A process for the preparation of a stick of doxycycline hydrochloride

Abstract

The application discloses a preparation method of rod-shaped doxycycline hydrochloride and relates to the technical field of medicine preparation. The preparation process comprises the following steps: S1, preparing a mixed solvent: mixing and uniformly stirring methanol and water to obtain a mixed solvent, which is prepared for use; S2, dissolving raw materials and adding an additive: adding doxycycline hydrochloride raw materials into the mixed solvent obtained in the step S1, stirring until completely dissolved, and adding a eutectic solvent and polyvinylpyrrolidone into the mixed solvent to obtain a doxycycline hydrochloride solution; S3, crystallization: under stirring, the temperature is reduced to 3-8 DEG C at a rate of 0.3-1.0 DEG C / min, and crystallization is carried out for 2-4 hours; and S4, separation and purification: after the crystallization is completed, filter cake is obtained through reduced-pressure filtration, and the filter cake is dried to obtain rod-shaped doxycycline hydrochloride. The doxycycline hydrochloride product obtained by the preparation method has a regular rod shape, a length-diameter ratio of about 2-3:1, uniform particle size distribution and good preparation processing performance.

Description

Technical Field

[0001] This invention relates to the field of drug preparation technology, specifically a method for preparing rod-shaped doxycycline hydrochloride. Background Technology

[0002] Doxycycline hydrochloride is a broad-spectrum tetracycline antibiotic with a wide antibacterial spectrum, strong antibacterial activity, and good oral absorption. It is widely used to treat various diseases, including respiratory tract infections, urinary tract infections, and gastrointestinal infections, and has broad application prospects. The crystallization state of a drug directly affects its flowability, solubility, stability, and bioavailability. Different morphologies of doxycycline hydrochloride exhibit significant differences during formulation processing. Currently, the preparation of doxycycline hydrochloride mostly employs conventional crystallization methods, resulting in products with irregular granular or flaky crystals. These methods suffer from poor flowability, uneven dispersion, and difficulty in mixing during formulation, affecting the uniformity and stability of the final drug product. On the other hand, rod-shaped crystals possess excellent flowability and dispersibility, effectively improving formulation processing performance and enhancing product quality. However, currently, there is no easily operable and stable method for preparing rod-shaped doxycycline hydrochloride.

[0003] Therefore, there is an urgent need to develop an easy-to-operate and stable method for preparing rod-shaped doxycycline hydrochloride to improve its flowability and dispersibility. Summary of the Invention

[0004] To address the above problems, the purpose of this invention is to provide a method for preparing rod-shaped doxycycline hydrochloride.

[0005] To achieve the above objectives, the present invention employs the following technical solution: A method for preparing rod-shaped doxycycline hydrochloride includes the following steps: S1. Preparation of mixed solvent: Mix methanol and water and stir evenly to obtain a mixed solvent for later use; S2. Dissolve raw materials and add additives: Add doxycycline hydrochloride raw material to the mixed solvent obtained in step S1, stir until completely dissolved, add eutectic solvent and polyvinylpyrrolidone to obtain doxycycline hydrochloride solution. The mass ratio of doxycycline hydrochloride raw material, the mixed solvent obtained in step S1, the eutectic solvent, and polyvinylpyrrolidone is 0.8~1.2:100:0.05~0.1:0.02~0.05; S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, and cool it to 3-8°C at a rate of 0.3-1.0°C / min with stirring, and keep it at this temperature for 2-4 hours for crystallization. S4. Separation and purification: After crystallization, filter cake is obtained by vacuum filtration. The filter cake is dried to obtain rod-shaped doxycycline hydrochloride.

[0006] Preferably, the polyvinylpyrrolidone is at least one of PVPK15, PVPK30, PVPK60, and PVPK90.

[0007] Preferably, the eutectic solvent is composed of choline chloride and organic acid in a mass ratio of 3:1 to 16.

[0008] Preferably, the organic acid is at least one of malonic acid, oxalic acid, or citric acid.

[0009] Preferably, the stirring rate in step S3 is 200~300 rpm.

[0010] Preferably, the mass ratio of methanol to water in step S1 is 3~10:12~17.

[0011] Preferably, the polyvinylpyrrolidone is PVPK30, and the eutectic solvent is obtained by mixing choline chloride and oxalic acid in a mass ratio of 1:2.

[0012] Preferably, the drying temperature is 45~55℃ and the drying time is 4~8 hours.

[0013] The present invention has the following advantages over the prior art: The present invention provides a method for preparing rod-shaped doxycycline hydrochloride, which is easy to operate and has a stable process. By precisely controlling the process parameters and adding specific eutectic solvents and polyvinylpyrrolidone, the crystal morphology can be directionally controlled to obtain rod-shaped products with uniform morphology and good flowability.

