A novel preparation process of water-soluble florfenicol and product thereof

Abstract

The application relates to a novel preparation process and product of water-soluble florfenicol, and belongs to the technical field of medicine preparation processes. The preparation process provided by the application comprises the following steps: 1) performing superfine crushing or spray drying pretreatment on beta-cyclodextrin to obtain pretreated beta-cyclodextrin; 2) dissolving florfenicol in an organic solvent, adding a solubilizer and uniformly mixing to obtain a florfenicol liquid medicine; 3) adding the pretreated beta-cyclodextrin into a fluidized bed granulation device to perform fluidization, then spraying the florfenicol liquid medicine into the beta-cyclodextrin in a fluidized state, so that the florfenicol is attached to the surface of the beta-cyclodextrin; and 4) continuously performing fluidization and drying after the spraying is completed, to obtain water-soluble florfenicol. The preparation process combining beta-cyclodextrin pretreatment, fluidized spraying and attachment and fluidization and drying can effectively reduce the generation of related substances in the processing process while ensuring the water solubility of the product, and improve the quality stability of the product.

Description

Technical Field

[0001] This application relates to a novel preparation process and product for water-soluble florfenicol, belonging to the field of pharmaceutical preparation technology. Background Technology

[0002] Florfenicol is a broad-spectrum amyl alcohol antibacterial drug with advantages such as a broad antibacterial spectrum, strong antibacterial activity, and relatively low drug resistance, and is widely used in livestock, poultry, and aquaculture. Because florfenicol raw material has poor water solubility, water-soluble florfenicol formulations are currently prepared using techniques such as cyclodextrin inclusion complexation and solubilization to improve the solubility and ease of use of the product, thus meeting the requirements for applications such as drinking water administration.

[0003] In the prior art, authorized patent CN105477642B discloses a method for preparing water-soluble florfenicol. This method uses beta-cyclodextrin to form an inclusion system with florfenicol, and combines it with excipients such as povidone. The water-soluble florfenicol product is prepared through processes such as organic solvent dissolution, inclusion, and spray drying. This technology can effectively improve the water solubility of florfenicol, enhance the product's dissolution performance and bioavailability, and therefore has been applied in the industry. In addition, existing published literature also contains technical solutions for preparing water-soluble florfenicol formulations using methods such as reflux inclusion, high-temperature drying, and spray drying. The technical objectives of these solutions are mainly focused on improving inclusion efficiency, water solubility, yield, or product stability.

[0004] However, the aforementioned existing technologies are all based on the old veterinary drug quality standard system. Their process design mainly focuses on water solubility and inclusion effect, with less attention paid to the degradation side reactions of florfenicol and the control of related substances during the preparation process. Existing processes generally require high-temperature inclusion, spray drying or other continuous heat treatment processes, keeping florfenicol in a heated state for a long time during processing.

[0005] With the implementation of the 2025 edition (7th edition) of the Veterinary Pharmacopoeia of the People's Republic of China on December 1, 2026, related substance testing items have been added for florfenicol soluble powder, and product quality control requirements have been raised, with stricter limits on related substance content. Under the new quality standards, the applicant found that water-soluble florfenicol products prepared using existing technologies (including the process disclosed in CN105477642B), while meeting the water solubility requirements, are prone to degradation side reactions of heat-sensitive florfenicol during processing due to continuous heat treatment, resulting in the generation of related substances. This leads to an increase in the related substance content of the product, approaching or exceeding the limits stipulated in the new edition of the Veterinary Pharmacopoeia, making it difficult to meet the new quality standards.

[0006] Therefore, how to ensure the good solubility of water-soluble florfenicol products while reducing the impact of heat treatment on the stability of florfenicol during preparation, inhibiting the formation of related substances during processing, and ensuring that the resulting products meet the requirements of the new edition of the "Veterinary Pharmacopoeia of the People's Republic of China" regarding the limits of related substances has become a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0007] While existing processes for water-soluble florfenicol can improve solubility, they are prone to generating related substances during processing. Simply reducing the heat treatment intensity may affect drug adhesion and final water solubility. Therefore, the challenge lies in how to reduce the processing heat load while still ensuring uniform and rapid adhesion of florfenicol to the β-cyclodextrin carrier, thereby simultaneously achieving low levels of related substances and good water solubility.

