Process method for preparing amoxicillin large crystal by coupling crystallization method

Abstract

The invention relates to a process method for preparing an amoxicillin large crystal by a coupling crystallization method, which comprises the following steps: preparing an amoxicillin dissolving solution, adding a solvating-out agent into the filtered amoxicillin dissolving solution in a fed-batch manner, adding ammonia water in a fed-batch manner, and adjusting the pH value of the obtained solution to 1.4-1.6; then continuously adding a solventing-out agent in a fed-batch manner under the condition of slow cooling, simultaneously adding ammonia water in a fed-batch manner until crystals are separated out, growing the crystals, and continuously adding ammonia water until the pH value is 4.8-5.0 to obtain an amoxicillin crystal solution; and sequentially carrying out suction filtration, washing and drying to obtain the amoxicillin large crystal. According to the method, the growth speed of the amoxicillin crystal is controlled and slowed down through a coupling synergistic process of a solventing-out agent and cooling crystallization, the phenomenon of explosive nucleation in the amoxicillin crystallization process is avoided, and meanwhile, the shape of the obtained amoxicillin crystal is changed, so that the grain size of the crystal is larger, more stable and more regular compared with that of a traditional method, and the quality of the amoxicillin crystal is improved. And the yield and the purity of the amoxicillin crystal can be improved.

Description

Technical Field

[0001] This invention belongs to the field of drug preparation technology, specifically relating to a process for preparing large amoxicillin crystals using a coupled crystallization method. Background Technology

[0002] Amoxicillin is a commonly used β-lactam antibiotic, also known as amoxicillin, belonging to the aminopenicillin class of the penicillin family. Amoxicillin inhibits bacterial cell wall synthesis, exhibiting highly effective broad-spectrum antibacterial activity with few side effects. It is widely used in the treatment of bacterial infections, such as middle ear infections, streptococcal laryngitis, pneumonia, skin infections, and urinary tract infections. Its marketed formulations include tablets, capsules, granules, and dispersible tablets.

[0003] The main methods for synthesizing amoxicillin include chemical synthesis and enzyme-catalyzed synthesis. Because enzyme-catalyzed synthesis involves milder reaction conditions, is more environmentally friendly, and produces amoxicillin with higher purity than that obtained through chemical synthesis, it is increasingly being researched and applied.

[0004] In the enzyme-catalyzed synthesis of amoxicillin, D-p-hydroxyphenylglycine methyl ester is mostly used as the acyl side chain donor. Under the catalysis of immobilized penicillin acylase, it condenses with 6-APA (6-aminopenicillanic acid) to generate amoxicillin, which is then crystallized to obtain amoxicillin crystals. In traditional crystallization processes, the pH of the amoxicillin condensation solution is adjusted to the isoelectric point of amoxicillin (4-5) by adding acid / alkali. Under these isoelectric point conditions, amoxicillin carries zero charge, at which point crystal formation begins. The formation and growth of crystal nuclei are controlled by adjusting the pH, temperature, and stirring during the crystallization process.

[0005] Existing crystallization processes often result in amoxicillin crystals with small and irregular particle sizes. Small particle sizes not only hinder the filtration, separation, and drying of the product and generate dust during formulation, but also lead to poor stability of amoxicillin, which in turn poses a risk of degradation during storage and transportation. In contrast, as an active pharmaceutical ingredient, amoxicillin with large and regular crystal particle sizes is beneficial for improving the flowability of the drug powder, thus facilitating the formulation process.

[0006] A Chinese patent (CN115490706A) published by Sinopharm Group Weichida Pharmaceutical Co., Ltd. discloses a method for preparing amoxicillin crystals. The method involves acidifying an amoxicillin condensation solution to achieve a pH < 0.2, with a molar ratio of amoxicillin to hydrochloric acid of 1:5.8-7.6, ensuring complete dissolution of the amoxicillin crystals. The pH is then adjusted to the isoelectric point with ammonia, and the solution is cooled to 0-10°C to precipitate amoxicillin crystals. The amoxicillin crystals obtained by this method have a suitable large particle size, with Dv(10) of 10-15 μm, Dv(50) of 45-60 μm, and Dv(90) of 145-165 μm. However, this method uses excessive hydrochloric acid during acidification, which increases the amount of alkali used in subsequent crystallization, leading to an increased amount of mother liquor and higher waste disposal costs.

