A hollow spherical cefuroxime axetil preparation raw powder and preparation method thereof

Abstract

The present invention provides a hollow spherical cefuroxime axetil preparation raw powder and a preparation method thereof. The method comprises the following steps: firstly, preparing a suspension: dissolving cefuroxime axetil crystalline powder in anhydrous acetone, stirring and dissolving at 20-40°C, filtering after clarification to obtain a cefuroxime axetil acetone solution, and then cooling to 0-5°C; then adding cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone, stirring for 30-50 minutes to form a uniform suspension; then adding the obtained suspension to a centrifugal atomizer for atomization drying to obtain a hollow spherical cefuroxime axetil preparation raw powder. The product particle size D70 obtained by the method of the present invention has only one interval, which is 15-75 μm; and its angle of repose is 40-47 degrees. Therefore, the particle size distribution of the raw powder in the present invention is more uniform, and the efficiency of the preparation in the later stage is higher.

Description

Technical Field

[0001] The invention relates to the field of medicine manufacturing, in particular to a hollow spherical cefuroxime axetil preparation raw powder and a preparation method thereof. Background Art

[0002] Cefuroxime axetil is the acetoethyl ester of cefuroxime, which releases cefuroxime after hydrolysis in the body to exert its antibacterial activity. The mechanism of action, antibacterial spectrum and antibacterial effect of cefuroxime axetil are the same as those of cefuroxime. Cefuroxime axetil is mainly used clinically for mild and moderate respiratory tract infections, urogenital system infections, skin and soft tissue infections and gonorrhea caused by sensitive bacteria. In order to improve the efficacy, the pharmacopoeia requires that cefuroxime axetil be an amorphous product. Cefuroxime axetil is a crystalline product prepared by esterification, hydrolysis and crystallization of cefuroxime acid, and then dried to obtain an amorphous product.

[0003] The raw powder of oral cefuroxime axetil preparations is usually amorphous cefuroxime axetil powder and excipients, and its particle size distribution usually has multiple different intervals at the same time. This results in poor material uniformity, uneven particle size, poor preparation applicability, and also increases the difficulty of the preparation powder mixing process. Summary of the invention

[0004] The purpose of the present invention is to provide a hollow spherical cefuroxime axetil preparation raw powder with a single particle size range, uniform particle size and good fluidity, and at the same time provide a method for preparing the raw powder, so as to solve the problems of uneven particle size and poor preparation applicability of the cefuroxime axetil preparation raw powder prepared by the existing process.

[0005] The present invention is achieved in that:

[0006] The hollow spherical cefuroxime axetil preparation raw powder provided by the present invention has a particle size distribution greater than 70% in only one interval, which is 15-75 μm; and a repose angle of 40-47 degrees.

[0007] The present invention abandons the traditional method of first preparing amorphous products from cefuroxime axetil crystalline powder by spray drying or anti-solvent and then mixing the amorphous cefuroxime axetil with auxiliary materials, but first mixes the cefuroxime axetil crystalline powder with cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone to prepare a suspension, and then atomizes and dries the suspension to obtain the original powder of cefuroxime axetil preparation.

[0008] The method for preparing the hollow spherical cefuroxime axetil preparation raw powder provided by the present invention comprises the following steps:

[0009] a. Prepare a suspension: dissolve the cefuroxime axetil crystalline powder in anhydrous acetone, stir and dissolve at 20-40°C, filter after clarification to obtain a cefuroxime axetil acetone solution, and then cool to 0-5°C; then add cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone, stir for 30-50 minutes to form a uniform suspension;

[0010] b. Add the suspension obtained in step a into a centrifugal atomizer for atomization drying to obtain hollow spherical cefuroxime axetil preparation raw powder.

[0011] In the above scheme, preferably, the parameters of atomization drying in step b are: feed flow rate 30-40 Kg / h; atomizer speed 18000-25000 rpm, fan speed 1000-2000 rpm, air inlet temperature 90-110°C, air outlet temperature 60-80°C; tower pressure 1000-3000 Pa, tube pressure 1200-3500 Pa, high efficiency filter pressure difference 200-300 Pa, cyclone separator pressure difference 500-1000 Pa, bag filter pressure difference 30-100 Pa, condenser 1 outlet temperature below 8°C, condenser 2 outlet temperature below 0°C; oxygen concentration below 2%.

[0012] In the above scheme, in step a, 10-20 kg of cefuroxime axetil crystalline powder is dissolved in 100-200 L of anhydrous acetone.

[0013] In the above scheme, in step a, the mass ratio of the added cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch, and polyvinyl pyrrolidone to cefuroxime axetil crystalline powder is: 10-15:25-35:50-75:5-25:100.

