Preparation method of amoxicillin micropowder
By employing ultrasonic mixing and jet crystallization techniques, the problem of excessively high temperatures during the amoxicillin micronization process was solved, resulting in amoxicillin micronized powder with fine particle size and high purity, meeting the requirement of D90 < 30 μm. This improved the flowability of the amoxicillin micronized powder and its adaptability to subsequent formulations.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANXI XINBAOYUAN PHARMA CO LTD
- Filing Date
- 2025-12-31
- Publication Date
- 2026-05-01
AI Technical Summary
In the preparation of amoxicillin micron powder with D90 < 30 μm, the existing technology causes excessively high temperature during the pulverization process, which leads to overheating and decomposition of amoxicillin, reduces purity and affects flowability, and consequently affects the process adaptability of subsequent formulation products.
An ultrasonic mixer and jetting technology were used to control the mixing method of amoxicillin solution and ammonia water, and crystallization was carried out at low temperature. The efficient mixing and collision crystallization of ultrasound were combined, and finally amoxicillin micro powder was obtained by drying with hot air.
This method achieves the requirement that the particle size of amoxicillin micronized powder meets the requirement of D90 < 30 μm, while maintaining high purity, thus improving the flowability of amoxicillin micronized powder and its adaptability to subsequent formulations.
Smart Images
Figure CN121944869A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of amoxicillin micron powder preparation, specifically a method for preparing amoxicillin micron powder. Background Technology
[0002] Currently, the production of amoxicillin with a D90 < 30 μm typically involves air jet milling or mechanical milling with a D90 < 80 μm. However, the high temperature during the milling process leads to overheating and decomposition of some amoxicillin, resulting in reduced purity and poor flowability of the milled amoxicillin. This negatively impacts the adaptability of the powder to subsequent formulation processes and consequently affects the production process. Therefore, there is an urgent need for a process that can both guarantee the quality of amoxicillin and produce amoxicillin micronized powder with a D90 < 30 μm. Summary of the Invention
[0003] This invention provides a method for preparing amoxicillin micronized powder to overcome the deficiencies in the prior art.
[0004] This invention is achieved through the following technical solution: A method for preparing amoxicillin micronized powder includes the following steps: Step 1: Add amoxicillin solution and ammonia water to the first ultrasonic mixer; Step 2: When the liquid level in the first ultrasonic mixer reaches the specified height, the mixture in the first ultrasonic mixer is sent into the second mixer. Step 3: The mixture in the first ultrasonic mixer is injected into the second mixer and collides with the obstruction in the second mixer; Step 4: After all the mixture in the first ultrasonic mixer is pumped into the second mixer, ammonia water is added again and mixed to continue crystallization. Step 5: After crystallization, filter the solid and dry it to obtain amoxicillin micro powder.
[0005] In the above-described method for preparing amoxicillin micronized powder, the concentration of the amoxicillin solution is 12%.
[0006] In the method for preparing amoxicillin micronized powder as described above, the concentration of ammonia water is 10%.
[0007] In the preparation method of amoxicillin micro powder as described above, the volume ratio of amoxicillin solution to ammonia in step one is 19-22:1.1-1.3.
[0008] In the amoxicillin micron powder preparation method described above, the mixing temperature in step one is controlled at 0-5℃, and the output power of the ultrasonic oscillator is 3000W.
[0009] In the preparation method of amoxicillin micro powder as described above, in step two, the liquid level is increased to one-third of the height of the first ultrasonic mixer, and the liquid discharge rate is the same as the overall liquid addition rate of amoxicillin solution and ammonia.
[0010] In the method for preparing amoxicillin micronized powder as described above, in step three, the mixture in the first mixer is sprayed onto the barrier at a pressure of ≥0.5MPa in the second mixer.
[0011] In the above-described method for preparing amoxicillin micronized powder, the volume of ammonia added in step four is 0.005-0.007 times the total volume of the mixture added to the second mixer.
[0012] In the preparation method of amoxicillin micro powder as described above, after adding ammonia water in step four, crystallization is carried out at a rotation speed of 100-150 r / min. During the crystallization process, the temperature is controlled at 0-5℃ and the crystallization time is 1-1.5 h.
[0013] In the preparation method of amoxicillin micro powder as described above, the drying in step five is carried out by hot air drying at 40-42℃ for 1.4-1.6 hours.