[0007] A Chinese patent (CN 118638131A) published by Federal Pharmaceuticals (Inner Mongolia) Co., Ltd. discloses a crystallization process for preparing large crystals of amoxicillin using an enzymatic synthesis method. This process employs the method of adding amoxicillin solution to a seed crystal solution, effectively avoiding explosive nucleation and promoting the formation of regular large crystals. By controlling different amounts of seed crystals added, crystals of different particle sizes can be obtained to meet the needs of different customers. The yield of amoxicillin large crystals prepared using this method is 2-3% higher than that of traditional crystallization methods. Compared to CN115490706A, this method reduces the amount of hydrochloric acid used, correspondingly reducing the amount of alkali required for crystallization and lowering costs.

[0008] Scientists in this field are exploring and researching, hoping to discover a simple process for producing large crystals of amoxicillin that offers good crystal stability, easy control over the formulation process, and high purity. This would help avoid explosive nucleation, reduce the risk of degradation during storage and transportation, facilitate formulation processing, and improve production efficiency and formulation uniformity. Summary of the Invention

[0009] To address the shortcomings and deficiencies of existing crystallization processes for amoxicillin large crystals, the present invention aims to provide a coupled crystallization method for preparing amoxicillin large crystals. The resulting amoxicillin large crystals exhibit good stability, reducing the risk of degradation during storage and transportation. Furthermore, they facilitate formulation processing, are easier to control during formulation, reduce dust generation, and improve production efficiency and formulation uniformity.

[0010] To achieve the above objectives, the technical solution adopted by this invention is: a process for preparing large amoxicillin crystals using a coupled crystallization method, the method comprising the following steps:

[0011] S1. Preparation of amoxicillin solution: Add amoxicillin powder to purified water, then add hydrochloric acid to dissolve the amoxicillin, and filter to obtain the amoxicillin solution;

[0012] S2. Preparation of amoxicillin crystallization solution: Add a solvent and ammonia water to the amoxicillin solution by feeding in a continuous feed manner, and adjust the pH of the resulting solution to 1.4-1.6 to obtain the amoxicillin crystallization solution; then slowly cool to 10-15℃, and continue to add solvent and ammonia water by feeding in a continuous feed manner until crystals precipitate. Then, continue to add ammonia water until the pH reaches 4.8-5.0 to obtain the amoxicillin crystallization solution.

[0013] S3. Preparation of amoxicillin large crystals: The amoxicillin crystallization solution is sequentially filtered, washed and dried to obtain amoxicillin large crystals.

[0014] Furthermore, in step S1, the mass percentage concentration of the amoxicillin solution is 10-15%.

[0015] Furthermore, in step S2, the solvent is selected from one of ethanol, acetone, and methanol.

[0016] Further, in step S2, at 25-30°C, a solvent is added to the filtered amoxicillin solution by a feeding method, and ammonia is added by a feeding method at the same time to adjust the pH value of the resulting solution to 1.4-1.6, thereby obtaining the amoxicillin crystallization solution.

[0017] Furthermore, in step S2, the mass percentage concentration of the ammonia water is 7% to 8%.

[0018] Furthermore, in step S2, before the cooling operation, the amount of precipitant added is 50% of the volume of the filtered amoxicillin solution, the flow rate of the precipitant is 1-3 mL / min, and the flow rate of the ammonia is 0.2-1 mL / min.

[0019] Furthermore, in step S2, after the cooling operation begins, the amount of precipitant added is 50% of the volume of the filtered amoxicillin solution, the flow rate of the precipitant is 1-3 mL / min, and the flow rate of the ammonia is 0.2-1 mL / min.

[0020] Furthermore, in step S2, the cooling rate is 0.5–2 °C / min.

[0021] Furthermore, in step S2, after crystals precipitate, the crystals are cultured for 30–40 minutes.

[0022] Further, in step S2, after adding ammonia water to pH 4.8-5.0, continue crystal growth for 1.5-2 hours to obtain amoxicillin crystal solution.

