Preparation method of cefditoren pivoxil granules

Abstract

The invention provides a cefditoren pivoxil particle and a preparation method thereof, the particle comprises a cefditoren pivoxil amorphous substance, hydroxypropyl methylcellulose, croscarmellose sodium, sucrose, aspartame, sucrose fatty acid ester, a coloring agent, sodium chloride and fruity essence, and the particle is obtained through a fluidized bed rotational flow side spraying granulation coating technology. The cefditoren pivoxil granules are round, controllable in particle size distribution range, fast in dissolution, good in stability, good in taste, good in in-vivo bioavailability and suitable for clinical use of children and old patients.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a ceftoranil granule and its preparation method. Background Technology

[0002] Ceftoranil is an esterified prodrug of ceftoran, an oral third-generation broad-spectrum antibiotic. It exerts its bactericidal effect by inhibiting bacterial cell wall synthesis and has broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria. It shows particularly strong antibacterial activity against Gram-positive Staphylococcus spp., including Streptococcus pneumoniae, as well as Gram-negative bacteria such as Escherichia coli, Moraxella catarrhalis, Klebsiella spp., Proteus spp., and Haemophilus influenzae, and anaerobic bacteria such as Peptostreptococcus spp., Propionibacterium acnes, and Bacteroides spp.

[0003] Ceftoranil granules are widely used for infections and inflammations in adults and children due to their broad antibacterial spectrum, strong antibacterial effect, rapid onset of action, and low allergic reaction rate. As a cephalosporin, it has a bitter taste and is easily hydrolyzed under humid and hot conditions, resulting in poor stability. Therefore, certain formulation techniques are needed to mask its taste, reduce moisture content, and improve patient compliance and stability, especially in children. If the granules have uneven particle size distribution, a high content of fine powder, and poor flowability, the granule filling weight will vary significantly during packaging. Patent CN116019815A uses a wet granulation machine with a binder for granulation and drying. This process, due to its high sucrose content, produces large clumps and coarse, uneven granules during wet granulation. CN117883391A uses fluidized bed top-spray granulation. While this process avoids large clumps, the top-spray granulation produces more fine powder, resulting in poor flowability and significant variations in granule filling weight during subsequent packaging. Regardless of whether it is wet granulation or top spray granulation, both methods involve directly adding a large amount of sucrose as a filler to increase sweetness and reduce bitterness, resulting in a poor taste-masking effect.

[0004] Therefore, there is an urgent need to develop a ceftoranil granule with uniform particle size distribution, low moisture content, good stability, good taste, and bioavailability that meets the requirements for use.

[0005] Currently, commonly used methods for particle preparation include wet granulation, fluidized bed granulation, and extrusion spheronization.

[0006] Conventional wet granulation produces irregular, poorly rounded particles with uneven size, wide particle size distribution, large batch-to-batch differences, and difficult quality control.

[0007] Existing fluidized bed granulation and coating technologies include bottom spray, side spray, and top spray granulation and coating. In fluidized bed granulation, a fixed air inlet distribution plate at the bottom allows material to flow and interact with the spray, drying and forming particles. The particles produced by fluidized bed granulation are generally fine and soft, generating a large amount of fine powder with poor flowability.

[0008] The extrusion-spheronization process produces particles with good sphericity, but the particles are coarser and more compact, which affects the subsequent dissolution behavior and in vivo absorption.

[0009] Through extensive experimental research, we unexpectedly discovered that combining centrifugal pelleting technology with fluidized bed granulation technology, and using a unique processing technique, replacing the traditional fluidized bed airflow distribution plate with a rotating chassis and air intake at the edge of the turntable at the bottom of the fluidized bed, and installing a side spray device on the bottom of the fixed fluidized bed pot, forms a fluidized bed swirl side spray granulation and coating device. Combined with pharmaceutical technology, this perfectly solves the above-mentioned formulation process technology and product quality problems, thus completing this invention. Summary of the Invention

[0010] One of the objectives of this invention is to provide ceftoranil granules suitable for the clinical treatment of children and patients with dysphagia.

