which is a white or off-white crystalline powder, slightly soluble in water, insoluble in chloroform and ether, stable in acid, and easily degraded in an alkaline environment. The molecular formula of cephalosporin monohydrate is C16H17N3O5S·H2O, with a molecular weight of 381.41. The chemical structure of cephalosporin is shown in Formula I: .

[0003] The introduction to the preparation of cefradine is mainly based on synthesis. The methods introduced in patents and literature are mainly as follows: In the papers "Study on the Reaction Crystallization Process of Cefuroxime" and "Optimization of the Reaction Crystallization Process of Cefuroxime Monohydrate", Gong Junbo et al. introduced the preparation of Cefuroxime by crystallization of Cefuroxime DMF solvate. The system involves the use of Class II solvent DMF, which is not environmentally friendly and increases product quality risks.

[0004] At present, the purification of cefradine mainly relies on extraction phase separation and isoelectric point crystallization. However, the cefradine products obtained by such methods have some unsatisfactory aspects. For example, the product has a high impurity content and a low crystallization yield, which leads to a lot of waste of raw materials in the production process and impaired economic benefits; the product has a wide particle size distribution, which not only affects the uniformity and stability of the product, but also brings difficulties to subsequent processing and application. Summary of the invention

[0005] In view of the defects of the prior art, the object of the present invention is to provide a method for purifying cephradine, so as to improve the purity, stability and yield of the cephradine product, reduce production costs and improve production efficiency.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions: A method for purifying cefuroxime comprises the following steps: (1) suspending the cefradine to be purified in a mixture of purified water and petroleum ether, controlling the temperature at 5-10°C, adding an acidic reagent dropwise under stirring to adjust the pH of the system to 1.0-1.2, stirring until dissolved, allowing to stand for phase separation, retaining the aqueous phase, and filtering through a membrane to obtain a filtrate; (2) adding a dispersant to the filtrate obtained in step (1) to obtain a feed solution, and causing the feed solution to be crystallized and grown in four stages of connected crystallization production tanks by simultaneously gradient controlling the temperature and pH of each stage of crystallization production tanks; (3) After the crystal growth is completed, the product is filtered, washed, vacuum dried, and discharged to obtain a white solid of cefradine.

[0007] Furthermore, the cefradine to be purified in step (1) is the contents of cefradine capsules or tablets of degraded quality or approaching the expiration date, or a crude cefradine product.

[0008] Furthermore, in step (1), the ratio of the volume L of the purified water, the volume L of the petroleum ether and the mass Kg of the cefradine to be purified is (3-4): (3-4): 1.

[0009] Furthermore, the acidic reagent in step (1) is glacial acetic acid or carbonic acid.

[0010] Furthermore, the filter membrane in step (1) has a molecular weight cutoff of 800 to 1200 Daltons.

[0011] Furthermore, the dispersant in step (2) is butanone or acetone, and the ratio of the volume L of the dispersant to the mass Kg of the cephradine to be purified is (1-2):1.

[0012] Furthermore, in step (2), the temperatures of the crystallization production tanks of levels 1 to 4 are respectively controlled at 25-30°C, 15-20°C, 5-10°C, and -5-0°C, and the pH of the feed solution after entering the crystallization production tanks of each level and mixing with the alkali solution already in the crystallization production tanks is respectively controlled at 1.8-2.2, 2.8-3.2, 3.8-4.2, and 4.8-5.

[0013] Among them, the alkali solution in the crystallization production tank is triethylamine or diisopropylamine; its dosage is calculated according to the pH of the mixed system of the feed liquid and the alkali solution in the crystallization production tanks at each level and the mass of the cefradine to be purified, and can be appropriately supplemented later according to the actual pH after the feed liquid and the alkali solution are mixed.

