Preparation method of low-water-activity amoxicillin
By using multi-crystallizer mixing and crystal growth technology, combined with pH adjustment with ammonia and low-temperature drying, the problem of high water activity in amoxicillin was solved, and high-purity, low-water-activity amoxicillin was prepared, improving the quality and production efficiency of amoxicillin.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANXI XINBAOYUAN PHARMA CO LTD
- Filing Date
- 2025-12-30
- Publication Date
- 2026-05-01
AI Technical Summary
Amoxicillin's high water activity leads to poor physical stability, clumping, reduced flowability, accelerated chemical degradation, and stringent storage and transportation requirements. Existing drying technologies are inefficient and struggle to completely reduce water activity.
By employing multi-crystallizer mixing and crystal growth technology, combined with ammonia water to adjust pH value and low-temperature drying, the water activity of amoxicillin is reduced through a multi-step crystallization and washing process.
This method enables the preparation of high-purity, low-water-activity amoxicillin, improving the quality of amoxicillin, reducing production costs and management difficulties, and increasing production efficiency.
Smart Images
Figure CN121949347A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of low water activity amoxicillin production, specifically a method for preparing low water activity amoxicillin. Background Technology
[0002] Amoxicillin, a commonly used semi-synthetic penicillin-type broad-spectrum β-lactam antibiotic, is widely used in clinical practice. However, the presence of polar groups such as amide and carboxyl groups in its molecular structure gives it strong hygroscopicity, directly resulting in a high water activity. This high water activity not only affects the physical stability of amoxicillin, leading to clumping and reduced flowability, but also accelerates its chemical degradation, reducing efficacy and even producing harmful substances, posing a serious threat to the quality and safety of the drug. Furthermore, amoxicillin with high water activity requires more stringent environmental humidity control during storage and transportation, increasing production costs and management difficulties. In the production of amoxicillin, regardless of the particle size range, it is necessary to increase the drying temperature and extend the drying time to dry the water activity to below 0.1. However, the above operations also have the following problems: ① High temperature and extended time can easily cause the material impurities to increase and the drying time to be extended by more than 3 times, affecting production efficiency; ② The amoxicillin crystallized from amoxicillin produced by normal process has a certain amount of free water encapsulation, which is difficult to completely remove by conventional drying methods. As a result, even after long-term high-temperature drying, the water activity is still difficult to be reduced to the ideal low level. Summary of the Invention
[0003] This invention provides a method for preparing low water activity amoxicillin to overcome the deficiencies in the prior art.
[0004] This invention is achieved through the following technical solution: A method for preparing low water activity amoxicillin includes the following steps: Step 1: Amoxicillin solution and ammonia water are flushed into the first crystallizer for mixing; Step 2: The first crystallization solution obtained in the first crystallizer and ammonia water are flushed into the second crystallizer for mixing; Step 3: The second crystallization solution obtained in the second crystallizer is transferred to the third crystallizer for crystal growth; Step 4: After crystal growth is complete, centrifuge and discharge the material. Wash the resulting solid with deionized water. Step 5: After washing and drying, the solid yields amoxicillin with low water activity.
[0005] In the method for preparing low water activity amoxicillin as described above, the concentration of the amoxicillin solution is 12%.
[0006] In the method for preparing low water activity amoxicillin as described above, the concentration of ammonia water is 10%.
[0007] In the preparation method of low water activity amoxicillin described above, in step one, the feed rate of amoxicillin solution is 100-120 L / min, the feed rate of ammonia is 5 L / min, the pressure of the two feed pipes needs to be ≥0.1 MPa, the mixing temperature is controlled at 0-5℃, and the pH value is controlled at 2.5-3.0 during the mixing process.
[0008] In the preparation method of low water activity amoxicillin described above, after feeding for 5-10 minutes in step one, the liquid in the first crystallizer is transferred to the second crystallizer, and the discharge rate is the same as the feeding rate.
[0009] In the preparation method of low water activity amoxicillin described above, in step two, the feed rate of the first crystallization liquid is 105-125 L / min, the feed rate of ammonia water is 2 L / min, the pressure of the two feed pipes needs to be ≥0.1 MPa, the mixing temperature is controlled at 0-5℃, and the pH value is controlled at 4.5-5.0 during the mixing process.
[0010] In the preparation method of low water activity amoxicillin described above, after feeding for 5-10 minutes in step two, the liquid from the second crystallizer is transferred to the third crystallizer, and the discharge rate is the same as the feed rate.