[0011] The second objective of this invention is to provide a method for preparing ceftoranil granules. This method, based on fluidized bed coating technology and centrifugal granulation coating technology, innovatively designs an integrated fluidized bed swirl side-spray granulation and coating technology. This fluidized bed swirl side-spray granulation and coating technology effectively solves the aforementioned problems and defects of existing technologies. The prepared ceftoranil granules are round, with a controllable particle size distribution, rapid dissolution, good stability, good taste, and good bioavailability, making them suitable for clinical use in children and elderly patients.

[0012] To achieve the objectives of this invention, the following implementation scheme is provided.

[0013] In one embodiment, a ceftoranil granule of the present invention comprises the following components: 30-50 parts of amorphous ceftoranil (calculated as ceftoranil), 100-400 parts of sucrose, 5-20 parts of croscarmellose sodium, 6-30 parts of hydroxypropyl methylcellulose binder, 25-70 parts of aspartame, 0-4 parts of colorant, 0.05-0.2 parts of surfactant sucrose fatty acid ester, 0.1-1.0 parts of sodium chloride, and 1-3 parts of fruit flavoring, characterized in that: the ceftoranil granules are prepared by fluidized bed swirl side spray granulation coating technology.

[0014] In another embodiment, the present invention provides a method for preparing the above-described ceftoranil granule composition, comprising the following steps: Step 1: Add ceftoranil amorphous, sucrose, croscarmellose sodium, hydroxypropyl methylcellulose, and aspartame to a high-efficiency mixing granulator for mixing to obtain a mixed powder; Step 2: Pour the mixed powder obtained in Step 1 into a fluidized bed pot, and granulate it by adding a binder solution using a fluidized bed swirl side spray granulation method. The binder solution contains colorant, surfactant and binder. Step 3: The granules prepared in Step 2 are coated with a coating agent solution by adding a fluidized bed swirl side spray coating method to mask the taste and obtain coated granules. The coating agent solution contains flavoring agent, coloring agent, binder and optional coloring agent. Step 4: After the coated granules obtained in Step 3 are dried in a fluidized bed, they are sieved and granulated. Finally, fruit flavoring is added and mixed to obtain the final product.

[0015] Preferably, the method for preparing ceftoranil granules according to the present invention is characterized in that the blade speed of the high-efficiency mixing granulator in step one is 60~140 rpm, the blade speed is 200~600 rpm, and the mixing time is 200~400 s.

[0016] Preferably, in the method for preparing ceftoranil granules of the present invention, the fluidized bed swirl side spraying in steps two and three includes a fluidized bed pot with a hollow cavity, a turntable inside the fluidized bed pot, and a spray gun fixed to the side of the fluidized bed pot. The turntable inside the pot has an adjustable rotation speed, and the combination of centrifugal pelletizing and fluidized bed granulation forms a fluidized bed swirl side spraying granulation and coating device.

[0017] Preferably, the method for preparing ceftoranil granules according to the present invention is characterized in that the swirl side spraying in steps two and three is specifically as follows: air inlet volume 300~800m³ 3 The spraying process involves setting the air volume to 300-800 m³ / h, with an inlet air temperature of 50-80℃, a turntable speed of 80-160 rpm, a peristaltic pump speed of 80-120 rpm, a spray atomization pressure of 0.1-0.3 MPa, and a spray protective gas pressure of 0.05-0.15 MPa. The material temperature is controlled at 25-40℃ during the process. Further steps include drying, the specific drying process of which is as follows: The inlet air volume is set to 300-800 m³ / h. 3 / h, inlet air temperature 50~80℃, drying until loss on drying ≤1.0%.

[0018] Preferably, in the preparation method of ceftoranil granules of the present invention, the sieving and granulation in step four is as follows: granulation is carried out using a 35-mesh sieve, and particles that can pass through the 35-mesh sieve are collected for subsequent mixing. The mixing speed is 5~12 rpm and the time is 5~20 min.