[0023] Further, in step S3, the amoxicillin crystallization solution is filtered and washed to obtain amoxicillin wet powder, and the amoxicillin wet powder is dried at 45-50℃ for 2-2.5h to obtain amoxicillin large crystals.

[0024] The beneficial effects of this invention are as follows: The process for preparing large amoxicillin crystals using the coupled crystallization method provided by this invention involves preparing an amoxicillin solution, adding a solvent and ammonia water simultaneously in a fed-batch manner to the filtered amoxicillin solution to adjust the pH of the resulting solution to 1.4–1.6, thus obtaining an amoxicillin crystallization solution; then, under slow cooling conditions, continuing to add the solvent and ammonia water simultaneously in a fed-batch manner until crystals precipitate, followed by crystal growth, and continuing to add ammonia water until the pH reaches 4.8–5.0, obtaining an amoxicillin crystallization solution; finally, the solution is subjected to filtration, washing, and drying to obtain large amoxicillin crystals. This method, through the coupled and synergistic process of solvent and cooling crystallization, controls and slows down the growth rate of amoxicillin crystals, avoiding explosive nucleation during the crystallization process. It also alters the morphology of the obtained amoxicillin crystals, resulting in larger, more stable, and more regular crystal particles compared to traditional methods, and also improves the yield and purity of amoxicillin crystals.

[0025] The large amoxicillin crystals obtained using the method provided in this invention exhibit good stability, reducing the risk of degradation during storage and transportation. They are also easier to process and control during formulation, reducing dust generation and improving production efficiency and formulation uniformity. Furthermore, this method helps improve the purity and quality of amoxicillin, reducing the potential impact of impurities on its efficacy and safety. Attached Figure Description

[0026] Figure 1 This is a schematic diagram of a process for preparing large amoxicillin crystals using a coupled crystallization method according to an embodiment of the present invention;

[0027] Figure 2 This is the crystal pattern of amoxicillin A obtained under a microscope, as provided in Example 1 of this invention.

[0028] Figure 3 This is the crystal pattern of amoxicillin B obtained under a microscope, as provided in Example 2 of this invention.

[0029] Figure 4 This is the crystal pattern of amoxicillin C obtained under a microscope, as provided in Example 3 of this invention.

[0030] Figure 5 This is the crystal pattern of amoxicillin D obtained under a microscope, as provided in Example 4 of this invention.

[0031] Figure 6 This is the crystal pattern of amoxicillin E obtained under a microscope, provided in Comparative Example 1 of this invention.

[0032] Figure 7 This is the crystal pattern of amoxicillin F obtained under a microscope, provided in Comparative Example 2 of this invention.

[0033] Figure 8 This is a crystal pattern of amoxicillin G obtained under a microscope, provided in Comparative Example 3 of this invention. Detailed Implementation

[0034] The technical solutions in the embodiments of the present invention will be further described clearly and completely below with reference to the accompanying drawings and examples. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0035] It should be noted that the raw materials and reagents used in this embodiment are all commercially available products well known to those skilled in the art, or can be obtained by those skilled in the art through existing methods and conventional operations.

[0036] This embodiment provides a coupled crystallization method for preparing large amoxicillin crystals, employing a synergistic process of solvent addition and cooling crystallization to couple the crystallization of amoxicillin. The method uses ethanol, methanol, or acetone as the solvent, utilizing the lower solubility of amoxicillin in new solvent systems (such as ethanol-water) to obtain a higher mass of precipitated amoxicillin crystals. Furthermore, by controlling the rate at which ethanol is added to the amoxicillin solution, the composition of the ethanol-water system in the solution can be controlled to change slowly, allowing the supersaturation of the solute to increase gradually at a controllable rate, thereby controlling the crystallization rate and the crystal form of the precipitated crystals. Simultaneously, the cooling operation before the crystallization process begins further controls the crystallization rate and the crystal form of the precipitated crystals, preventing explosive nucleation during the crystallization process.