[0008] In the existing technology, there is currently no research on fluidized bed spraying adhesion and fluidized bed drying processes for florfenicol, nor on optimization of related substances and solubility requirements. Although fluidized bed technology has been applied to the preparation of other pharmaceutical products, the application of fluidized bed technology in the preparation of florfenicol, its impact on related substances, and the optimization and key control details of fluidized bed technology still require experimental and research clarification. Proposing a mature preparation process that can be directly applied to replace the current process that does not meet the requirements is a technical problem that urgently needs to be solved. Based on this, the proposed solution in this application is hereby put forward.

[0009] To address the problems of long heat treatment time and easy degradation side reactions leading to the generation of related substances in existing water-soluble florfenicol preparation processes, this application provides a novel preparation process and product for water-soluble florfenicol. A preparation process centered on β-cyclodextrin pretreatment, fluidized bed spraying, and fluidized bed drying is established. By optimizing drug adhesion and drying methods and reducing the thermal environment during processing, the product's water solubility is ensured while effectively inhibiting the generation of processing-induced related substances, thus enabling the obtained product to meet the related substance limits requirements of the new edition of the *Pharmacopoeia of the People's Republic of China*.

[0010] This application provides a novel preparation process for water-soluble florfenicol, the preparation process comprising the following steps: 1) Pre-treat β-cyclodextrin by ultra-fine grinding and / or spray drying to obtain pre-treated β-cyclodextrin; 2) Dissolve florfenicol in an organic solvent, add a solubilizer and mix well to obtain a florfenicol solution; 3) The pretreated β-cyclodextrin is added to a fluidized bed granulation device for fluidization, and then the florfenicol solution is sprayed into the fluidized β-cyclodextrin to make florfenicol adhere to the surface of the β-cyclodextrin. 4) After the spraying is completed, continue fluidized drying to obtain water-soluble florfenicol.

[0011] This application maintains rapid and complete dissolution while keeping related substances generated during processing at low levels. In the preparation process, β-cyclodextrin is treated to a specific pretreatment state, which improves the carrier's support / adhesion to the drug solution, ensuring rapid final dissolution. Furthermore, the β-cyclodextrin is first fluidized and then continuously sprayed with florfenicol solution. This continuous spraying and adhesion in a fluidized state improves the product's water solubility compared to traditional wet mixing and avoids prolonged heat treatment to achieve water solubility. Moreover, the bed temperature is controlled throughout the spraying-drying process, keeping the preparation process within a specific low-temperature range, especially controlling the bed material temperature from the start of spraying to the end of drying, reducing the formation of related substances induced by florfenicol processing.

[0012] Optionally, in step 3), the bed material temperature is controlled at 48~55℃ during fluidization; Optionally, the bed material temperature is controlled at 50~54℃ during fluidization; Optionally, the spraying rate can be controlled at 5~18 g / (min·kg material); Optionally, the spraying rate can be controlled at 8~12 g / (min·kg material).

[0013] Optionally, a continuous spraying method is used during the spraying process, and the fluidized bed continues fluidized drying after continuous spraying.

[0014] Optionally, from the start of liquid spraying to the end of fluidized drying, the bed material is kept below 55°C. Optionally, from the start of liquid spraying to the end of fluidized drying, the bed material is kept below 50°C.

[0015] Optionally, in step 1), the β-cyclodextrin is pretreated by ultrafine grinding to reduce the particle size D of the β-cyclodextrin particles. 90 The diameter should be controlled to 20~50 μm; Optionally, the particle size D of the β-cyclodextrin particles can be adjusted. 90 The diameter should be controlled to 25~40 μm; Optionally, the moisture content of the pretreated β-cyclodextrin is controlled to be 1.5~6.0%; Optionally, the moisture content of the pretreated β-cyclodextrin is controlled to be 2.0~4.0%.

[0016] Optionally, in step 1), the β-cyclodextrin is pretreated by spray drying to control the particle size range of the β-cyclodextrin particles to 200~300 mesh. Optionally, the moisture content of the β-cyclodextrin particles after spray drying pretreatment is controlled to be 2.0~3.0%.

[0017] In this application, the β-cyclodextrin obtained after pretreatment with specific particle size and water content provides a suitable carrier state for continuous spraying and rapid adhesion of the drug solution under fluidized conditions, thereby improving the dispersion / adhesion of florfenicol on β-cyclodextrin and giving the final product good rapid dissolution performance. This avoids the problem of high impurity content in the product caused by the need for high temperature environment in order to improve product solubility in the prior art.