[0014] The doxycycline hydrochloride product obtained by the preparation method of the present invention exhibits a regular rod-shaped morphology with an aspect ratio of about 2 to 3:1, uniform particle size distribution, and good formulation processing performance. Attached Figure Description

[0015] Figure 1 Microscopic morphology of the rod-shaped doxycycline hydrochloride obtained in Example 5; Figure 2 This is a scanning electron microscope image of the rod-shaped doxycycline hydrochloride obtained in Example 5; Figure 3 Microscopic morphology of doxycycline hydrochloride obtained in Comparative Example 1; Figure 4 The image shows the scanning electron microscope morphology of doxycycline hydrochloride obtained in Comparative Example 1. Figure 5 The image shows the scanning electron microscope morphology of doxycycline hydrochloride obtained in Comparative Example 2. Figure 6The image shows the scanning electron microscope morphology of doxycycline hydrochloride obtained in Comparative Example 3. Detailed Implementation

[0016] The purpose of this invention is to provide a method for preparing rod-shaped doxycycline hydrochloride. The invention will be further described below with reference to specific embodiments. Example 1

[0017] A method for preparing rod-shaped doxycycline hydrochloride includes the following steps: S1. Preparation of mixed solvent: Mix 1.5 kg of methanol and 8.5 kg of water and stir until homogeneous to obtain a mixed solvent for later use; S2. Dissolve raw materials and add additives: Add 80g of doxycycline hydrochloride raw material to 10kg of the mixed solvent obtained in step S1, stir until completely dissolved, add 5g of eutectic solvent and 2g of polyvinylpyrrolidone PVPK15 to obtain doxycycline hydrochloride solution. The eutectic solvent is composed of choline chloride and malonic acid in a mass ratio of 3:1. S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, stir at a rate of 200 rpm, cool to 3°C at a rate of 0.3°C / min, and maintain the temperature for crystallization for 2 hours. S4. Separation and purification: After crystallization, filter cake is obtained by vacuum filtration. The filter cake is dried at 45°C for 8 hours to obtain rod-shaped doxycycline hydrochloride. Example 2

[0018] A method for preparing rod-shaped doxycycline hydrochloride includes the following steps: S1. Preparation of mixed solvent: Mix 5 kg of methanol and 6 kg of water and stir evenly to obtain a mixed solvent for later use; S2. Dissolve raw materials and add additives: Add 120g of doxycycline hydrochloride raw material to 10kg of the mixed solvent obtained in step S1, stir until completely dissolved, add 10g of eutectic solvent and 5g of polyvinylpyrrolidone PVPK90 to obtain doxycycline hydrochloride solution. The eutectic solvent is composed of choline chloride and oxalic acid in a mass ratio of 3:16. S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, stir at a rate of 300 rpm, cool to 8°C at a rate of 1.0°C / min, and maintain the temperature for crystallization for 4 hours. S4. Separation and purification: After crystallization, filter cake is obtained by vacuum filtration. The filter cake is dried at 55°C for 4 hours to obtain rod-shaped doxycycline hydrochloride. Example 3

[0019] A method for preparing rod-shaped doxycycline hydrochloride includes the following steps: S1. Preparation of mixed solvent: Mix 2 kg of methanol and 8 kg of water and stir evenly to obtain a mixed solvent for later use; S2. Dissolve raw materials and add additives: Add 90g of doxycycline hydrochloride raw material to 10kg of the mixed solvent obtained in step S1, stir until completely dissolved, add 6g of eutectic solvent and 4g of polyvinylpyrrolidone to obtain doxycycline hydrochloride solution. The eutectic solvent is composed of choline chloride and organic acid in a mass ratio of 3:10. S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, stir at a rate of 220 rpm, cool down to 4°C at a rate of 0.4°C / min, and maintain the temperature for crystallization for 2.5 hours. S4. Separation and purification: After crystallization, filter cake is obtained by vacuum filtration. The filter cake is dried at 48°C for 5 hours to obtain rod-shaped doxycycline hydrochloride.

[0020] In this embodiment, the types of organic acids and polyvinylpyrrolidone can be selected according to Table 1.

[0021] Table 1. Types of organic acids and polyvinylpyrrolidone Example 4

[0022] A method for preparing rod-shaped doxycycline hydrochloride includes the following steps: S1. Preparation of mixed solvent: Mix 3 kg of methanol and 7 kg of water and stir evenly to obtain a mixed solvent for later use; S2. Dissolve raw materials and add additives: Add 110g of doxycycline hydrochloride raw material to 10kg of the mixed solvent obtained in step S1, stir until completely dissolved, add 8g of eutectic solvent and 3g of polyvinylpyrrolidone PVPK90 to obtain doxycycline hydrochloride solution. The eutectic solvent is composed of choline chloride and organic acid in a mass ratio of 3:8. S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, stir at a rate of 280 rpm, cool to 5°C at a rate of 0.6°C / min, and maintain the temperature for crystallization for 3.5 hours. S4. Separation and purification: After crystallization, filter cake is obtained by vacuum filtration. The filter cake is dried at 52°C for 5 hours to obtain rod-shaped doxycycline hydrochloride.