[0014] The advantages of this invention are: This invention uses a spraying method and controls the spray flow rate of amoxicillin solution and ammonia water, so that the supersaturation of the two after mixing is very high, crystallization is fast, and the resulting crystals are fine. At the same time, the introduction of an ultrasonic oscillator can effectively improve the mixing, mass transfer and heat transfer efficiency of amoxicillin solution and ammonia water, reduce the adhesion between crystals after crystallization, and thus reduce the particle size. In the second mixer, the crystals entering the second mixer with the mixed liquid collide with the obstructions at high speed, which will further break the crystals, so that the final product particle size meets D90<30μm. Attached Figure Description
[0015] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0016] Figure 1 This is a 100x magnified microscopic schematic diagram of the amoxicillin micropowder prepared in Example 1 of the present invention; Figure 2 This is a 100x magnified microscopic schematic diagram of the amoxicillin micropowder prepared in Example 2 of the present invention; Figure 3 This is a 100x magnified microscopic schematic diagram of the amoxicillin micropowder prepared in Example 3 of the present invention; Figure 4 This is a 100x magnified microscopic schematic diagram of the amoxicillin powder prepared in comparison with the present invention; Figure 5 This is a schematic diagram illustrating the purity of the amoxicillin micropowder prepared in Example 1 of the present invention; Figure 6 This is a schematic diagram illustrating the purity of the amoxicillin micropowder prepared in Example 2 of the present invention; Figure 7 This is a schematic diagram illustrating the purity of the amoxicillin micropowder prepared in Example 3 of the present invention; Figure 8 This is a schematic diagram illustrating the purity of the amoxicillin powder prepared in the comparative example of the present invention. Figure 9 This is one of the schematic diagrams showing the particle size distribution of amoxicillin micro powder prepared in Example 1 of the present invention; Figure 10 This is the second schematic diagram of the particle size distribution of amoxicillin micro powder prepared in Example 1 of the present invention; Figure 11 This is the third schematic diagram of the particle size distribution of amoxicillin micro powder prepared in Example 1 of the present invention; Figure 12 This is the fourth schematic diagram of the particle size distribution of amoxicillin micro powder prepared in Example 1 of the present invention; Figure 13 This is one of the schematic diagrams showing the particle size distribution of amoxicillin micro powder prepared in Example 2 of the present invention; Figure 14 This is the second schematic diagram of the particle size distribution of amoxicillin micro powder prepared in Example 2 of the present invention; Figure 15 This is the third schematic diagram of the particle size distribution of amoxicillin micro powder prepared in Example 2 of the present invention; Figure 16 This is the fourth schematic diagram of the particle size distribution of amoxicillin micro powder prepared in Example 2 of the present invention; Figure 17 This is one of the schematic diagrams showing the particle size distribution of amoxicillin micro powder prepared in Example 3 of the present invention; Figure 18 This is the second schematic diagram of the particle size distribution of amoxicillin micro powder prepared in Example 3 of the present invention; Figure 19 This is the third schematic diagram of the particle size distribution of amoxicillin micro powder prepared in Example 3 of the present invention; Figure 20 This is the fourth schematic diagram of the particle size distribution of amoxicillin micro powder prepared in Example 3 of the present invention; Figure 21 This is one of the schematic diagrams showing the particle size distribution of amoxicillin powder prepared in comparison to the present invention; Figure 22This is the second schematic diagram of the particle size distribution of amoxicillin powder prepared in the comparative example of the present invention; Figure 23 This is the third schematic diagram of the particle size distribution of amoxicillin powder prepared in the comparative example of the present invention; Figure 24 This is the fourth schematic diagram of the particle size distribution of amoxicillin powder prepared in the comparative example of the present invention. Detailed Implementation
[0017] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0018] A method for preparing amoxicillin micronized powder includes the following steps: Step 1: Add amoxicillin solution and ammonia water to the first ultrasonic mixer; Step 2: When the liquid level in the first ultrasonic mixer reaches the specified height, the mixture in the first ultrasonic mixer is sent into the second mixer. Step 3: The mixture in the first ultrasonic mixer is injected into the second mixer and collides with the obstruction in the second mixer; Step 4: After all the mixture in the first ultrasonic mixer is pumped into the second mixer, ammonia water is added again and mixed to continue crystallization. Step 5: After crystallization, filter the solid and dry it to obtain amoxicillin micro powder.
[0019] Preferably, the concentration of the amoxicillin solution described in this embodiment is 12%.
[0020] Preferably, the concentration of ammonia water in this embodiment is 10%.
[0021] Preferably, in step one of this embodiment, the volume ratio of amoxicillin solution to ammonia is 19-22:1.1-1.3.
[0022] Preferably, in step one of this embodiment, the mixing temperature is controlled at 0-5℃, and the output power of the ultrasonic oscillator is 3000W.
[0023] Preferably, in step two of this embodiment, liquid discharge begins when the liquid level reaches one-third of the height of the first ultrasonic mixer, and the discharge rate is the same as the overall liquid addition rate of amoxicillin solution and ammonia.