[0011] In the preparation method of low water activity amoxicillin described above, after all the second crystallization solution in step three is transferred to the third crystallizer, the pH is adjusted to 4.8-5.2 with ammonia water, the crystal growth temperature is controlled at 0-5℃, and the crystal growth time is 30-60 minutes.
[0012] In the preparation method of low water activity amoxicillin described above, the solid in step four is washed with deionized water 3-5 times.
[0013] In the preparation method of low water activity amoxicillin described above, the drying in step five is carried out by air-blown boiling drying, and the material temperature is controlled at 35-38℃ for 1 hour.
[0014] The advantage of this invention is that the preparation method of this invention can obtain amoxicillin with high purity and low water activity, thereby improving the quality of amoxicillin. 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 schematic diagram of the product according to Embodiment 1 of the present invention; Figure 2 This is the purity test report for Example 1 of the present invention; Figure 3 This is the water activity test report of Embodiment 1 of the present invention; Figure 4 This is a schematic diagram of the product according to Embodiment 2 of the present invention; Figure 5 This is the purity test report for Example 2 of the present invention; Figure 6 This is the water activity test report of Embodiment 2 of the present invention; Figure 7 This is a schematic diagram of the product according to Embodiment 3 of the present invention; Figure 8 This is the purity test report for Example 3 of the present invention; Figure 9 This is the water activity test report of Embodiment 3 of the present invention; Figure 10 This is a comparative example product schematic diagram of the present invention; Figure 11 This is a purity test report for a comparative example of the present invention; Figure 12 This is a comparative water activity test report 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 low water activity amoxicillin includes the following steps: Step 1: Amoxicillin solution and ammonia water are flushed into the first crystallizer for mixing; Step 2: The first crystallization solution obtained in the first crystallizer and ammonia water are flushed into the second crystallizer for mixing; Step 3: The second crystallization solution obtained in the second crystallizer is transferred to the third crystallizer for crystal growth; Step 4: After crystal growth is complete, centrifuge and discharge the material. Wash the resulting solid with deionized water. Step 5: After washing and drying, the solid yields amoxicillin with low water activity.
[0019] Specifically, the concentration of the amoxicillin solution described in this embodiment is 12%.
[0020] Specifically, the concentration of ammonia water described in this embodiment is 10%.
[0021] More specifically, in step one of this embodiment, the amoxicillin solution feed rate is 100-120 L / min, the ammonia feed rate is 5 L / min, the pressure of the two feed pipes needs to be ≥0.1 MPa, the mixing temperature is controlled at 0-5℃, and the pH value is controlled at 2.5-3.0 during the mixing process.
[0022] More specifically, in step one of this embodiment, after feeding for 5-10 minutes, the liquid in the first crystallizer is transferred to the second crystallizer, and the discharge rate is the same as the feeding rate.
[0023] More specifically, in step two of this embodiment, the feed rate of the first crystallization liquid is 105-125 L / min, the feed rate of ammonia water is 2 L / min, the pressure of the two feed pipes needs to be ≥0.1 MPa, the mixing temperature is controlled at 0-5℃, and the pH value is controlled at 4.5-5.0 during the mixing process.
[0024] Furthermore, in step two of this embodiment, after feeding for 5-10 minutes, the liquid from the second crystallizer is transferred to the third crystallizer, and the discharge rate is the same as the feeding rate.
[0025] Furthermore, in step three of this embodiment, after all the second crystallizing solution is transferred to the third crystallizer, the pH is adjusted to 4.8-5.2 with ammonia water, the crystal growth temperature is controlled at 0-5℃, and the crystal growth time is 30-60 minutes.
[0026] Furthermore, in step four of this embodiment, the solid is washed with deionized water 3-5 times.
[0027] Furthermore, in step five of this embodiment, the drying process employs airflow-driven boiling drying, controlling the material temperature at 35-38℃ for 1 hour.