[0018] Currently, the preparation process of florfenicol inevitably involves two high-temperature processes to ensure solubility: a high-temperature inclusion process and a high-temperature spray drying process. These high temperatures can lead to florfenicol degradation and the generation of impurities. The solution presented in this application addresses this issue by pretreating cyclodextrin separately. This breaks down the crystal structure of the cyclodextrin particles, increases their surface area, and enhances their water solubility. Furthermore, it clarifies that the florfenicol solution can be sprayed onto the pretreated cyclodextrin at a lower temperature, achieving semi-solid inclusion while still meeting the water solubility requirements of florfenicol. This avoids the original process of heating and dissolving cyclodextrin and florfenicol in water to achieve inclusion of florfenicol molecules, thus preventing high-temperature degradation and the generation of impurities.

[0019] Optionally, in step 2), the preparation temperature of the florfenicol solution is controlled at 25~45℃; Optionally, the preparation temperature of the florfenicol solution is controlled at 30~40℃; Optionally, the florfenicol solution is sprayed within 60 minutes after preparation.

[0020] Optionally, the solubilizer is one or more of povidone K30, povidone K90, poloxamer 188, polyethylene glycol 4000, or sodium dodecyl sulfate. Optionally, the amount of solubilizer added is 10-40% of the mass of florfenicol; Optionally, the amount of solubilizer added is 20-30% of the mass of florfenicol.

[0021] Optionally, in step 2), the organic solvent is one or more of methanol, ethanol, isopropanol, or acetone; Optionally, the amount of organic solvent used is 2 to 5 times the mass of florfenicol; Optionally, the amount of organic solvent used is 3 to 4 times the mass of florfenicol; Optionally, the organic solvent is ethanol.

[0022] Optionally, in step 4), the residual organic solvent mass fraction of the product at the end of fluidized drying is less than 0.50%. Optionally, the residual organic solvent mass fraction of the product at the end of fluidized bed drying is less than 0.30%; Optionally, the moisture content of the resulting product is controlled to be 1.5~4.0%; Optionally, the moisture content of the resulting product is controlled to be 2.0~3.0%.

[0023] This application provides a water-soluble florfenicol product obtained by the above preparation process.

[0024] The beneficial effects of this application include, but are not limited to: 1. According to the novel preparation process and product of water-soluble florfenicol of this application, compared with the existing continuous heat treatment processes such as reflux and spray drying, this application uses pretreated β-cyclodextrin as a carrier and combines fluidized bed spraying and fluidized drying processes. The temperature of the bed material is controlled during the spraying and drying processes, and the spraying process and heat treatment time are controlled at the same time. This reduces the thermal environment of florfenicol during processing and effectively inhibits the related substances generated by thermal degradation during processing, so that the obtained product can meet the requirements of the new edition of the "Veterinary Pharmacopoeia of the People's Republic of China" for the limit of related substances.

[0025] 2. According to the novel preparation process and product of water-soluble florfenicol of this application, by pretreating β-cyclodextrin to give it a suitable particle size and water content, it can quickly adsorb florfenicol solution during fluidized spraying, reducing the continuous residence time of the solution on the particle surface. Combined with continuous spraying and fluidized drying process, it improves the uniformity of solution adhesion and reduces the continuous heating phenomenon caused by local over-wetting, thereby further reducing the risk of related substances being generated during processing.

[0026] 3. According to the novel preparation process and product of water-soluble florfenicol of this application, the combination of florfenicol and β-cyclodextrin is completed by spraying and adhering under fluidized state, which avoids the continuous heat treatment processes such as long-term reflux inclusion and high-temperature spray drying in the prior art. While ensuring that the product has good water solubility, it reduces the impact of the processing on the stability of florfenicol, resulting in a product with extremely low content of related substances, and improves process stability and batch consistency.

[0027] 4. Based on the novel preparation process and product of water-soluble florfenicol of this application, a process control method with bed material temperature, spraying rate and spraying process control as the core has been established, so that the drug adhesion and drying process can be completed under low heat environment conditions. This not only reduces the side reactions caused by heat during processing, but also improves the repeatability of the process and the stability of industrial production, which is conducive to the consistent control of product quality and suitable for continuous industrial production.