[0037] In other words, the method utilizes a coupled and synergistic process of solvent and cooling crystallization to control and slow down the growth rate of amoxicillin crystals. Simultaneously, it monitors the precipitated crystals to ensure they have a regular crystal structure, preventing explosive nucleation during crystallization. This process also alters the morphology of the obtained amoxicillin crystals, resulting in larger, more stable, and more regular crystal sizes compared to traditional methods. Furthermore, it improves the yield and purity of amoxicillin crystals. The large amoxicillin crystals obtained using this method exhibit good stability, reducing the risk of degradation during storage and transportation. They are also easier to process and control during formulation, reducing dust generation and improving production efficiency and formulation uniformity. Furthermore, this method helps improve the purity and quality of amoxicillin, reducing the potential impact of impurities on its efficacy and safety.

[0038] like Figure 1 As shown in this embodiment, a process for preparing large amoxicillin crystals using a coupled crystallization method is provided. The method includes the following steps:

[0039] S1. Preparation of amoxicillin solution: Add amoxicillin powder to purified water, then add 20% hydrochloric acid to dissolve the amoxicillin, and filter to obtain the amoxicillin solution;

[0040] Optionally, in step S1, the mass percentage concentration of the amoxicillin solution is 10-15%.

[0041] Optionally, in step S1, the pH value of the amoxicillin solution is 0.8 to 1.2.

[0042] S2. Preparation of amoxicillin crystallization solution: Add the solvent and ammonia water to the amoxicillin solution by feeding in a continuous feed manner, and adjust the pH of the resulting solution to 1.4-1.6 to obtain the amoxicillin crystallization solution; then, under slow cooling conditions, continue to add the solvent and ammonia water by feeding in a continuous feed manner until crystals precipitate, then continue to add ammonia water until the pH reaches 4.8-5.0 to obtain the amoxicillin crystallization solution;

[0043] Optionally, in step S2, the solvent is selected from one of ethanol, acetone, and methanol.

[0044] Optionally, in step S2, at 25–30°C, a solvent is added to the filtered amoxicillin solution by a feeding method, and ammonia is added by a feeding method at the same time, so that the pH value of the resulting solution is adjusted to 1.4–1.6 to obtain the amoxicillin crystallization solution.

[0045] Optionally, in step S2, before the cooling operation, the amount of precipitant added is 50% of the volume of the amoxicillin solution after filtration, the flow rate of the precipitant is 1-3 mL / min, and the flow rate of the ammonia is 0.2-1 mL / min.

[0046] Optionally, the mass percentage concentration of the ammonia solution is 7% to 8%.

[0047] Optionally, in step S2, after the cooling operation begins, the amount of precipitant added is 50% of the volume of the filtered amoxicillin solution, the flow rate of the precipitant is 1-3 mL / min, and the flow rate of ammonia is 0.2-1 mL / min.

[0048] Optionally, in step S2, the cooling rate is 0.5–2 °C / min, and the temperature is reduced to 10–15 °C.

[0049] Optionally, in step S2, after crystals precipitate, the crystals are cultured for 30–40 minutes.

[0050] Specifically, in step S2, after adding ammonia water to pH 4.8-5.0, continue crystal growth for 1.5-2 hours to obtain amoxicillin crystal solution.

[0051] In step S2, the solvent is added at a very slow rate. When the solvent is added to the solution at a very slow rate, the composition of the solution changes slowly, and the supersaturation of the solute amoxicillin increases slowly as well. Under these circumstances, the crystallization rate of the solute amoxicillin will slow down; cooling also has the effect of slowing down the crystallization rate of amoxicillin.

[0052] In traditional methods, amoxicillin typically begins to crystallize at around pH 2.0, and the crystallization process is generally plagued by uncontrollable burst nucleation. In step S2 of this embodiment, the rate of increase in amoxicillin supersaturation is controlled before crystallization (pH 1.4–1.6), and the temperature is lowered to 10–15°C before crystallization. In other words, a coupled and synergistic process of solvent and cooling crystallization is employed before crystallization begins to control the growth rate of amoxicillin crystals, thereby altering the crystal morphology and preventing burst nucleation during crystallization. This results in larger, more stable, and more regular amoxicillin crystals compared to traditional methods, and also improves the yield and purity of amoxicillin crystals.

[0053] S3. Preparation of amoxicillin large crystals: The amoxicillin crystallization solution is sequentially filtered, washed and dried to obtain amoxicillin large crystals.