[0019] The ceftoranil granules of the present invention have the following particle size distribution: 100% should pass through an 850μm sieve, no more than 5% should not pass through a 500μm sieve, and no more than 10% should pass through a 75μm sieve.

[0020] Preferably, in the method for preparing ceftoranil granules of the present invention, the related substances of the obtained ceftoranil granule product have the following characteristics: IB762≤1.0%, IB771≤0.3%, IB760≤2.2%, IB761≤0.2%, IB770≤0.5%, IB763≤0.4%, IB786≤0.3%, IB764≤1.7%, IB769≤1.6%, other single impurities not exceeding 0.2%, and the total impurities not exceeding 8.0%.

[0021] The ceftoranil granules of the present invention still meet the quality control requirements after being stored at 40°C and 75% humidity for 6 months.

[0022] The drying loss of the ceftoranil granules prepared by this invention is ≤1.0%.

[0023] The ceftoranil granules of the present invention have the following in vitro dissolution characteristics: they dissolve rapidly in hydrochloric acid medium at pH 1.2, with a dissolution rate of >85% within 10 minutes.

[0024] The ceftoranil granule composition of the present invention, when taken orally in a single dose of 50 mg on an empty stomach by a healthy adult, C max Blood drug concentration was 500-1400 ng / mL, AUC (0-t) The blood drug concentration is 1500~5000 ng•h / mL.

[0025] The ceftoranil granules of the present invention, when taken orally at a dose of 50 mg ceftoranil granules after a single high-fat meal by a healthy adult, C max Blood drug concentration was 200-600 ng / mL, AUC (0-t) The blood drug concentration is 1000~4000 ng•h / mL.

[0026] Compared with the prior art, the ceftoranil granules of the present invention have the following advantages: (1) In the preparation process of the ceftoranil granules of the present invention, granulation is first carried out with a binder to make the particle size distribution uniform and the flowability good. Then, a flavoring agent and a coloring agent are added for coating to achieve the effect of masking unpleasant taste, thereby improving the medication compliance of patients, especially children. Subsequently, the granules are dried by fluidized bed drying to reduce moisture content and ensure stability during storage.

[0027] (2) The ceftriaxone granules of the present invention adopt the swirl-flow side-spray granulation method. Compared with the traditional fluidized bed top-spray granulation, the airflow distribution plate is replaced with a centrifugal disc with a rotation function, which effectively combines centrifugal pelleting and fluidized bed granulation. This solves the problem of excessive fine powder in fluidized bed granulation and avoids the problem of coarse particles in centrifugal pelleting, resulting in more uniform particles and better flowability. In addition, when side-spraying coating, compared with the traditional fluidized bed bottom-spray coating, if the bottom spray gun is blocked by solid material, the equipment needs to be stopped before the gun can be cleaned. Side spraying, like top spraying, can achieve gun cleaning without stopping the machine, making the operation simpler and the production efficiency higher. Attached Figure Description

[0028] Figure 1 This is a schematic diagram of the swirl side spray device of the present invention, wherein 1-powder inlet, 2-rotating disk, 3-liquid inlet, and 4-fluidized bed hot air; Figure 2 The dissolution curve of ceftoranil granules in hydrochloric acid solution at pH 1.2 is shown in Example 5. Figure 3 This is a blood concentration curve of ceftoranil granules in Example 9 under fasting conditions; Figure 4 The blood concentration curve of ceftoranil granules in Example 9 is shown in the postprandial state. Detailed implementation method: The present invention will be further described below with reference to specific embodiments, which are intended to explain the present invention and should not be construed as limiting the present invention.

[0029] Example 1: Preparation of ceftoranil granules The components and their weight parts of ceftoranil granules are as follows:

[0030] The preparation method includes the following steps: (1) Premixing: Sucrose, ceftorepnitin amorphous, croscarmellose sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and aspartame are added to a high-efficiency mixing granulator in sequence. The blade speed is set to 60~140rpm, the blade speed to 200~600rpm, and the mixing time to 200~400s for premixing.