[0028] 5. Based on the novel preparation process and product of water-soluble florfenicol in this application, and in response to the newly added related substance control requirements in the new edition of the "Veterinary Pharmacopoeia of the People's Republic of China", the existing preparation process of water-soluble florfenicol has been redesigned. It does not rely on changing the drug composition or adding new functional excipients, but achieves effective control of the generation of related substances during the processing by optimizing the key process parameters. While maintaining the water solubility of the product, it meets the quality requirements of the new edition of the Veterinary Pharmacopoeia, providing a new technical solution for the process upgrade of existing water-soluble florfenicol products. Attached Figure Description

[0029] The accompanying drawings, which are included to provide a further understanding of this application and form part of this application, illustrate exemplary embodiments and are used to explain this application, but do not constitute an undue limitation of this application. In the drawings: Figure 1A This is the HPLC chromatogram of the blank control in the test of Sample 1 involved in this application.

[0030] Figure 1B This is the HPLC chromatogram of the system adaptability control in the test of Sample 1 involved in this application.

[0031] Figure 1C This is the HPLC chromatogram of the reference standard (diluted 100 times) used in the test of Sample 1 involved in this application.

[0032] Figure 1D This is the HPLC chromatogram of sample 1 in the test of sample 1 involved in this application.

[0033] Figure 2A This is the HPLC chromatogram of the blank control in the test of Sample 2 involved in this application.

[0034] Figure 2B This is the HPLC chromatogram of the system adaptability control in the test of Sample 2 involved in this application.

[0035] Figure 2C This is the HPLC chromatogram of the reference standard (diluted 100 times) used in the test of Sample 2 involved in this application.

[0036] Figure 2D This is the HPLC chromatogram of sample 2 in the test of sample 2 involved in this application. Detailed Implementation

[0037] The present application is described in detail below with reference to the embodiments, but the present application is not limited to these embodiments. Unless otherwise specified, the raw materials and reagents in the embodiments of the present application are all purchased through commercial channels.

[0038] The present application solution will be described below through specific embodiments.

[0039] Example 1 1) Weigh 400 g of pharmaceutical-grade β-cyclodextrin and perform ultrafine grinding using an air jet mill. Control the grinding pressure at 0.75 MPa and the classifier speed at 4200 r / min. After grinding, use a laser particle size analyzer to detect the particle size and control D... 90 The β-cyclodextrin was then placed in a vacuum drying oven at 60℃ and dried at -0.08 MPa for 2 h to control its moisture content to 2.5%, and set aside for later use.

[0040] 2) Weigh 100 g of florfenicol, add 350 g of anhydrous ethanol and 25 g of povidone K30, and stir to dissolve at 35°C at a stirring speed of 350 r / min. After the florfenicol is completely dissolved, continue stirring for 15 min to obtain a uniform and clear solution. After the solution is prepared, seal it and store it in a sealed container. Spray the solution within 60 min after opening.

[0041] 3) Add the pretreated β-cyclodextrin to a fluidized bed granulator, turn on the fluidization system, control the inlet air temperature to 52℃, and maintain the bed material temperature at 48℃ for 10 min of pre-fluidization. Then, use a two-fluid spray gun to spray florfenicol solution into the fluidized bed, control the atomization pressure to 0.18 MPa, and the spray rate to 10 g / (min·kg material). During the spraying process, continuously monitor the bed material temperature to maintain it at 48℃. The entire spraying process lasts for 24 min. After spraying, continue fluidized drying, control the bed material temperature at 48℃, and continue drying for 18 min. Use headspace gas chromatography to detect residual ethanol. Stop drying when the residual ethanol content is below 0.30% (mass fraction). Use a moisture analyzer to detect the product moisture content and control the final moisture content to 2.8%.

[0042] 4) From the start of the spraying process to the end of fluidized bed drying, the material in the bed is kept at a temperature not higher than 50°C. After drying, heating is stopped, and clean ambient air is introduced for cooling for 8 minutes to reduce the material temperature to below 30°C. The material is then granulated through a 20-mesh granulation sieve and packaged to obtain water-soluble florfenicol powder.

[0043] Example 2 1) Weigh 400 g of pharmaceutical-grade β-cyclodextrin and perform ultrafine grinding using an air jet mill. Control the grinding pressure at 0.72 MPa and the classifier speed at 3900 r / min. After grinding, use a laser particle size analyzer to detect the particle size and control D... 90 The β-cyclodextrin was then placed in a vacuum drying oven at 60℃ and dried at -0.08 MPa for 2 h to control its moisture content to 1.8%, and set aside for later use.