[0054] Optionally, in step S3, the amoxicillin crystallization solution is filtered and washed to obtain amoxicillin wet powder, and the amoxicillin wet powder is dried at 45-50℃ for 2-2.5h to obtain amoxicillin large crystals.

[0055] The following examples further illustrate specific embodiments of the present invention.

[0056] Specifically, the following embodiments are based on the above-mentioned process for preparing large amoxicillin crystals by coupled crystallization. By using a coupled and synergistic process of solvent and cooling crystallization, the growth rate of amoxicillin crystals is controlled and slowed down, avoiding the phenomenon of explosive nucleation during the crystallization process of amoxicillin. At the same time, the morphology of the obtained amoxicillin crystals is changed, making the crystal particle size larger and more stable compared with traditional methods, and also improving the yield and purity of amoxicillin crystals.

[0057] Example 1: Preparation of Amoxicillin A

[0058] S11. Add 10g of amoxicillin calomel powder to 100g of purified water, then add 20% hydrochloric acid to dissolve the amoxicillin, filter to obtain an amoxicillin solution with a mass percentage concentration of 10% and a pH value of 0.85.

[0059] S12. Take 100 mL of amoxicillin solution with a mass percentage concentration of 10%, add 50 mL of ethanol at 25-30℃ at a flow rate of 1 mL / min, and add ammonia at a flow rate of 0.2 mL / min. Adjust the pH of the resulting solution to 1.4-1.6 to obtain the amoxicillin crystallization solution.

[0060] Then, the temperature was lowered at a rate of 1℃ / min to 10-15℃, and 50mL of ethanol was added at the same rate as above. The ammonia was also added at the same rate as above. Crystallization occurred at pH 2.96. After crystallization for 30min, ammonia was added to adjust the pH to 4.8-5.0. Crystallization was continued for 1.5h, and amoxicillin wet powder was obtained by filtration.

[0061] S13. Amoxicillin wet powder was dried at 45℃ for 2 hours to obtain amoxicillin A.

[0062] S14. The Malvern particle size D10, D50, and D90 of amoxicillin A were determined, and the results are shown in Table 1 below. At the same time, the purity and yield of amoxicillin A were determined, and the results are also listed in Table 1.

[0063] The crystal pattern of amoxicillin A obtained under a microscope is shown below. Figure 2 As shown.

[0064] Example 2: Preparation of Amoxicillin B

[0065] S21. Add 15g of amoxicillin calomel powder to 100g of purified water, then add 20% hydrochloric acid to dissolve the amoxicillin, filter to obtain an amoxicillin solution with a mass percentage concentration of 15% and a pH value of 0.90.

[0066] S22. Take 100 mL of a 15% amoxicillin solution, add 50 mL of ethanol at 25-30℃ at a flow rate of 1 mL / min, and add ammonia at a flow rate of 0.2 mL / min. Adjust the pH of the resulting solution to 1.4-1.6 to obtain the amoxicillin crystallization solution.

[0067] Then, the temperature was lowered at a rate of 1℃ / min to 10-15℃, and 50mL of ethanol was added at the same rate as above. The ammonia was also added at the same rate as above. Crystallization occurred at pH 2.88. After crystallization for 30min, ammonia was added to adjust the pH to 4.8-5.0. Crystallization continued for 1.5h, and amoxicillin wet powder was obtained by filtration.

[0068] S23. Amoxicillin wet powder was dried at 45℃ for 2 hours to obtain amoxicillin B.

[0069] S24. The Malvern particle size D10, D50, and D90 of amoxicillin B were determined, and the results are shown in Table 1 below. At the same time, the purity and yield of amoxicillin B were determined, and the results are also listed in Table 1.

[0070] The crystal pattern of amoxicillin B obtained under a microscope is shown below. Figure 3 As shown.

[0071] Example 3: Preparation of Amoxicillin C

[0072] S31. Add 10g of amoxicillin powder to 100g of purified water, then add 20% hydrochloric acid to dissolve the amoxicillin, filter to obtain an amoxicillin solution with a mass percentage concentration of 10% and a pH value of 0.88.