[0024] Preferably, in step three of this embodiment, the mixture in the first mixer is sprayed onto the obstruction at a pressure of ≥0.5MPa in the second mixer.
[0025] Preferably, in step four of this embodiment, the volume of ammonia added is 0.005-0.007 times the total volume of the mixture added to the second mixer.
[0026] Preferably, in step four of this embodiment, after adding ammonia, crystallization is carried out at a speed of 100-150 r / min, the temperature is controlled at 0-5℃ during the crystallization process, and the crystallization time is 1-1.5 h.
[0027] Preferably, in step five of this embodiment, the drying process uses hot air drying at 40-42°C for 1.4-1.6 hours.
[0028] Example 1 Step 1: Add 12% amoxicillin solution and 10% ammonia solution to the first ultrasonic mixer at a volume ratio of 19:1.1. The mixing temperature is controlled at 0-5℃ and the output power of the ultrasonic oscillator is 3000W. Step 2: When the liquid level in the first ultrasonic mixer reaches one-third of the height of the first ultrasonic mixer, start discharging the liquid into the second mixer. The discharging rate is the same as the overall discharging rate of amoxicillin solution and ammonia. Step 3: The mixture in the first ultrasonic mixer is injected into the second mixer and sprayed at a pressure of ≥0.5MPa towards the obstruction in the second mixer to collide with it; Step 4: After all the mixture in the first ultrasonic mixer is pumped into the second mixer, ammonia water with a volume of 0.005 times the total volume of the mixture in the second mixer is added and mixed. The mixture is then crystallized at a speed of 100 r / min. During the crystallization process, the temperature is controlled at 0-5℃ and the crystallization time is 1.5h. Step 5: After crystallization, filter the solid. Dry the solid in hot air at 40-42℃ for 1.4 hours to obtain amoxicillin micro powder (its 100x microscopic diagram is shown in Figure 1). Figure 1 As shown), its purity is 99.704% (as shown). Figure 5 As shown), its particle size distribution is as follows: Figures 9-12 As shown.
[0029] Example 2 Step 1: Add 12% amoxicillin solution and 10% ammonia solution to the first ultrasonic mixer at a volume ratio of 22:1.3. The mixing temperature is controlled at 0-5℃ and the output power of the ultrasonic oscillator is 3000W. Step 2: When the liquid level in the first ultrasonic mixer reaches one-third of the height of the first ultrasonic mixer, start discharging the liquid into the second mixer. The discharging rate is the same as the overall discharging rate of amoxicillin solution and ammonia. Step 3: The mixture in the first ultrasonic mixer is injected into the second mixer and sprayed at a pressure of ≥0.5MPa towards the obstruction in the second mixer to collide with it; Step 4: After all the mixture in the first ultrasonic mixer is pumped into the second mixer, ammonia water with a volume of 0.007 times the total volume of the mixture in the second mixer is added and mixed. The mixture is then crystallized at a speed of 150 r / min. During the crystallization process, the temperature is controlled at 0-5℃ and the crystallization time is 1 hour. Step 5: After crystallization, filter the solid. Dry the solid in hot air at 40-42℃ for 1.6 hours to obtain amoxicillin micro powder (its 100x microscopic diagram is shown in Figure 1). Figure 2 As shown), its purity is 99.747% (as shown). Figure 6 As shown), its particle size distribution is as follows: Figures 13-16 As shown.
[0030] Example 3 Step 1: Add 12% amoxicillin solution and 10% ammonia solution to the first ultrasonic mixer at a volume ratio of 20:1.2. The mixing temperature is controlled at 0-5℃ and the output power of the ultrasonic oscillator is 3000W. Step 2: When the liquid level in the first ultrasonic mixer reaches one-third of the height of the first ultrasonic mixer, start discharging the liquid into the second mixer. The discharging rate is the same as the overall discharging rate of amoxicillin solution and ammonia. Step 3: The mixture in the first ultrasonic mixer is injected into the second mixer and sprayed at a pressure of ≥0.5MPa towards the obstruction in the second mixer to collide with it; Step 4: After all the mixture in the first ultrasonic mixer is pumped into the second mixer, ammonia water with a volume of 0.006 times the total volume of the mixture in the second mixer is added and mixed. The mixture is then crystallized at a speed of 130 r / min. During the crystallization process, the temperature is controlled at 0-5℃ and the crystallization time is 1.3h. Step 5: After crystallization, filter the solid. Dry the solid in hot air at 40-42℃ for 1.5 hours to obtain amoxicillin micro powder (its 100x microscopic diagram is shown in Figure 1). Figure 3 As shown), its purity is 99.759% (as shown). Figure 7 As shown), its particle size distribution is as follows: Figures 17-20 As shown.