[0044] 2) Weigh 100 g of florfenicol, add 400 g of anhydrous ethanol and 12 g of povidone K90, and stir to dissolve at 28°C at a stirring speed of 320 r / min. After the florfenicol is completely dissolved, continue stirring for 18 min to obtain a uniform and clear solution. After the solution is prepared, seal it and store it in a sealed container. Spray the solution within 60 min after opening.

[0045] 3) Add the pretreated β-cyclodextrin to a fluidized bed granulator, turn on the fluidization system, control the inlet air temperature to 55℃, and maintain the bed material temperature at 50℃ for 12 min of pre-fluidization. Then, use a two-fluid spray gun to spray florfenicol solution into the fluidized bed, control the atomization pressure to 0.16 MPa, and the spray rate to 6 g / (min·kg material). During the spraying process, continuously monitor the bed material temperature to maintain it at 50℃ until all the solution is sprayed. The entire spraying process takes 37 min. After spraying, continue fluidized drying, control the bed material temperature at 50℃, and continue drying for 22 min. Use headspace gas chromatography to detect residual ethanol. Stop drying when the residual ethanol content is below 0.45% (mass fraction). Use a moisture analyzer to detect the product moisture content and control the final moisture content to 2.8%.

[0046] 4) From the start of the spraying process to the end of fluidized bed drying, the material in the bed is kept at a temperature not higher than 50°C. After drying, heating is stopped, and clean ambient air is introduced for cooling for 8 minutes to reduce the material temperature to below 30°C. The material is then granulated through a 20-mesh granulation sieve and packaged to obtain water-soluble florfenicol powder.

[0047] Example 3 1) Weigh 400 g of pharmaceutical-grade β-cyclodextrin and perform ultrafine grinding using an air jet mill. Control the grinding pressure at 0.80 MPa and the classifying wheel speed at 4500 r / min. After grinding, use a laser particle size analyzer to detect the particle size and control D... 90 The β-cyclodextrin was then placed in a vacuum drying oven at 60℃ and dried at -0.08 MPa for 2 h to control its moisture content to 1.8%, and then set aside for later use.

[0048] 2) Weigh 100 g of florfenicol, add 480 g of anhydrous ethanol and 38 g of polyethylene glycol 4000, and stir to dissolve at 43°C at a stirring speed of 380 r / min. After the florfenicol is completely dissolved, continue stirring for 12 min to obtain a uniform and clear solution. After the solution is prepared, seal it and store it in a sealed container. Spray the solution within 60 min after opening.

[0049] 3) Add the pretreated β-cyclodextrin to a fluidized bed granulator, turn on the fluidization system, control the inlet air temperature to 60℃, and maintain the bed material temperature at 54℃ for 8 min of pre-fluidization. Then, use a two-fluid spray gun to spray florfenicol solution into the fluidized bed, control the atomization pressure to 0.20 MPa, and control the spray rate to 14 g / (min·kg material). During the spraying process, continuously monitor the bed material temperature to maintain it at 54℃ until all the solution is sprayed. The entire spraying process takes 40 min. After spraying, continue fluidized drying, control the bed material temperature at 54℃, and continue drying for 15 min. Use headspace gas chromatography to detect residual ethanol. Stop drying when the residual ethanol content is below 0.18% (mass fraction). Use a moisture analyzer to detect the product moisture content and control the final moisture content to 2.8%.

[0050] 4) From the start of the spraying process to the end of fluidized bed drying, the material in the bed is kept at a temperature not higher than 54°C. After drying, heating is stopped, and clean ambient air is introduced for 6 minutes to cool the material down to below 30°C. The material is then granulated through a 20-mesh granulation sieve and packaged to obtain water-soluble florfenicol powder.

[0051] Comparative Example 1 The preparation was carried out according to the method disclosed in the background technology CN105477642B, in which β-cyclodextrin was included with florfenicol, and water-soluble florfenicol was obtained by reflux inclusion and spray drying.

[0052] Comparative Example 2 Except for step 3), in which wet mixing is used to complete the drug application and fluidized bed spraying is not used for application, the other steps are the same as in Example 1.

[0053] Comparative Example 3 Except for step 1), where the β-cyclodextrin was not pretreated by ultrafine grinding and was directly used from commercially available β-cyclodextrin, all other steps were the same as in Example 1.