[0014] Furthermore, the specific operation steps of step (2) are as follows: Add a dispersant to the filtrate obtained in step (1) to obtain a feed solution, and add alkali solution to each level of crystallization production tank in advance. The temperature of the first level crystallization production tank is controlled at 25-30°C. The feed solution is added to the first level crystallization production tank, mixed with the alkali solution to adjust the system to 1.8-2.2, stirred and crystallized for 30-60 minutes, and discharged to the second level crystallization production tank; the temperature of the second level crystallization production tank is controlled at 15-20°C, the feed solution and the alkali solution are mixed to adjust the pH value of the system to 2.8-3.2, stirred and crystallized for 30-60 minutes, and discharged to the third level crystallization production tank; the temperature of the third level crystallization production tank is controlled at 5-10°C, the feed solution and the alkali solution are mixed to adjust the pH value of the system to 3.8-4.2, stirred and crystallized for 30-60 minutes, and discharged to the fourth level crystallization production tank; the temperature of the fourth level crystallization production tank is controlled at -5-0°C, the feed solution and the alkali solution are mixed to adjust the pH value of the system to 4.8-5, and stirred and crystallized for 30-60 minutes.

[0015] Furthermore, the washing method in step (3) is to first wash with purified water and then wash with acetone; and the vacuum drying temperature is 40°C.

[0016] The beneficial effects of the present invention are: The present invention simultaneously controls the crystallization temperature and pH value by gradient, and crystallizes and grows the cephradine to be purified, and the crystallization process is stable, and explosive crystallization can be avoided, and the risk of impurity precipitation is reduced, and the product is easy to filter and dry; the obtained cephradine product has the advantages of high content of active ingredients, less impurities, and good stability, and effectively solves the problem that the quality of products such as cephradine capsules or tablets near the effective period is degraded due to content, impurities, and visible foreign matter, and the active ingredients cannot be recovered. The method of the present invention can also be applied to the preparation of high-purity cephradine standard products.

[0017] The purification method of the invention is not only simple and easy to operate, but also energy-saving and environmentally friendly, and is particularly suitable for large-scale industrial production. DETAILED DESCRIPTION

[0018] The following examples are used to further illustrate the present invention, but are not intended to limit the present invention in any form.

[0019] Example 1 Take the contents of cefradine capsules (equivalent to 20 g of cefradine), suspend them in a mixture of 60 ml of purified water and 60 ml of petroleum ether, control the temperature at 5°C, add dropwise glacial acetic acid to adjust the system pH to 1.0, stir until dissolved, let stand for phase separation, retain the aqueous phase, and perform ultrafiltration using a filter membrane with a molecular weight cutoff of 1000 Daltons.

[0020] Add 20 ml of butanone to the filtrate, and make the feed liquid crystallize and grow crystals in 4 connected crystal production tanks in turn: add triethylamine to each level of crystal production tank in advance, add the feed liquid to the crystal production tank from the top of the crystal production tank, wait for the feed liquid to be fully mixed with the alkali solution in the crystal production tank, stir and grow crystals for 30-60 minutes, and discharge the material to the next level of crystal production tank; Specifically: the temperature of production tank 1 is controlled at 25°C, the feed liquid is added into production tank 1, mixed with triethylamine to adjust the pH value of the system to 2.0, stirred and crystallized for 30 minutes, and discharged to the second-level crystallization production tank; the temperature of production tank 2 is controlled at 15°C, the feed liquid and triethylamine are mixed to adjust the pH value of the system to 3.0, stirred and crystallized for 30 minutes, and discharged to the third-level crystallization production tank; the temperature of production tank 3 is controlled at 5°C, the feed liquid and triethylamine are mixed to adjust the pH value of the system to 4.0, stirred and crystallized for 30 minutes, and discharged to the fourth-level crystallization production tank; the temperature of production tank 4 is controlled at -5°C, the feed liquid and triethylamine are mixed to adjust the pH value of the system to 4.8, stirred and crystallized for 30 minutes.

[0021] After the crystal growth was completed, the crystal liquid was filtered, washed twice with 60 ml of purified water, washed twice with 60 mL of acetone and then dried; vacuum dried at 40°C for 2 h to obtain a white solid with a yield of 86.8%.