[0073] S32. Take 100 mL of a 10% solution, add 50 mL of ethanol at 25-30℃ at a flow rate of 1 mL / min, add ammonia at a flow rate of 1 mL / min, adjust the pH of the resulting solution to 1.4-1.6, and obtain the amoxicillin crystallization solution.

[0074] Then, the temperature was lowered at a rate of 1℃ / min to 10-15℃, and 50mL of ethanol was added at the same rate as above. The ammonia was also added at the same rate as above. Crystallization occurred at pH 2.91. After crystallization for 30min, ammonia was added to adjust the pH to 4.8-5.0. Crystallization was continued for 1.5h, and amoxicillin wet powder was obtained by filtration.

[0075] S33. Amoxicillin wet powder was dried at 45℃ for 2 hours to obtain amoxicillin C.

[0076] S34. The Malvern particle size D10, D50, and D90 of amoxicillin C were determined, and the results are shown in Table 1 below. At the same time, the purity and yield of amoxicillin C were determined, and the results are also listed in Table 1.

[0077] The crystal form of amoxicillin C obtained under a microscope is shown below. Figure 4 As shown.

[0078] Example 4: Preparation of Amoxicillin D

[0079] S41. Add 10g of amoxicillin powder to 100g of purified water, then add 20% hydrochloric acid to dissolve the amoxicillin, filter to obtain an amoxicillin solution with a mass percentage concentration of 10% and a pH value of 0.90.

[0080] S42. Take 100 mL of a 10% amoxicillin solution, add 50 mL of ethanol at 25-30℃ at a flow rate of 3 mL / min, and add ammonia at a flow rate of 1 mL / min. Adjust the pH of the resulting solution to 1.4-1.6 to obtain the amoxicillin crystallization solution.

[0081] Then, the temperature was lowered at a rate of 1℃ / min to 10-15℃, and 50mL of ethanol was added at the same rate as above. The ammonia was also added at the same rate as above. Crystallization occurred at pH 2.86. After crystallization for 30min, ammonia was added to adjust the pH to 4.8-5.0. Crystallization was continued for 1.5h, and amoxicillin wet powder was obtained by filtration.

[0082] S43. Amoxicillin wet powder was dried at 45℃ for 2 hours to obtain amoxicillin D.

[0083] S44. The Malvern particle size D10, D50, and D90 of amoxicillin D were determined, and the results are shown in Table 1 below. At the same time, the purity and yield of amoxicillin D were determined, and the results are also listed in Table 1.

[0084] The crystal pattern of amoxicillin D obtained under a microscope is shown below. Figure 5 As shown.

[0085] Comparative Example 1: Preparation of Amoxicillin E by Traditional Isoelectric Point Crystallization Process

[0086] 100 mL of the amoxicillin solution from Example 4 was taken, and the pH was adjusted to 5.00 with ammonia at room temperature. Crystallization was carried out for 1.5 h, and the amoxicillin wet powder was obtained by filtration. The amoxicillin wet powder was dried at 45 °C for 2 h to obtain amoxicillin E. The Malvern particle size D10, D50, and D90 of amoxicillin E were determined, and the results are shown in Table 1 below. At the same time, the purity and yield of amoxicillin E were determined, and the results are also listed in Table 1.

[0087] The crystal pattern of amoxicillin E obtained under a microscope is as follows: Figure 6 As shown.

[0088] Comparative Example 2: Preparation of Amoxicillin F by Solvent Crystallization Process

[0089] Take 100 mL of the amoxicillin solution from Example 4, add 100 mL of ethanol at 25-30 °C at a flow rate of 3 mL / min, add ammonia at a flow rate of 1 mL / min, crystallize at pH 2.86, and continue adding ammonia to adjust the pH to 4.8-5.0 after 30 min of crystal growth, and continue crystal growth for 1.5 h. Filter to obtain amoxicillin wet powder; dry the amoxicillin wet powder at 45 °C for 2 h to obtain amoxicillin F.

[0090] The Malvern particle sizes D10, D50, and D90 of amoxicillin F were determined, and the results are shown in Table 1 below. At the same time, the purity and yield of amoxicillin F were determined, and the results are also listed in Table 1.

[0091] The crystal pattern of amoxicillin F obtained under a microscope is as follows: Figure 7 As shown.