[0054] Example 4 Except for controlling the temperature at 58°C throughout the spraying and drying stages, the remaining steps are the same as in Example 1.

[0055] Example 5 Except for step 3), in which the spraying speed is adjusted to 18 g / (min·kg material), the other steps are the same as in Example 1.

[0056] Example 6 Except for step 2), which involves letting the prepared herbal solution stand at room temperature for 60 minutes before spraying, all other steps are the same as in Example 1.

[0057] Example 7 Except for step 1), where the moisture content of β-cyclodextrin is controlled to be 5.5% after pretreatment, all other steps are the same as in Example 1.

[0058] Example 8 Except for the β-cyclodextrin particle size D in step 1), 90 Except for controlling the size to 70 μm, all other steps are the same as in Example 1.

[0059] Example 9 Except for step 1), all other steps are the same as in Example 1. Step 1) is as follows: Weigh 400g of pharmaceutical-grade β-cyclodextrin, add purified water, and prepare a 30wt% β-cyclodextrin aqueous solution. Stir at 80℃ for 30min to ensure complete dissolution. Then, spray dry using a spray dryer, controlling the inlet air temperature at 150℃, the outlet air temperature at 75℃, the feed rate at 12mL / min, and the atomizer speed at 15000rpm. The powder obtained from spray drying is tested for particle size using a standard sieve, controlling the particle size to be 200~300 mesh. Subsequently, the moisture content is tested using a moisture analyzer and controlled to be 3.0%. The obtained β-cyclodextrin powder is then ready for use.

[0060] Test Example 1 The test was conducted according to the quality standard of "Florfenicol Soluble Powder" in Part I of the 7th edition of the "Veterinary Pharmacopoeia of the People's Republic of China". The test results for related substances and solubility are shown in Table 1 below.

[0061] also, Figure 1A , Figure 1B , Figure 1C , Figure 1D The corresponding HPLC chromatograms are the blank control HPLC chromatogram, the system adaptability control HPLC chromatogram, the reference standard (sample diluted 100 times) HPLC chromatogram, and the HPLC chromatogram of sample 1, respectively.

[0062] Figure 2A , Figure 2B , Figure 2C , Figure 2D The corresponding HPLC chromatograms are blank control, system adaptability control, reference standard (sample diluted 100 times), and sample 2, respectively, in the test of sample 2 (comparative example 1).

[0063] Table 1

[0064] Table 1 (continued)

[0065] As shown in Table 1, while the related substances in the product of Comparative Example 1 prepared using the existing process meet the quality requirements of the new edition of the *Pharmacopoeia of the People's Republic of China for Veterinary Medicine*, they are close to the upper limit of the regulations, posing a risk of exceeding the limit and failing to meet the internal quality control standards specified by the enterprise according to the new edition of the veterinary drug standard. Although the related substances in Comparative Examples 2 and 3 meet the internal quality control standards, their water solubility does not meet the quality requirements. In contrast, the florfenicol in the product obtained in this application's embodiment is well protected, and no florfenicol degradation products were detected. This indicates that the detection results are below the method limit of quantitation / limit of detection; therefore, the maximum single related substance and the total related substances are both 0.00. The scheme of this application better meets the quality requirements of the new edition of the *Pharmacopoeia of the People's Republic of China for Veterinary Medicine* and the enterprise's internal quality control standards. These test results demonstrate that the process measures in this application, such as β-cyclodextrin pretreatment, spray adhesion, and thermal environment control, effectively inhibit the thermal degradation of florfenicol during processing and significantly reduce the generation of related substances during processing.

[0066] Further comparison of Examples 4-8 reveals that some related substances are generated when the bed material temperature is increased; controlling the moisture content, increasing the spraying rate, and using the solution after it has stood have little impact on the related substances and solubility of the product; changing the pretreatment state of β-cyclodextrin does not lead to an increase in related substances, but it does affect the water solubility of the product. Example 9 shows that β-cyclodextrin pretreated by spray drying, when sprayed and boiled dry according to the florfenicol solution of Example 1, maintains the stability of florfenicol during the preparation process while meeting the standard requirements for water solubility, and the related substances level is 0.00.