[0014] In the above scheme, in step a, the added cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone are all sieved through a 120-140 mesh sieve.

[0015] In the above scheme, in step a, after adding cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone, stirring is carried out at a high speed of 40 Hz for 30 to 50 minutes.

[0016] Beneficial Effects

[0017] The raw powder of the cefuroxime axetil preparation provided by the present invention has a hollow spherical structure, the particle size distribution of the product is more uniform, and the RSD value of the product does not change much with the increase of the storage time; moreover, the hollow spherical structure improves the fluidity of the product, thereby improving the preparation efficiency. DETAILED DESCRIPTION

[0018] The present invention provides a novel method for preparing raw powder of cefuroxime axetil preparation, and the product prepared by the method has a hollow spherical structure. The preparation process of the present invention is as follows:

[0019] Step 1, preparation of suspension: dissolve 10-20Kg of cefuroxime axetil crystalline powder in 100-200L anhydrous acetone, stir and dissolve at 20-40°C, filter after clarification to obtain cefuroxime axetil acetone solution, then cool to 0-5°C, add cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone, and stir for 30 minutes under 40Hz high-speed shear stirring to form a uniform suspension. The mass ratio of the added cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone to the mass ratio of the cefuroxime axetil crystalline powder is: 10-15:25-35:50-75:5-25:100, and cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone need to pass through a 120-140 mesh sieve.

[0020] Step 2, add the above suspension to the centrifugal atomizer at a continuous and stable flow rate of 30-40Kg / h. The atomizer speed is maintained at 18000-25000rpm. The fan speed is 1000-2000rpm, the air inlet temperature is 90-110°C, and the air outlet temperature is 60-80°C. The pressure in the tower is 1000-3000Pa, the pressure in the tube is 1200-3500Pa, the high-efficiency filter pressure difference is 200-300Pa, the cyclone separator pressure difference is 500-1000Pa, the bag filter pressure difference is 30-100Pa, the condenser 1 outlet temperature is lower than 8°C, and the condenser 2 outlet temperature is lower than 0°C. The oxygen concentration in the system is lower than 2%. After atomization drying, a hollow spherical cefuroxime axetil oral preparation raw powder with uniform particle size is obtained, which is used to directly prepare an oral preparation. Then secondary drying is performed to make the acetone residue meet the internal control standards of the enterprise.

[0021] Table 1 below shows the parameters in Examples 1-4.

[0022] Table 1 Comparison of parameters of Examples 1 to 4

[0023]

[0024] Scanning electron microscopy tests were performed on the products obtained in Examples 1-4, and it was found that they were spherical. By crushing the samples and then performing electron microscopy tests, it was found that the spheres were hollow. That is, the products obtained according to the method of the present invention were hollow spherical structures.

[0025] Comparative Example 1

[0026] 20 kg of cefuroxime axetil crystalline powder was dissolved in 200 L of anhydrous acetone, stirred and dissolved at 20-40 ° C, filtered after clarification to obtain a cefuroxime axetil acetone solution, then cooled to 0-5 ° C, spray-dried according to the parameters of step 2 in Example 1 to obtain an amorphous product of cefuroxime axetil, and secondary drying was performed to make the acetone reach the internal control standard of the enterprise. Then 2.5 kg of cross-linked polyvinyl pyrrolidone passing through a 120 mesh sieve, 6 kg of microcrystalline cellulose passing through a 120 mesh sieve, 12 kg of sodium carboxymethyl starch passing through a 120 mesh sieve, and 2 kg of polyvinyl pyrrolidone passing through a 120 mesh sieve were added, stirred and mixed to obtain a mixed powder of cefuroxime axetil oral preparation raw material.

[0027] Comparative Example 2

[0028] 20 kg of cefuroxime axetil crystalline powder was dissolved in 200 L of anhydrous acetone, stirred and dissolved at 20-40° C., then anti-solvent isopropyl ether was added, filtered and dried to obtain nano-scale amorphous cefuroxime axetil. Then 2.5 kg of cross-linked polyvinyl pyrrolidone passed through a 120-mesh sieve, 6 kg of microcrystalline cellulose passed through a 120-mesh sieve, 12 kg of sodium carboxymethyl starch passed through a 120-mesh sieve, and 2 kg of polyvinyl pyrrolidone passed through a 120-mesh sieve were added, stirred and mixed to obtain a cefuroxime axetil oral preparation raw material mixed powder.