[0092] Comparative Example 3: Preparation of Amoxicillin G using a Cooling Crystallization Process

[0093] Take 100 mL of the amoxicillin solution from Example 4, add ammonia water at 25-30℃ at a flow rate of 1 mL / min, and adjust the pH of the resulting solution to 1.4-1.6; then cool down at a rate of 1℃ / min to 10-15℃, and continue adding ammonia water at the same flow rate as above. Crystallization occurs at pH = 2.86. After crystallization for 30 min, continue adding ammonia water to adjust the pH to 4.8-5.0, and crystallize for 1.5 h. Filter to obtain amoxicillin wet powder; dry the amoxicillin wet powder at 45℃ for 2 h to obtain amoxicillin G.

[0094] The Malvern particle sizes D10, D50, and D90 of amoxicillin G were determined, and the results are shown in Table 1 below. At the same time, the purity and yield of amoxicillin G were determined, and the results are also listed in Table 1.

[0095] The crystal form of amoxicillin G obtained under a microscope is shown below. Figure 8 As shown.

[0096] Table 1. Malvern particle size (D10, D50, D90), purity, and yield of amoxicillin (A, B, C, D, E)

[0097] Amoxicillin D10(μm) D50(μm) D90(μm) content yield A 21.66 70.93 153.96 99％ 91％ B 18.40 58.27 153.52 98.4％ 90.3％ C 15.36 64.55 143.29 98.4％ 90％ D 14.52 43.41 98.65 98.1％ 89％ E 2.980 7.503 17.668 98％ 88％ F 5.39 32.3 66.5 98％ 88.9％ G 5.24 13.3 51.4 98％ 88.2％

[0098] Will Figures 2-5 The crystal patterns of amoxicillin A to D obtained in Examples 1 to 4 shown are, in contrast to... Figure 6 A comparison of the crystal patterns of amoxicillin E obtained by the conventional isoelectric point crystallization process in Comparative Example 1 shows that the crystal forms of amoxicillin A-D obtained in Examples 1-4 are significantly larger and more regular, while the amoxicillin obtained by the conventional isoelectric point crystallization process is mostly powdery or needle-like and amorphous. Combining the particle size comparison of the amoxicillin crystals obtained by the examples and comparative examples shown in Table 1, it can be seen that compared with amoxicillin E obtained by the conventional isoelectric point crystallization process, the amoxicillin crystals A-D obtained by the method provided in this embodiment have larger, more stable, and more regular particle sizes. Moreover, by controlling the flow rate of the solvent and ammonia, crystals of different particle sizes can be obtained; the slower the flow rate of the solvent and ammonia, the larger the crystals obtained. Figure 2 and Figure 3 , Figure 4 and Figure 5 Furthermore, the yield and purity of amoxicillin crystals obtained using the method described in this embodiment are higher than those obtained using traditional isoelectric point crystallization processes.

[0099] Will Figures 2-5 The crystal patterns of amoxicillin A to D obtained in Examples 1 to 4 shown are, in contrast to... Figure 7 Comparative Example 2 shows that only the solvent crystallization process was used to prepare amoxicillin F. Figure 8 As shown in Comparative Example 3, which only uses the cooling crystallization process to prepare amoxicillin G, the crystal forms of amoxicillin A-D obtained in Examples 1-4 are significantly larger and more regular. Combining the particle size comparison of the amoxicillin crystals obtained in the examples and comparative examples shown in Table 1, it can be seen that the increase in particle size of amoxicillin crystals A-D obtained by the method provided in this embodiment compared to amoxicillin E prepared by the conventional isoelectric point crystallization process is significantly greater than the simple sum of the increase in particle size of amoxicillin F crystals prepared by the solvent crystallization process alone and amoxicillin G crystals prepared by the cooling crystallization process alone. Furthermore, the yield and purity of amoxicillin crystals obtained by the method described in this embodiment are higher than those obtained by the solvent crystallization process alone and the solvent crystallization process alone.