[0022] Example 2 Take the contents of cefradine capsules (equivalent to 20 g of cefradine), suspend them in a mixture of 80 ml of purified water and 80 ml of petroleum ether, control the temperature at 10°C, add glacial acetic acid dropwise to adjust the pH of the system to 1.2, stir until dissolved, let stand for phase separation, retain the aqueous phase, and perform ultrafiltration using a filter membrane with a molecular weight cutoff of 800 Daltons.

[0023] Add 40 ml of butanone to the filtrate, and make the feed liquid crystallize and grow crystals in 4 connected crystal production tanks in turn: add diisopropylamine to each level of crystal production tank in advance, add the feed liquid from the top of the crystal production tank to the first level crystal production tank, wait for the feed liquid to be fully mixed with the alkali solution in the crystal production tank, stir and grow crystals for 30-60 minutes, and discharge the material to the next level crystal production tank; Specifically: the temperature of production tank 1 is controlled at 30°C, the feed liquid is added into production tank 1, mixed with diisopropylamine to adjust the system pH = 1.8, stirred and crystallized for 30 minutes, and discharged to the second-level crystallization production tank; the temperature of production tank 2 is controlled at 20°C, the feed liquid and diisopropylamine are mixed to adjust the system pH = 2.8, stirred and crystallized for 30 minutes, and discharged to the third-level crystallization production tank; the temperature of production tank 3 is controlled at 10°C, the feed liquid and diisopropylamine are mixed to adjust the system pH = 3.8, stirred and crystallized for 30 minutes, and discharged to the fourth-level crystallization production tank; the temperature of production tank 4 is controlled at 0°C, the feed liquid and diisopropylamine are mixed to adjust the system pH = 5.0, stirred and crystallized for 30 minutes.

[0024] After the crystal growth was completed, the crystal liquid was filtered, washed twice with 60 ml of purified water, washed twice with 60 mL of acetone and then dried; vacuum dried at 40°C for 2.5 h to obtain a white solid with a yield of 84.8%.

[0025] Example 3 Take the contents of cefradine capsules (equivalent to 20 g of cefradine), suspend them in a mixture of 70 ml of purified water and 70 ml of petroleum ether, control the temperature at 8°C, add glacial acetic acid dropwise to adjust the pH of the system to 1.1, stir until dissolved, let stand for phase separation, retain the aqueous phase, and perform ultrafiltration using a filter membrane with a molecular weight cutoff of 1200 Daltons.

[0026] Add 20 ml of acetone to the filtrate, and make the feed liquid crystallize and grow crystals in 4 connected crystal production tanks in turn: add triethylamine to each level of crystal production tank in advance, add the feed liquid from the top of the crystal production tank to the first level crystal production tank, wait for the feed liquid to be fully mixed with the alkali solution in the crystal production tank, stir and grow crystals for 30-60 minutes, and discharge the material to the next level crystal production tank; Specifically: the temperature of production tank 1 is controlled at 28°C, the feed liquid is added into production tank 1, mixed with triethylamine to adjust the pH value of the system to 2.2, stirred and crystallized for 30 minutes, and discharged to the second-level crystallization production tank; the temperature of production tank 2 is controlled at 18°C, the feed liquid and triethylamine are mixed to adjust the pH value of the system to 3.2, stirred and crystallized for 30 minutes, and discharged to the third-level crystallization production tank; the temperature of production tank 3 is controlled at 8°C, the feed liquid and triethylamine are mixed to adjust the pH value of the system to 4.2, stirred and crystallized for 30 minutes, and discharged to the fourth-level crystallization production tank; the temperature of production tank 4 is controlled at -2°C, the feed liquid and triethylamine are mixed to adjust the pH value of the system to 4.9, stirred and crystallized for 30 minutes.

[0027] After the crystal growth was completed, the crystal liquid was filtered, washed twice with 60 ml of purified water, washed twice with 60 mL of acetone and then dried; vacuum dried at 40 °C for 2.5 h to obtain a white solid with a yield of 85.7%.