[0023] In this embodiment, the types of organic acids and polyvinylpyrrolidone can be selected according to Table 2.

[0024] Table 2. Types of organic acids and polyvinylpyrrolidone Example 5

[0025] A method for preparing rod-shaped doxycycline hydrochloride includes the following steps: S1. Preparation of mixed solvent: Mix 2.5 kg of methanol and 7.5 kg of water and stir evenly to obtain a mixed solvent for later use; S2. Dissolve raw materials and add additives: Add 100g of doxycycline hydrochloride raw material to 10kg of the mixed solvent obtained in step S1, stir until completely dissolved, add 6g of eutectic solvent and 4g of polyvinylpyrrolidone PVPK30 to obtain doxycycline hydrochloride solution. The eutectic solvent is obtained by mixing choline chloride and oxalic acid in a mass ratio of 1:2. S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, stir at a rate of 200 rpm, cool to 5°C at a rate of 0.5°C / min, and maintain the temperature for crystallization for 3 hours. S4. Separation and purification: After crystallization, filter cake is obtained by vacuum filtration. The filter cake is dried at 50°C for 6 hours to obtain rod-shaped doxycycline hydrochloride.

[0026] The doxycycline hydrochloride products obtained in Examples 1-5 exhibited a regular rod-like morphology, with an aspect ratio of 2-3:1, uniform particle size distribution between 50-100 μm, excellent flowability and dispersibility, and good formulation processing performance. Taking Example 5 as an example, the microscopic morphology is as follows... Figure 1 As shown, the morphology under a scanning electron microscope is as follows: Figure 2 As shown, the aspect ratio is 2:1, the particle size distribution is uniform, and the flowability and dispersibility are excellent. The microscopic and scanning electron microscope morphologies of the other embodiments are similar to those of the embodiments.

[0027] Comparative Example 1 A method for preparing doxycycline hydrochloride includes the following steps: S1. Preparation of mixed solvent: Mix 2.5 kg of methanol and 7.5 kg of water and stir evenly to obtain a mixed solvent for later use; S2. Dissolve raw materials and add additives: Add 100g of doxycycline hydrochloride raw material to 10kg of the mixed solvent obtained in step S1, and stir until completely dissolved to obtain doxycycline hydrochloride solution. S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, stir at a rate of 200 rpm, cool to 5°C at a rate of 0.5°C / min, and maintain the temperature for crystallization for 3 hours. S4. Separation and Purification: After crystallization, the product is filtered under reduced pressure to obtain a filter cake. The filter cake is dried at 50°C for 6 hours to obtain doxycycline hydrochloride. The product's microscopic morphology is shown below. Figure 3As shown, the morphology under a scanning electron microscope is as follows: Figure 4 As shown, the product has an irregular particle morphology, no rod-shaped structure, poor flowability, and uneven dispersion, making it difficult to meet the requirements of formulation processing.

[0028] Comparative Example 2 A method for preparing doxycycline hydrochloride includes the following steps: S1. Preparation of mixed solvent: Mix 2.5 kg of methanol and 7.5 kg of water and stir evenly to obtain a mixed solvent for later use; S2. Dissolve the raw materials and add additives: Add 100g of doxycycline hydrochloride raw material to 10kg of the mixed solvent obtained in step S1, stir until completely dissolved, and add 4g of polyvinylpyrrolidone PVPK30 to obtain doxycycline hydrochloride solution. S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, stir at a rate of 200 rpm, cool to 5°C at a rate of 0.5°C / min, and maintain the temperature for crystallization for 3 hours. S4. Separation and Purification: After crystallization, the product is filtered under reduced pressure to obtain a filter cake. The filter cake is dried at 50°C for 6 hours to obtain doxycycline hydrochloride. The scanning electron microscope morphology of the product is shown below. Figure 5 As shown, the product exhibits a fan-shaped morphology, but its morphology is not regular and its particle size distribution is uneven.

[0029] Comparative Example 3 A method for preparing doxycycline hydrochloride includes the following steps: S1. Preparation of mixed solvent: Mix 2.5 kg of methanol and 7.5 kg of water and stir evenly to obtain a mixed solvent for later use; S2. Dissolve the raw materials and add additives: Add 100g of doxycycline hydrochloride raw material to 10kg of the mixed solvent obtained in step S1, stir until completely dissolved, and add 6g of eutectic solvent to obtain doxycycline hydrochloride solution. The eutectic solvent is obtained by mixing choline chloride and oxalic acid in a mass ratio of 1:2. S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, stir at a rate of 200 rpm, cool to 5°C at a rate of 0.5°C / min, and maintain the temperature for crystallization for 3 hours. S4. Separation and Purification: After crystallization, the product is filtered under reduced pressure to obtain a filter cake. The filter cake is dried at 50°C for 6 hours to obtain doxycycline hydrochloride. The scanning electron microscope morphology of the product is shown below. Figure 6 As shown, the product exhibits a fan-shaped morphology, but its morphology is not regular and its particle size distribution is uneven.