[0031] Comparative Example Step 1: Add 12% amoxicillin solution and 10% ammonia solution to the mixer at a volume ratio of 20:1. Control the crystallization temperature at 0-5℃, the crystallization stirring speed at 150r / min, and crystallize for 1.5h. Step 2: After crystallization, filter the solid. Dry the solid in hot air at 40-42℃ for 1.6 hours to obtain amoxicillin powder (its 100x microscopic diagram is shown in Figure 1). Figure 4 As shown), its purity is 99.641% (as shown). Figure 8 As shown), its particle size distribution is as follows: Figures 21-24 As shown.
[0032] As can be seen from Examples 1-3 and the comparative examples, through Figures 1-4 Comparing the crystal forms, the amoxicillin micropowder prepared in Examples 1-3 was more dispersed, mainly consisting of "single short needles" or "small clusters"; the amoxicillin powder prepared in the comparative example showed more obvious "single long needles" and "bundles / sets" of aggregation. Therefore, the crystal structure of the amoxicillin micropowder prepared in Examples 1-3 was more dispersed. The purity of Example 1 was 99.704%, the purity of Example 2 was 99.747%, the purity of Example 3 was 99.759%, while the purity of the comparative example was 99.641%. Therefore, the purity of the amoxicillin micropowder prepared in Examples 1-3 of this invention is slightly higher than that of the amoxicillin powder prepared in the comparative example. After three particle size tests, the average value of the amoxicillin micropowder prepared in Example 1 was taken, and more than 90% of the particles were below 23.6 μm. The amoxicillin micropowder prepared in Example 2... The amoxicillin micron powder prepared in Example 1-3 had a particle size of less than 24.7 μm after three particle size tests, with over 90% of the particles having a particle size below 24.1 μm. The amoxicillin micron powder prepared in Example 2 had a particle size of less than 24.1 μm after three particle size tests, with over 90% of the particles having a particle size below 78.0 μm. Therefore, the particle size of the amoxicillin micron powder prepared in Examples 1-3 is much smaller than that of the amoxicillin powder prepared in the comparative example, meeting the requirement of D90 < 30 μm. Furthermore, the amoxicillin micron powder prepared by this invention can meet the requirement of D90 < 30 μm while ensuring purity, facilitating its widespread application in the production of amoxicillin micron powder.
[0033] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing amoxicillin micronized powder, characterized in that: Includes the following steps: Step 1: Add amoxicillin solution and ammonia water to the first ultrasonic mixer; Step 2: When the liquid level in the first ultrasonic mixer reaches the specified height, the mixture in the first ultrasonic mixer is sent into the second mixer. Step 3: The mixture in the first ultrasonic mixer is injected into the second mixer and collides with the obstruction in the second mixer; Step 4: After all the mixture in the first ultrasonic mixer is pumped into the second mixer, ammonia water is added again and mixed to continue crystallization. Step 5: After crystallization, filter the solid and dry it to obtain amoxicillin micro powder.
2. The method for preparing amoxicillin micronized powder according to claim 1, characterized in that: The concentration of the amoxicillin solution is 12%.
3. The method for preparing amoxicillin micronized powder according to claim 1, characterized in that: The concentration of the ammonia solution is 10%.
4. The method for preparing amoxicillin micronized powder according to claim 1, characterized in that: In step one, the volume ratio of amoxicillin solution to ammonia is 19-22:1.1-1.
3.
5. The method for preparing amoxicillin micronized powder according to claim 1, characterized in that: In step one, the mixing temperature is controlled at 0-5℃, and the output power of the ultrasonic oscillator is 3000W.
6. The method for preparing amoxicillin micronized powder according to claim 1, characterized in that: In step two, liquid discharge begins when the liquid level reaches one-third of the height of the first ultrasonic mixer, and the discharge rate is the same as the overall addition rate of amoxicillin solution and ammonia.
7. The method for preparing amoxicillin micronized powder according to claim 1, characterized in that: In step three, the mixture from the first mixer is sprayed onto the obstruction at a pressure of ≥0.5MPa in the second mixer.
8. The method for preparing amoxicillin micronized powder according to claim 1, characterized in that: In step four, the volume of ammonia added is 0.005-0.007 times the total volume of the mixture added to the second mixer.
9. The method for preparing amoxicillin micronized powder according to claim 1, characterized in that: In step four, after adding ammonia, crystallization is carried out at a speed of 100-150 r / min. During the crystallization process, the temperature is controlled at 0-5℃, and the crystallization time is 1-1.5 h.
10. The method for preparing amoxicillin micronized powder according to claim 1, characterized in that: In step five, the drying process uses hot air at 40-42°C for 1.4-1.6 hours.