[0028] Comparative Example 1 Take the contents of cefradine capsules (equivalent to 20 g of cefradine), suspend them in a mixture of 60 ml of purified water and 60 ml of petroleum ether, control the temperature at 5°C, add dropwise glacial acetic acid to adjust the system pH to 1.0, stir until dissolved, let stand for phase separation, retain the aqueous phase, and perform ultrafiltration using a filter membrane with a molecular weight cutoff of 1000 Daltons.

[0029] Add 20 ml of butanone to the filtrate, and make the feed liquid crystallize and grow crystals in 4 connected crystal production tanks in turn: add triethylamine to each level of crystal production tank in advance, add the feed liquid from the top of the crystal production tank to the first level crystal production tank, wait for the feed liquid to be fully mixed with the alkali solution in the crystal production tank, stir and grow crystals for 30-60 minutes, and discharge the material to the next level crystal production tank; Specifically: production tank 1 is temperature controlled at 25°C, the feed liquid is added to production tank 1, mixed with triethylamine, stirred and crystallized for 30 minutes, and discharged to the second-level crystallization production tank; production tank 2 is temperature controlled at 15°C, the feed liquid is mixed with triethylamine, stirred and crystallized for 30 minutes, and discharged to the third-level crystallization production tank; production tank 3 is temperature controlled at 5°C, the feed liquid is mixed with triethylamine, stirred and crystallized for 30 minutes, and discharged to the fourth-level crystallization production tank; production tank 4 is temperature controlled at -5°C, the feed liquid and triethylamine are stirred and crystallized for 30 minutes. Among them, the pH of the system after the feed liquid and triethylamine are mixed in each production tank is always maintained at 4.8.

[0030] After the crystal growth was completed, the crystal liquid was filtered, washed twice with 60 ml of purified water, washed twice with 60 mL of acetone and then dried; vacuum dried at 40°C for 2 h to obtain a white solid with a yield of 79.2%.

[0031] Comparative Example 2 Take the contents of cefradine capsules (equivalent to 20 g of cefradine), suspend them in a mixture of 60 ml of purified water and 60 ml of petroleum ether, control the temperature at 5°C, add dropwise glacial acetic acid to adjust the system pH to 1.0, stir until dissolved, let stand for phase separation, retain the aqueous phase, and perform ultrafiltration using a filter membrane with a molecular weight cutoff of 1000 Daltons.

[0032] Add 20 ml of butanone to the filtrate, and make the feed liquid crystallize and grow crystals in 4 connected crystal production tanks in turn: add triethylamine to each level of crystal production tank in advance, add the feed liquid from the top of the crystal production tank to the first level crystal production tank, wait for the feed liquid to be fully mixed with the alkali solution in the crystal production tank, stir and grow crystals for 30-60 minutes, and discharge the material to the next level crystal production tank; Specifically: the temperature of production tanks 1-4 is always controlled at -5°C, the feed liquid is added to production tank 1, mixed with triethylamine to adjust the system pH to 2.0, stirred and crystallized for 30 minutes, and discharged to the second-level crystallization production tank; the feed liquid is mixed with the triethylamine in the second-level crystallization production tank, the system pH is adjusted to 3.0, stirred and crystallized for 30 minutes, and discharged to the third-level crystallization production tank; the feed liquid is mixed with the triethylamine in the third-level crystallization production tank, the system pH is adjusted to 4.0, stirred and crystallized for 30 minutes, and discharged to the fourth-level crystallization production tank; the feed liquid is mixed with the triethylamine in the fourth-level crystallization production tank, the system pH is adjusted to 4.8, and stirred and crystallized for 30 minutes.

[0033] After the crystal growth was completed, the crystal liquid was filtered, washed twice with 60 ml of purified water, washed twice with 60 mL of acetone and then dried; vacuum dried at 40°C for 2 h to obtain a white solid with a yield of 75.4%.

[0034] The samples of Examples 1-3 and Comparative Examples 1-2 were tested for quality, and the data are shown in Table 1: Table 1: It can be seen from the data in Table 1 that after being treated by the purification method of the present invention, the impurities 7-ADCA, p-hydroxyphenylglycine, cephradine △-3 isomer and unknown impurities in the cephradine product can be effectively reduced, the obtained target product has a high cephradine content, and the process reproducibility is good.