[0029] Table 2 Comparison of performance of mixed powder of raw materials of oral preparation of cefuroxime axetil

[0030]

[0031] In the RSD determination method, take the above samples, take 5 samples of each sample for content measurement and calculate the RSD value. The determination method is the Chinese Pharmacopoeia method.

[0032] As can be seen from Table 2: the product particle size D70 in Examples 1-4 (by drawing the product particle size distribution diagram and intercepting the horizontal line of the particle size distribution equal to 70% according to the ordinate to obtain the D70 particle size interval) corresponds to a particle size interval of 15 to 75 μm, while the D70 particle size interval in Comparative Examples 1 and 2 contains two particle size intervals. This results in poor uniformity of the cefuroxime axetil content in Comparative Examples 1 and 2, and a high RSD value. At the same time, as the product placement time increases, the products of Comparative Examples 1 and 2 experience separation of large and small particle sizes, which leads to more uneven products and larger RSD values. As a result, the efficacy gap is large during the preparation process, affecting the efficacy.

[0033] From the repose angle data in Table 2, it can be seen that the repose angles of Examples 1 to 4 are relatively small and the fluidity is good. However, the repose angles of Comparative Examples 1 and 2 are relatively large and the fluidity is poor, which in turn affects the preparation efficiency.

Claims

1. A hollow spherical raw powder of cefuroxime axetil preparation, characterized in that: There is only one interval in which the particle size distribution is greater than 70%, which is 15~75μm; its angle of repose is 40~47 degrees; The preparation method of the hollow spherical cefuroxime axetil preparation raw powder is as follows: a. Preparation of suspension: dissolve cefuroxime axetil crystalline powder in anhydrous acetone, stir and dissolve at 20-40°C, filter after clarification to obtain cefuroxime axetil acetone solution, and then cool to 0-5°C; then add cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone, stir for 30-50 min to form a uniform suspension; b. adding the suspension obtained in step a into a centrifugal atomizer for atomization drying to obtain a hollow spherical raw powder of cefuroxime axetil preparation; In step b, the parameters of atomization drying are: feed flow rate 30~40 Kg / h; atomizer speed 18000~25000 rpm, fan speed 1000~2000 rpm, air inlet temperature 90~110 ℃, air outlet temperature 60~80 ℃; tower pressure 1000~3000 Pa, tube pressure 1200~3500 Pa, high efficiency filter pressure difference 200~300 Pa, cyclone separator pressure difference 500~1000 Pa, bag filter pressure difference 30~100 Pa, condenser 1 outlet temperature below 8 ℃, condenser 2 outlet temperature below 0 ℃; oxygen concentration below 2%.

2. A method for preparing the hollow spherical cefuroxime axetil preparation powder according to claim 1, characterized in that: The steps include: a. Preparation of suspension: dissolve cefuroxime axetil crystalline powder in anhydrous acetone, stir and dissolve at 20-40°C, filter after clarification to obtain cefuroxime axetil acetone solution, and then cool to 0-5°C; then add cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone, stir for 30-50 min to form a uniform suspension; b. adding the suspension obtained in step a into a centrifugal atomizer for atomization drying to obtain a hollow spherical raw powder of cefuroxime axetil preparation; In step b, the parameters of atomization drying are: feed flow rate 30~40 Kg / h; atomizer speed 18000~25000 rpm, fan speed 1000~2000 rpm, air inlet temperature 90~110 ℃, air outlet temperature 60~80 ℃; tower pressure 1000~3000 Pa, tube pressure 1200~3500 Pa, high efficiency filter pressure difference 200~300 Pa, cyclone separator pressure difference 500~1000 Pa, bag filter pressure difference 30~100 Pa, condenser 1 outlet temperature below 8 ℃, condenser 2 outlet temperature below 0 ℃; oxygen concentration below 2%.

3. The method for preparing the hollow spherical cefuroxime axetil preparation raw powder according to claim 2, characterized in that: Dissolve 10-20 kg of cefuroxime axetil crystalline powder in 100-200 L of anhydrous acetone.

4. The method for preparing the hollow spherical cefuroxime axetil preparation raw powder according to claim 2, characterized in that: The mass ratio of cefuroxime axetil crystalline powder to cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone is: 100:10~15:25~35:50~75:5~25.

5. The method for preparing the hollow spherical cefuroxime axetil preparation raw powder according to claim 2, characterized in that: The added cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone were all sieved through a 120-140 mesh sieve.

6. The method for preparing the hollow spherical cefuroxime axetil preparation raw powder according to claim 2, characterized in that: After adding cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, sodium carboxymethyl starch and polyvinyl pyrrolidone, stir at a high speed of 40 Hz for 30 to 50 min.

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