[0031] (2) Swirl side spray granulation and coating Preheating: Pour the premixed powder into the pot and set the air intake to 300~800m³ / h. 3 / h, inlet air temperature 50~80℃, turntable speed 80~160rpm; turn on the equipment to preheat the material. When the material temperature is >25℃, switch to liquid spraying.

[0032] Liquid spraying: Set the air intake volume to 300~800m³ / h3 The spraying process is carried out at the following parameters: inlet air temperature 50~80℃, turntable speed 80~160rpm, peristaltic pump speed 80~120rpm, spray atomization pressure 0.1~0.3MPa, and spray protective gas pressure 0.05~0.15MPa. The material temperature is controlled at 25~40℃ during the process. After the adhesive is sprayed, the coating agent is sprayed; after the coating agent is sprayed, the process switches to discharge.

[0033] Drying: After discharge, replace the pot body and pour the wet granules into the pot; set the air intake to 300-800 m³ / h. 3 / h, inlet air temperature 50~80℃, start the equipment and dry the material until the loss on drying is ≤1.0%.

[0034] (3) Screening and granulation All particles were sieved through a 35-mesh sieve to remove impurities, and particles that could pass through the 35-mesh sieve were collected for subsequent mixing.

[0035] (4) Total Mix Add the dry granules of ceftriaxone granules and fruit flavoring to a mixing tank, set the mixing speed to 5-12 rpm, and the time to 5-20 min.

[0036] (5) Granule packaging The resulting granules were packaged in composite bags, 50mg / bag.

[0037] In the above preparation method, the swirl side-spray granulation and coating process uses a swirl side-spray device, the structural schematic of which is shown in the figure. Figure 1 The same applies to the following.

[0038] Example 2: Preparation of ceftoranil granules The components and their weight parts of ceftoranil granules are as follows:

[0039] The preparation method of the ceftoranil granule composition in this embodiment is the same as in Example 1.

[0040] Example 3: Preparation of ceftoranil granules The components and their weight parts of ceftoranil granules are as follows:

[0041] The preparation method is the same as in Example 1.

[0042] Example 4: Preparation of ceftoranil granules The components and their weight parts of ceftoranil granules are as follows:

[0043] The preparation method is the same as in Example 1.

[0044] The following comparative examples show that samples were prepared using fluidized bed granulation, extrusion spheronization granulation, and wet granulation processes, respectively, for comparative study.

[0045] Comparative Example 1: Ceftoranil granules The components and their weight parts in this comparative example are the same as in Example 4; The preparation method includes the following steps: (1) Premixing: Sucrose, ceftorepnitin amorphous, croscarmellose sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and aspartame are added to a high-efficiency mixing granulator in sequence. The blade speed is set to 60~140rpm, the blade speed to 200~600rpm, and the mixing time to 200~400s for premixing.

[0046] (2) Fluidized bed top spray granulation Preheating: Pour the premixed powder into the pot and set the air intake to 400-650 m³ / h. 3 At a rate of / h, the inlet air temperature is 50-80℃ to preheat the material. Once the material temperature exceeds 28℃, the liquid spraying process begins.

[0047] Liquid spray granulation: Set the air inlet volume to 400-800 m³ / h. 3 / h, inlet air temperature 50~80℃, peristaltic pump speed 80~120rpm, spray atomization pressure 0.1~0.3MPa, for adhesive spraying, process control material temperature 30~40℃.

[0048] Drying: Set the air intake volume to 350-650 m³ / h 3 / h, with an inlet air temperature of 60~80℃, the material is dried until the loss on drying is ≤1.0%.

[0049] (3) Screening and granulation All particles were sieved through a 35-mesh sieve to remove impurities, and particles that could pass through the 35-mesh sieve were collected for subsequent mixing.

[0050] (4) Total Mix Add the dry granules of ceftriaxone and fruit flavoring to the mixing tank, set the mixing speed to 5-12 rpm, and the time to 5-20 min.