[0030] The study found that only by strictly following the process parameters defined in this invention, such as the solvent system ratio, the type and amount of eutectic solvent and polyvinylpyrrolidone, the stirring rate, and the cooling rate, can a stable product of rod-shaped doxycycline hydrochloride with uniform morphology and excellent performance be prepared. Any deviation of process parameters from the defined range or failure to add additives as required will lead to irregular product morphology and decreased performance, further proving the scientific nature and superiority of the process of this invention.

[0031] Preparation method of doxycycline hydrochloride powder: First, add 5g of pulverized anhydrous glucose to a mixer and mix for 5 minutes; then, alternately add 25g of doxycycline hydrochloride and 10g of water-soluble starch obtained through the above examples or comparative examples to the mixer and mix for 15 minutes; finally, add 65g of pulverized anhydrous glucose to the mixer and mix for 20 minutes to obtain doxycycline hydrochloride powder. The angle of repose of the active pharmaceutical ingredient is shown in Table 3.

[0032] Table 3 Angle of repose of the examples and comparative products

[0033] As can be seen from Table 3, the angle of repose of the doxycycline hydrochloride product obtained by this invention is significantly lower than that of the comparative example, and the fluidity is excellent. The dissolution of doxycycline hydrochloride powder was only tested on some of the examples and comparative examples. The test was carried out in accordance with General Chapter 0931 of the Chinese Pharmacopoeia. The dissolution of doxycycline hydrochloride powder was measured after 1 hour, and the results are shown in Table 4.

[0034] Table 4 Dissolution rates of some examples and comparative products

[0035] The dissolution rate of doxycycline hydrochloride powder is related to the solvent. The dissolution rate is highest when using pure water and lowest when using well water. The users of this medicine are poultry farmers (farmers), who mostly use tap water or well water. The rod-shaped doxycycline hydrochloride of this invention overcomes the problem of low dissolution rate when using well water or tap water.

Claims

1. A method for preparing rod-shaped doxycycline hydrochloride, characterized in that: Includes the following steps: S1. Preparation of mixed solvent: Mix methanol and water and stir evenly to obtain a mixed solvent for later use; S2. Dissolve raw materials and add additives: Add doxycycline hydrochloride raw material to the mixed solvent obtained in step S1, stir until completely dissolved, add eutectic solvent and polyvinylpyrrolidone to obtain doxycycline hydrochloride solution. The mass ratio of doxycycline hydrochloride raw material, the mixed solvent obtained in step S1, the eutectic solvent, and polyvinylpyrrolidone is 0.8~1.2:100:0.05~0.1:0.02~0.05; S3. Crystallization: Transfer the doxycycline hydrochloride solution obtained in step S2 to a crystallization vessel, and cool it to 3-8°C at a rate of 0.3-1.0°C / min with stirring, and keep it at this temperature for 2-4 hours for crystallization. S4. Separation and purification: After crystallization, filter cake is obtained by vacuum filtration. The filter cake is dried to obtain rod-shaped doxycycline hydrochloride.

2. The method for preparing rod-shaped doxycycline hydrochloride according to claim 1, characterized in that: The polyvinylpyrrolidone is at least one of PVPK15, PVPK30, PVPK60, and PVPK90.

3. The method for preparing rod-shaped doxycycline hydrochloride according to claim 1, characterized in that: The eutectic solvent is composed of choline chloride and organic acid in a mass ratio of 3:1 to 16.

4. The method for preparing rod-shaped doxycycline hydrochloride according to claim 3, characterized in that: The organic acid is at least one of malonic acid, oxalic acid, or citric acid.

5. The method for preparing rod-shaped doxycycline hydrochloride according to claim 1, characterized in that: The stirring speed in step S3 is 200~300 rpm.

6. The method for preparing rod-shaped doxycycline hydrochloride according to claim 1, characterized in that: In step S1, the mass ratio of methanol to water is 3~10:12~17.

7. The method for preparing rod-shaped doxycycline hydrochloride according to claim 1, characterized in that: The polyvinylpyrrolidone is PVPK30, and the eutectic solvent is obtained by mixing choline chloride and oxalic acid in a mass ratio of 1:

2.

8. The method for preparing rod-shaped doxycycline hydrochloride according to claim 1, characterized in that: The drying temperature is 45~55℃ and the time is 4~8 hours.

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