[0035] Comparative Example 1: Under the condition of keeping the pH value of the system after the feed liquid and the alkali solution in the production tanks at each level unchanged, the temperature of the crystallization production tanks at each level is adjusted by gradient. During the purification process, the cefradine product has a crystal explosion phenomenon, resulting in the crystals being too fine and difficult to be effectively filtered and dried. The purified finished product still carries some impurities, which not only affects the product quality, but also has a low yield.

[0036] Comparative Example 2: Under the condition of keeping the temperature of each level of crystallization production tank unchanged, the pH of the system after the feed liquid and the alkali solution in the crystallization production tank at each level are adjusted separately. Although the impurity content is effectively reduced, the crystallization rate of the cefradine product is very slow during the purification process, which significantly reduces the yield and is not conducive to industrial promotion.

[0037] Table 2: Data table of accelerated stability study on impurities and contents of products in Example 3 Note: Acceleration conditions are 40±2℃; According to the data in Table 2, the cefradine sample obtained by the purification method of the present invention has good impurity and content stability, and the impurities 7-ADCA and p-hydroxyphenylglycine increase slightly during the accelerated experiment, and the quality is stable, and it can be used for the preparation of cefradine standards and the purification of cefradine products with adjacent validity periods.

Claims

1. A method for purifying cefuroxime, characterized in that: The following steps are involved: (1) suspending the cefradine to be purified in a mixture of purified water and petroleum ether, controlling the temperature at 5-10°C, adding an acidic reagent dropwise under stirring to adjust the pH of the system to 1.0-1.2, stirring until dissolved, allowing to stand for phase separation, retaining the aqueous phase, and filtering through a membrane to obtain a filtrate; (2) adding a dispersant to the filtrate obtained in step (1) to obtain a feed solution, and causing the feed solution to be crystallized and grown in four stages of connected crystallization production tanks by simultaneously gradient controlling the temperature and pH of each stage of crystallization production tanks; (3) After the crystal growth is completed, the product is filtered, washed, vacuum dried, and discharged to obtain a white solid of cefradine.

2. The method for purifying cefuroxime according to claim 1, wherein The cefradine to be purified in step (1) is the contents of cefradine capsules or tablets of degraded quality or approaching the expiration date, or a crude cefradine product.

3. The method for purifying cefuroxime according to claim 1, characterized in that: The ratio of the volume L of the purified water, the volume L of petroleum ether and the mass Kg of the cefradine to be purified in step (1) is (3-4): (3-4):

1.

4. The method for purifying cefuroxime according to claim 1, characterized in that: The acidic reagent in step (1) is glacial acetic acid or carbonic acid.

5. The method for purifying cefuroxime according to claim 1, characterized in that: The filter membrane in step (1) has a molecular weight cut-off of 800 to 1200 Daltons.

6. The method for purifying cefuroxime according to claim 1, characterized in that: The dispersant in step (2) is butanone or acetone, and the ratio of the volume L of the dispersant to the mass Kg of the cefradine to be purified is (1-2):

1.

7. The method for purifying cefuroxime according to claim 1, characterized in that: In step (2), the temperatures of the crystallization production tanks of levels 1 to 4 are respectively controlled at 25-30°C, 15-20°C, 5-10°C, and -5-0°C, and the pH of the feed solution after entering the crystallization production tanks of each level and mixing with the alkali solution already in the crystallization production tanks is respectively controlled at 1.8-2.2, 2.8-3.2, 3.8-4.2, and 4.8-5.

8. The method for purifying cefuroxime according to claim 7, characterized in that: The alkali solution already in the crystallization production tank in step (2) is triethylamine or diisopropylamine.

9. The method for purifying cefuroxime according to claim 1, characterized in that: The washing method in step (3) is to first wash with purified water and then wash with acetone; the vacuum drying temperature is 40°C.

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