[0028] Example 1 Step 1: Mix 12% amoxicillin solution and 10% ammonia solution by flushing them into the first crystallizer. The feed rate of amoxicillin solution is 100 L / min, and the feed rate of ammonia solution is 5 L / min. The pressure of both feed pipes must be ≥0.1 MPa. The mixing temperature is controlled at 0-5℃, and the pH value is controlled at 2.5-3.0 during the mixing process. After 5 minutes of feeding, start transferring the liquid from the first crystallizer to the second crystallizer, and the discharge rate is the same as the feed rate. Step 2: The first crystallization liquid obtained in the first crystallizer and 10% ammonia water are flushed into the second crystallizer for mixing. The feed rate of the first crystallization liquid is 105 L / min, and the feed rate of the ammonia water is 2 L / min. The pressure of the two feed pipes must be ≥0.1 MPa. The mixing temperature is controlled at 0-5℃. During the mixing process, the pH value is controlled at 4.5-5.0. After 5-10 minutes of feeding, the liquid from the second crystallizer is transferred to the third crystallizer, and the discharge rate is the same as the feed rate. Step 3: The second crystallization solution obtained in the second crystallizer is transferred to the third crystallizer for crystal growth. After all the second crystallization solution is transferred to the third crystallizer, the pH is adjusted to 4.9 with 10% ammonia water. The crystal growth temperature is controlled at 0-5℃ and the crystal growth time is 40 minutes. Step 4: After crystal growth is complete, centrifuge and discharge the material. Wash the resulting solid with deionized water three times. Step 5: The washed solids are then subjected to air-purged boiling drying, with the material temperature controlled at 35-38℃ for 1 hour to obtain low water activity amoxicillin (e.g., ...). Figure 1 As shown), the purity is 99.749% (as shown). Figure 2 As shown), the water activity is 0.0796 (as indicated). Figure 3 (As shown).
[0029] Example 2 Step 1: Mix 12% amoxicillin solution and 10% ammonia solution by flushing them into the first crystallizer. The feed rate of amoxicillin solution is 120 L / min, and the feed rate of ammonia solution is 5 L / min. The pressure of both feed pipes must be ≥0.1 MPa. The mixing temperature is controlled at 0-5℃, and the pH value is controlled at 2.5-3.0 during the mixing process. After feeding for 10 minutes, start transferring the liquid from the first crystallizer to the second crystallizer, and the discharge rate is the same as the feed rate. Step 2: The first crystallization liquid obtained in the first crystallizer and 10% ammonia water are flushed into the second crystallizer for mixing. The feed rate of the first crystallization liquid is 125L / min, and the feed rate of the ammonia water is 2L / min. The pressure of the two feed pipes must be ≥0.1Mpa. The mixing temperature is controlled at 0-5℃. During the mixing process, the pH value is controlled at 4.5-5.0. After 5-10 minutes of feeding, the liquid from the second crystallizer is transferred to the third crystallizer, and the discharge rate is the same as the feed rate. Step 3: The second crystallization solution obtained in the second crystallizer is transferred to the third crystallizer for crystal growth. After all the second crystallization solution is transferred to the third crystallizer, the pH is adjusted to 5.1 with 10% ammonia water. The crystal growth temperature is controlled at 0-5℃ and the crystal growth time is 60 minutes. Step 4: After crystal growth is complete, centrifuge and discharge the material. Wash the resulting solid with deionized water 5 times. Step 5: The washed solids are then subjected to air-purged boiling drying, with the material temperature controlled at 35-38℃ for 1 hour to obtain low water activity amoxicillin (e.g., ...). Figure 4 As shown), the purity is 99.701% (as shown). Figure 5 As shown), the water activity is 0.0530 (as indicated). Figure 6 (As shown).
[0030] Example 3 Step 1: Mix 12% amoxicillin solution and 10% ammonia solution by flushing them into the first crystallizer. The feed rate of amoxicillin solution is 110 L / min, and the feed rate of ammonia solution is 5 L / min. The pressure of both feed pipes must be ≥0.1 MPa. The mixing temperature is controlled at 0-5℃, and the pH value is controlled at 2.5-3.0 during the mixing process. After 8 minutes of feeding, start transferring the liquid from the first crystallizer to the second crystallizer, and the discharge rate is the same as the feed rate. Step 2: The first crystallization liquid obtained in the first crystallizer and 10% ammonia water are flushed into the second crystallizer for mixing. The feed rate of the first crystallization liquid is 115L / min, and the feed rate of the ammonia water is 2L / min. The pressure of the two feed pipes must be ≥0.1Mpa. The mixing temperature is controlled at 0-5℃. During the mixing process, the pH value is controlled at 4.5-5.0. After 8 minutes of feeding, the liquid from the second crystallizer is transferred to the third crystallizer, and the discharge rate is the same as the feed rate. Step 3: The second crystallization solution obtained in the second crystallizer is transferred to the third crystallizer for crystal growth. After all the second crystallization solution is transferred to the third crystallizer, the pH is adjusted to 5.0 with 10% ammonia water. The crystal growth temperature is controlled at 0-5℃ and the crystal growth time is 50 minutes. Step 4: After crystal growth is complete, centrifuge and discharge the material. Wash the resulting solid with deionized water 4 times. Step 5: The washed solids are then subjected to air-purged boiling drying, with the material temperature controlled at 35-38℃ for 1 hour to obtain low water activity amoxicillin (e.g., ...). Figure 7 As shown), the purity is 99.721% (as shown). Figure 8 As shown), the water activity is 0.033 (as indicated). Figure 9 (As shown).