[0067] In summary, this application establishes a process system centered on β-cyclodextrin pretreatment, fluidized bed granulation spray adhesion, and processing thermal environment control. While maintaining the product's solubility performance in accordance with the requirements of the new edition of the "Pharmacopoeia of the People's Republic of China for Veterinary Medicines", it further protects florfenicol from degradation and the generation of related substances. This verifies that the key process parameters jointly affect product performance and further demonstrates that the technical solution of this application has a significant process improvement effect compared with the prior art.

[0068] The above description is merely an embodiment of this application, and the scope of protection of this application is not limited to these specific embodiments, but is determined by the claims of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the technical concept and principles of this application should be included within the scope of protection of this application.

Claims

1. A novel preparation process for water-soluble florfenicol, characterized in that, The preparation process includes the following steps: 1) Pre-treat β-cyclodextrin by ultrafine grinding or spray drying to obtain pre-treated β-cyclodextrin; 2) Dissolve florfenicol in an organic solvent, add a solubilizer and mix well to obtain a florfenicol solution; 3) The pretreated β-cyclodextrin is added to a fluidized bed granulation device for fluidization, and then the florfenicol solution is sprayed into the fluidized β-cyclodextrin to make florfenicol adhere to the surface of the β-cyclodextrin. 4) After the spraying is completed, continue fluidized drying to obtain water-soluble florfenicol.

2. The novel preparation process for water-soluble florfenicol according to claim 1, characterized in that, In step 3), the temperature of the bed material is controlled at 48~55℃ during the fluidization process; Optionally, the bed material temperature is controlled at 50~54℃ during fluidization; Optionally, the spraying rate can be controlled at 5~18 g / (min·kg material); Optionally, the spraying rate can be controlled at 8~12 g / (min·kg material).

3. The novel preparation process for water-soluble florfenicol according to claim 1, characterized in that, The liquid spraying process is carried out in a continuous spraying manner, and the fluidized bed continues fluidized drying after continuous spraying.

4. The novel preparation process for water-soluble florfenicol according to claim 1, characterized in that, From the start of liquid spraying to the end of fluidized drying, the bed material is kept below 55°C. Optionally, from the start of liquid spraying to the end of fluidized drying, the bed material is kept below 50°C.

5. The novel preparation process for water-soluble florfenicol according to claim 1, characterized in that, In step 1), the β-cyclodextrin is pretreated by ultrafine grinding to reduce the particle size D of the β-cyclodextrin particles. 90 The size should be controlled to be 20~50 μm; Optionally, the particle size D of the β-cyclodextrin particles can be adjusted. 90 The diameter should be controlled to 25~40 μm; Optionally, the moisture content of the pretreated β-cyclodextrin is controlled to be 1.5~6.0%; Optionally, the moisture content of the pretreated β-cyclodextrin is controlled to be 2.0~4.0%; Optionally, in step 1), the β-cyclodextrin is pretreated by spray drying to control the particle size range of the β-cyclodextrin particles to 200~300 mesh. Optionally, the moisture content of the β-cyclodextrin particles after spray drying pretreatment is controlled to be 2.0~3.0%.

6. The novel preparation process for water-soluble florfenicol according to claim 1, characterized in that, In step 2), the preparation temperature of the florfenicol solution is controlled at 25~45℃; Optionally, the preparation temperature of the florfenicol solution is controlled at 30~40℃; Optionally, the florfenicol solution is sprayed within 60 minutes after preparation.

7. The novel preparation process for water-soluble florfenicol according to claim 1, characterized in that, The solubilizer is one or more of the following: povidone K30, povidone K90, poloxamer 188, polyethylene glycol 4000, or sodium dodecyl sulfate. Optionally, the amount of solubilizer added is 10-40% of the mass of florfenicol; Optionally, the amount of solubilizer added is 20-30% of the mass of florfenicol.

8. The novel preparation process for water-soluble florfenicol according to claim 1, characterized in that, In step 2), the organic solvent is one or more of methanol, ethanol, isopropanol or acetone; Optionally, the amount of organic solvent used is 2 to 5 times the mass of florfenicol; Optionally, the amount of organic solvent used is 3 to 4 times the mass of florfenicol; Optionally, the organic solvent is ethanol.

9. The novel preparation process for water-soluble florfenicol according to claim 1, characterized in that, In step 4), the residual organic solvent mass fraction of the product at the end of fluidized drying is less than 0.50%. Optionally, the residual organic solvent mass fraction of the product at the end of fluidized drying is less than 0.30%.

10. The water-soluble florfenicol product obtained by the preparation process according to any one of claims 1 to 9.

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