[0051] (5) Granule packaging The resulting granules were packaged in composite bags.

[0052] Comparative Example 2: Ceftoranil granules The components and their weight parts in this comparative example are the same as in Example 4; The preparation method includes the following steps: (1) Premixing and making soft material: Sucrose, ceftorepnitin amorphous, cross-linked sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and aspartame are added to a high-efficiency mixing granulator in sequence. The blade speed is set to 60~140rpm, the blade speed to 200~600rpm, and the mixing time to 200~400s for premixing. After premixing, the blade speed is set to 60~140rpm, the blade speed to 200~600rpm, and the running time to 100~200s. The binder is then added to make soft material.

[0053] (2) Extrusion and spheronization granulation Extrusion granulation: Add wet soft material to the extrusion granulator, set the extrusion speed to 10~50 rpm and the pressing speed to 20~40 rpm, and use a 0.6 mm round hole screen for extrusion granulation; Rounding: The obtained particles are added to a rounding machine, and the rounding speed is set to 500~1400rpm, and the running time is 1~3min for rounding. Drying: After rounding, the resulting particles are added to a fluidized bed with an air inlet volume of 350–650 m³ / h. 3 / h, with an inlet air temperature of 60~80℃, the material is dried until the loss on drying is ≤1.0%.

[0054] (3) Screening and granulation All particles were sieved through a 35-mesh sieve to remove impurities, and particles that could pass through the 35-mesh sieve were collected for subsequent mixing.

[0055] (4) Total Mix Add the dry granules of ceftriaxone and fruit flavoring to the mixing tank, set the mixing speed to 5-12 rpm, and the time to 5-20 min.

[0056] (5) Granule packaging The resulting granules were packaged in composite bags.

[0057] Comparative Example 3: Ceftoranil granules The components and their weight parts in this comparative example are the same as in Example 4; The preparation method includes the following steps: (1) Premixing: Sucrose, ceftorepnitin amorphous, croscarmellose sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and aspartame are added to a high-efficiency mixing granulator in sequence. The blade speed is set to 60~140rpm, the blade speed to 200~600rpm, and the mixing time to 200~400s for premixing. (2) Wet granulation After premixing, set the blade speed to 60~140rpm, the cutter speed to 200~600rpm, and the running time to 100~200s. Add the binder to make the soft material. Wet granulation: The resulting granules are added to a high-speed granulator, the speed is set to 800~1500rpm, and a 0.6mm round hole screen is used for wet granulation; Drying: After granulation, the resulting particles are added to a fluidized bed with an air inlet volume of 350–650 m³ / h. 3 / h, with an inlet air temperature of 60~80℃, the material is dried until the loss on drying is ≤1.0%.

[0058] (3) Screening and granulation All particles were sieved through a 35-mesh sieve to remove impurities, and particles that could pass through the 35-mesh sieve were collected for subsequent mixing.

[0059] (4) Total Mix Add the dry granules of ceftriaxone and fruit flavoring to the mixing tank, set the mixing speed to 5-12 rpm, and the time to 5-20 min.

[0060] (5) Granule packaging The resulting granules were packaged in composite bags.

[0061] Example 5: Particle property determination The particle properties of the ceftoranil granule compositions described in Examples 1-4 and Comparative Examples 1-3 were determined, and the results are shown in Table 1.

[0062] Table 1. Results of ceftoranil particle property tests in the examples and comparative examples.

[0063] Note: 20 mesh corresponds to an 850μm sieve, 35 mesh corresponds to a 500μm sieve, and 200 mesh corresponds to a 75μm sieve.

[0064] The results in Table 1 above show that the conventional fluidized bed top spraying process (Comparative Example 1) produces more fine powder and poorer particle uniformity, further affecting particle flowability; the conventional extrusion rounding process (Comparative Example 2) produces relatively round particles, but with poor uniformity and more coarse particles; the conventional wet granulation process (Comparative Example 3) produces particles with a size similar to those obtained by side spraying, but with poor roundness and uniformity; while the particles obtained using the swirl side spraying process (the ceftoranil granule compositions described in Examples 1-4) are round and uniform with good flowability, significantly better than Comparative Examples 1-3.