[0100] As can be seen from the above embodiments and corresponding analysis results, the coupled crystallization method for preparing large amoxicillin crystals provided by the embodiments of the present invention controls and slows down the growth rate of amoxicillin crystals through a coupled and synergistic process of solvent and cooling crystallization, avoiding the phenomenon of explosive nucleation during the crystallization process of amoxicillin. Simultaneously, it alters the morphology of the obtained amoxicillin crystals, resulting in larger, more stable, and more regular crystal particles compared to traditional methods. Furthermore, by controlling the flow rate of the solvent and ammonia, crystals of different particle sizes can be obtained.

[0101] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims and their equivalents, this invention is also intended to include these modifications and variations. The above embodiments or implementations are merely illustrative examples of this invention, and it can also be implemented in other specific ways or forms without departing from its gist or essential characteristics. Therefore, the described embodiments should be considered illustrative rather than limiting in any respect. The scope of this invention should be defined by the appended claims, and any changes equivalent to the intent and scope of the claims should also be included within the scope of this invention.

Claims

1. A process for preparing large amoxicillin crystals using a coupled crystallization method, characterized in that, The method includes the following steps: S1. Preparation of amoxicillin solution: Add amoxicillin powder to purified water, then add hydrochloric acid to dissolve the amoxicillin, and filter to obtain the amoxicillin solution; S2. Preparation of amoxicillin crystallization solution: Add a solvent and ammonia water to the amoxicillin solution by feeding in a continuous feed manner, and adjust the pH of the resulting solution to 1.4-1.6 to obtain the amoxicillin crystallization solution; then slowly cool to 10-15℃, and continue to add solvent and ammonia water by feeding in a continuous feed manner until crystals precipitate. Then, continue to add ammonia water until the pH reaches 4.8-5.0 to obtain the amoxicillin crystallization solution. S3. Preparation of amoxicillin large crystals: The amoxicillin crystallization solution is sequentially filtered, washed and dried to obtain amoxicillin large crystals.

2. The process for preparing large amoxicillin crystals by coupled crystallization according to claim 1, characterized in that, In step S1, the mass percentage concentration of the amoxicillin solution is 10-15%.

3. The process for preparing large amoxicillin crystals by coupled crystallization according to claim 1, characterized in that, In step S2, the solvent is selected from one of ethanol, acetone, and methanol.

4. The process for preparing large amoxicillin crystals by coupled crystallization according to claim 1, characterized in that, In step S2, at 25–30°C, a solvent and ammonia are added to the filtered amoxicillin solution by feeding, and the pH of the resulting solution is adjusted to 1.4–1.6 to obtain the amoxicillin crystallization solution.

5. The process for preparing large amoxicillin crystals by coupled crystallization according to claim 1, characterized in that, In step S2, the mass percentage concentration of the ammonia water is 7% to 8%.

6. The process for preparing large amoxicillin crystals by coupled crystallization according to claim 1, characterized in that, In step S2, before the cooling operation, the amount of precipitant added is 50% of the volume of the amoxicillin solution after filtration, the flow rate of the precipitant is 1-3 mL / min, and the flow rate of ammonia is 0.2-1 mL / min.

7. The process for preparing large amoxicillin crystals by coupled crystallization according to claim 1, characterized in that, In step S2, after the cooling operation begins, the amount of solvent added is 50% of the volume of the filtered amoxicillin solution, the flow rate of the solvent is 1-3 mL / min, and the flow rate of ammonia is 0.2-1 mL / min.

8. The process for preparing large amoxicillin crystals by coupled crystallization according to claim 1, characterized in that, In step S2, the cooling rate is 0.5–2 °C / min.

9. The process for preparing large amoxicillin crystals by coupled crystallization according to claim 1, characterized in that, In step S2, after crystals precipitate, the crystals are cultured for 30–40 minutes.

10. The process for preparing large amoxicillin crystals by coupled crystallization according to claim 1, characterized in that, In step S2, ammonia water is added until the pH reaches 4.8-5.0, and crystal growth continues for 1.5-2 hours to obtain amoxicillin crystal solution.

11. A process for preparing large amoxicillin crystals by coupled crystallization according to any one of claims 1-10, characterized in that, In step S3, the amoxicillin crystallization solution is filtered and washed to obtain amoxicillin wet powder, and the amoxicillin wet powder is dried at 45-50℃ for 2-2.5h to obtain amoxicillin large crystals.

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