[0031] Comparative Example Step 1: Place 19.5m 3 A 12% amoxicillin solution and 1.35 mg / L... 3 A 10% ammonia solution was added to the crystallizer, the crystallization temperature was controlled at 0-5℃, the pH was controlled at 5-5.5 during the crystallization process, and the crystallization time was 1 hour. Step 2: After crystallization, centrifuge and discharge the material. Wash the obtained solid with deionized water 4 times. Step 3: The washed solids are then subjected to air-purged boiling drying, with the material temperature controlled at 35-38℃ for 1 hour to obtain amoxicillin (e.g., ...). Figure 10 As shown), the purity is 99.681% (as shown). Figure 11 As shown), the water activity is 0.2323 (as indicated). Figure 12 (As shown).
[0032] As can be seen from Examples 1-3 and the comparative example, by comparing the 100x microscopic schematic diagrams, the purity of Example 1 is 99.749%, Example 2 is 99.701%, and Example 3 is 99.721%, all slightly higher than the 99.681% of the comparative example. Furthermore, the water activity index is as follows: the water activity of Example 1 is 0.0796, the water activity of Example 2 is 0.0530, and the water activity of Example 3 is 0.033, while the water activity of the comparative example is 0.2323. Therefore, the water activity of Examples 1-3 is significantly lower than that of the comparative example. Thus, this invention can effectively reduce water activity while ensuring purity, thereby obtaining a higher quality amoxicillin. Moreover, the operation is relatively simple and easy to widely promote and use.
[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 low water activity amoxicillin, characterized in that: Includes the following steps: Step 1: Amoxicillin solution and ammonia water are flushed into the first crystallizer for mixing; Step 2: The first crystallization solution obtained in the first crystallizer and ammonia water are flushed into the second crystallizer for mixing; Step 3: The second crystallization solution obtained in the second crystallizer is transferred to the third crystallizer for crystal growth; Step 4: After crystal growth is complete, centrifuge and discharge the material. Wash the resulting solid with deionized water. Step 5: After washing and drying, the solid yields amoxicillin with low water activity.
2. The method for preparing low water activity amoxicillin according to claim 1, characterized in that: The concentration of the amoxicillin solution is 12%.
3. The method for preparing low water activity amoxicillin according to claim 1, characterized in that: The concentration of the ammonia solution is 10%.
4. The method for preparing low water activity amoxicillin according to claim 1, characterized in that: In step one, the amoxicillin solution feed rate is 100-120 L / min, the ammonia feed rate is 5 L / min, the pressure of the two feed pipes must be ≥0.1 MPa, the mixing temperature is controlled at 0-5℃, and the pH value is controlled at 2.5-3.0 during the mixing process.
5. The method for preparing low water activity amoxicillin according to claim 1, characterized in that: In step one, after feeding for 5-10 minutes, the liquid in the first crystallizer is transferred to the second crystallizer, and the discharge rate is the same as the feeding rate.
6. The method for preparing low water activity amoxicillin according to claim 1, characterized in that: In step two, the feed rate of the first crystallization liquid is 105-125 L / min, the feed rate of ammonia water is 2 L / min, the pressure of the two feed pipes must be ≥0.1 MPa, the mixing temperature is controlled at 0-5℃, and the pH value is controlled at 4.5-5.0 during the mixing process.
7. The method for preparing low water activity amoxicillin according to claim 1, characterized in that: In step two, after feeding for 5-10 minutes, the liquid from the second crystallizer is transferred to the third crystallizer, and the discharge rate is the same as the feeding rate.
8. The method for preparing low water activity amoxicillin according to claim 1, characterized in that: In step three, after all the second crystallization solution is transferred to the third crystallizer, the pH is adjusted to 4.8-5.2 with ammonia water, the crystal growth temperature is controlled at 0-5℃, and the crystal growth time is 30-60 minutes.
9. The method for preparing low water activity amoxicillin according to claim 1, characterized in that: In step four, the solid is washed with deionized water 3-5 times.
10. The method for preparing low water activity amoxicillin according to claim 1, characterized in that: The drying process in step five is carried out by air-blown boiling drying, with the material temperature controlled at 35-38℃ for 1 hour.