[0065] Example 6: Taste Test The palatability of ceftorepimidine granules from Examples 1-4 and Comparative Examples 1-3 was tested, and the evaluation method was as follows: Number of cases: 20 cases; Administration method: The granules were added to 80 ml of drinking water at about 40°C, stirred evenly (stirring for 1-2 min), and then taken. The palatability evaluation form was filled out according to the taste. The results are shown in Table 2.

[0066] Table 2. Summary of taste test results for ceftoranil granules in the examples and comparative examples.

[0067] Note: The evaluation levels are divided into A, B, C, D, and E, with A being the best and E being the worst.

[0068] As shown in Table 2, the ceftoranil granules of Examples 1-4 had a higher proportion of Grade A in terms of odor, appearance, mouthfeel, taste, and aftertaste. The granules obtained by other processes (ceftoranil granules of Comparative Examples 1-3) had a worse mouthfeel than the ceftoranil granules described in Examples 1-4. The results indicate that the ceftoranil granules prepared by the cyclone side spray granulation process have a better mouthfeel and a better taste masking effect.

[0069] Example 7 Dissolution curve determination The ceftoranil granules from Examples 1-4 were subjected to in vitro dissolution curve determination. The evaluation method is as follows: Method: Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method II (paddle method), rotation speed: 50 rpm, medium: pH 1.2 hydrochloric acid solution, medium volume: 900 ml, temperature: 37 ± 0.5℃. The results are shown in Table 3 below. Figure 2 .

[0070] Table 3. Results of in vitro dissolution curves of ceftoranil particles in the examples.

[0071] From Table 3 and Figure 2 It can be seen that the ceftoranil granules in Examples 1-4 not only have a masking effect, but also dissolve very quickly in hydrochloric acid medium at pH 1.2.

[0072] Example 8 Stability Study The ceftriaxone granules from Examples 1 to 4 were subjected to related substance tests under accelerated conditions (temperature 40°C, humidity 75%). The results are shown in Table 4. Table 4. Results of stability study of ceftoranil particles in Examples 1-4

[0073] As shown in Table 4, the ceftoranil granule composition prepared by the swirl side spraying process has good stability of related substances.

[0074] Example 9 Pharmacokinetic Study The fasting and postprandial pharmacokinetic studies were conducted using ceftoranil granules from Example 4. Both studies were randomized, open-label, two-period, double-crossover trials. Twelve patients were enrolled on an empty stomach, and eight patients were enrolled after a meal. Each patient received a single oral dose of one sachet of ceftoranil granules (50 mg) per cycle. The results are shown in Table 5 below. Figure 3 and Figure 4 .

[0075] Table 5. Pharmacokinetic results of (50 mg) ceftoranil granules in Example 4

[0076] The swirl-side-spray granulation method described in this invention produces uniform particles with good flowability, is easy to operate, and has high production efficiency. The particle property test results of the examples and comparative examples show that the particles obtained using the swirl-side-spray process (cefotaxime granules in Examples 1-4) are round and uniform, have good flowability, good taste, good taste masking effect, good stability of related substances, and dissolve very rapidly in hydrochloric acid medium at pH 1.2, exhibiting good in vivo absorption. This method is suitable for pharmaceutical formulation research and clinical applications.

[0077] Based on the disclosure and teachings of the foregoing specification, those skilled in the art can make changes and modifications to the above embodiments. Therefore, the present invention is not limited to the specific embodiments disclosed and described above, and some modifications and changes to the present invention should also fall within the protection scope of the claims of the present invention. Furthermore, although some specific terms are used in this specification, these terms are only for convenience of explanation and do not constitute any limitation on the present invention. Other devices that are the same as or similar to these terms are all within the protection scope of the present invention.

Claims

1. A ceftoranil granule, comprising the following components: 30-50 parts of amorphous ceftoranil (calculated as ceftoran), 100-400 parts of sucrose, 5-20 parts of croscarmellose sodium, 6-30 parts of hydroxypropyl methylcellulose binder, 25-70 parts of aspartame, 0-4 parts of colorant, 0.05-0.2 parts of surfactant sucrose fatty acid ester, 0.1-1.0 parts of sodium chloride, and 1-3 parts of fruit flavoring, characterized in that: The ceftoranil granules were prepared using a fluidized bed swirl side-spray granulation and coating technology.

2. A method for preparing ceftoranil granules according to claim 1, comprising the following steps: Step 1: Add ceftoranil amorphous, sucrose, croscarmellose sodium, hydroxypropyl methylcellulose, and aspartame to a high-efficiency mixing granulator for mixing to obtain a mixed powder; Step 2: Pour the mixed powder obtained in Step 1 into a fluidized bed pot, and granulate it by adding a binder solution using the fluidized bed swirl side spray granulation method. The binder solution contains colorant, surfactant and binder. Step 3: The granules prepared in Step 2 are coated and flavor-masked by adding a coating agent solution using a fluidized bed swirl side spray coating method to obtain coated granules. The coating agent solution contains flavoring agents, coloring agents, and binders. Step 4: After the coated granules obtained in Step 3 are dried in a fluidized bed, they are sieved and granulated, and then fruit flavoring is added and mixed to obtain the final product.

3. The preparation method according to claim 2, characterized in that, In step one, the paddle speed of the high-efficiency mixing granulator is 60~140rpm, the blade speed is 200~600rpm, and the mixing time is 200~400s.

4. The manufacturing method as described in claim 2, wherein the fluidized bed swirl side spraying device in steps two and three includes a fluidized bed pot with a hollow cavity, a turntable inside the fluidized bed pot and a spray gun fixed to the side of the fluidized bed pot, the turntable inside the pot having an adjustable rotation speed, and the combination of centrifugal pelletizing and fluidized bed granulation forms a fluidized bed swirl side spraying granulation and coating device.

5. The preparation method according to claim 2, characterized in that, The swirl side spray described in steps two and three has an air intake volume of 300~800m³. 3 / h, inlet air temperature 50~80℃, turntable speed 80~160rpm, peristaltic pump speed 80~120rpm, liquid atomization pressure 0.1~0.3MPa, liquid protective gas pressure 0.05~0.15Mpa, process control material temperature 25~40℃.

6. The preparation method according to claim 1, characterized in that, The drying process described in step four involves an air intake volume of 300–800 m³. 3 / h, inlet air temperature 50~80℃, drying until loss on drying ≤1.0%.

7. The preparation method according to claim 2, wherein the sieving and granulation in step four is as follows: granulation is carried out using a 35-mesh sieve, and particles that can pass through the 35-mesh sieve are collected for subsequent mixing, with a mixing speed of 5~12 rpm and a time of 5~20 min.

8. The ceftoranil granules prepared by the preparation method according to claim 2 shall have the following particle size distribution: 100% shall pass through an 850 μm sieve, no more than 5% shall not pass through a 500 μm sieve, and no more than 10% shall pass through a 75 μm sieve.

9. The preparation method according to claim 1, wherein the drying loss of the ceftorepnitin granules is ≤1.0%.

10. The preparation method of claim 1, wherein the related substances of the obtained ceftoranil granules have the following characteristics: IB762≤1.0%, IB771≤0.3%, IB760≤2.2%, IB761≤0.2%, IB770≤0.5%, IB763≤0.4%, IB786≤0.3%, IB764≤1.7%, IB769≤1.6%, other single impurities not exceeding 0.2%, and the total impurities not exceeding 8.0%.

11. The ceftoranil granules as described in claim 1 have the following specific characteristics in vitro dissolution: rapid dissolution in hydrochloric acid medium at pH 1.2, with a dissolution rate of >85% within 10 minutes.

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