Crystallization process of small-particle-size azithromycin fumarate with low solvent residue

Abstract

The invention belongs to the technical field of medicine crystallization processes, and particularly relates to a crystallization process of small-particle-size azithromycin fumarate with low solvent residue. In the prior art, azithromycin fumarate is crystallized in an alcohol solvent, which is often accompanied by the residue of an ethanol reagent. The invention provides a crystallization process of azithromycin fumarate, which comprises the following steps: feeding part of fumaric acid into azithromycin, adding an azithromycin fumarate seed crystal, carrying out ultrasonic induced crystallization, continuing feeding fumaric acid, and carrying out vacuum concentration for constant-temperature crystal growing. According to the azithromycin fumarate crystal prepared by the method, the particle size distribution range is 15-30 microns, the ethanol residue is also reduced to 0.5% or below, and the azithromycin fumarate crystal can be directly used for preparation processing, does not need to be purified again, and is a raw material medicine product with high quality and good economic benefits.

Description

Technical Field

[0001] This invention belongs to the field of drug crystallization technology, specifically relating to a crystallization process for small-particle-size azithromycin fumarate with low solvent residue. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Azithromycin fumarate (chemical formula C) 42 H 76 N2O 16 It is a macrolide antibiotic with a broader antibacterial spectrum than erythromycin. It has broad-spectrum antibacterial activity against aerobic Gram-positive bacteria, Gram-negative cocci, anaerobic bacteria, as well as pathogenic bacteria such as Legionella, Campylobacter, Chlamydia, and Mycoplasma, and its antibacterial activity is also stronger than that of erythromycin.

[0004] Azithromycin fumarate is a prodrug of azithromycin. In practical applications, a significant drawback of azithromycin has been identified—it is almost insoluble in water. This characteristic directly leads to its low bioavailability, only about 37%. This significant drug waste not only increases the economic cost of clinical treatment but also creates a greater environmental burden. To address this issue, Chinese patents CN101412740B and CN1810253A proposed improvements through salt formation, significantly enhancing the water solubility and stability of azithromycin, thereby improving its bioavailability. Azithromycin fumarate, with its superior performance, has gained market recognition, and Jinzhou Jiutai Pharmaceutical and Dezhou Deyao Pharmaceutical have obtained marketing approvals for capsules and dispersible tablets, respectively. Furthermore, Dezhou Deyao has also patented a specific crystal form of azithromycin fumarate and its preparation method through patent CN119060109A.

[0005] The preparation of azithromycin fumarate is mainly achieved through the reaction of the free base of azithromycin with fumaric acid. Given that azithromycin fumarate has relatively low solubility in alcohol solvents, such solvents can achieve higher yields; at the same time, considering drug safety, production costs and environmental requirements, ethanol is generally considered to be the most ideal solvent system for this product.

[0006] Conventional crystallization processes often struggle to effectively control ethanol residue in azithromycin fumarate. Even with thorough vacuum drying, solvent residue is difficult to reduce below 0.5%. Currently, the common solution adopted by companies is to first prepare large-particle crystals to reduce the problem of ethanol solvent inclusion due to agglomeration, and then process them into small-particle raw materials required by pharmaceutical manufacturers through mechanical pulverization. However, this process has many drawbacks: it is not only cumbersome, inefficient, and costly, but also results in significant material loss, severe dust pollution, and poor reproducibility of particle size distribution between different batches. Summary of the Invention

[0007] In view of the current research status, this invention proposes a production process for azithromycin fumarate with small particle size and low ethanol solvent residue, which is of great significance for improving the industrial production efficiency of this drug formulation. To solve the aforementioned technical problems, this invention designs a process using fumaric acid and azithromycin as raw materials. The process involves flowing a fumaric acid solution into an azithromycin solution for reaction and crystallization. Combining seed crystals with ultrasound-induced crystallization and using flow acceleration to control the crystal growth process, a production process for azithromycin fumarate with low ethanol residue, controllable particle size, and uniform distribution is ultimately constructed.

[0008] Based on the above-mentioned technical achievements, the present invention provides the following technical solution: In a first aspect, the present invention provides a crystallization process for small-particle-size azithromycin fumarate with low solvent residue, comprising the following steps: S1: Add the ethanol solution of fumaric acid to the ethanol solution of azithromycin at a uniform rate, and stop when the molar ratio of fumaric acid to azithromycin is 1:2~3; add fumaric acid-azithromycin seed crystals, introduce ultrasonic waves to induce crystallization for a period of time, and then stop. The reaction temperature is controlled at 20~30℃ during the above stages. S2: Continue adding an ethanol solution of fumaric acid until the molar ratio of fumaric acid to azithromycin in the system reaches 0.9~1.1:1. Heat and concentrate under reduced pressure until the total liquid-solid ratio in the reaction system is 2~3:1. Maintain constant temperature for crystal growth, filter and dry to obtain the above-mentioned small-particle azithromycin fumaric acid.

[0009] In step S1 above, there is a preferred embodiment as follows: The fumaric acid ethanol solution is an anhydrous ethanol solution of fumaric acid. To prepare it, fumaric acid is added to anhydrous ethanol at a dosage ratio of 1g:8~12mL, stirred and dissolved at 60~70℃ for 25~35 minutes, filtered to remove insoluble matter, and then set aside.

[0010] The azithromycin ethanol solution is an anhydrous azithromycin ethanol solution. To prepare it, azithromycin is added to anhydrous ethanol at a dosage ratio of 1g:2~4mL, stirred and dissolved at 40~60℃ for 25~35min, and the insoluble matter is removed by filtration to obtain the azithromycin solution. Then, the solution is cooled to 20~30℃ for later use.

[0011] In the above operation, the ethanol solution of fumaric acid was fed at a rate of 3.5~6 mL / h. During the feeding process, the reaction system was continuously stirred and the reaction temperature was controlled within the range of 20~30℃.

[0012] The preferred particle size Dv(90) of the above-mentioned azithromycin fumarate seed crystals is 10~15 μm. The seed crystals are preferably pharmaceutical grade, and there are no specific limitations on the synthesis process, water content, or other indicators. They can be obtained by micronizing commercially available products. The amount of seed crystals added is 0.05%~0.1% of the initial azithromycin mass.

[0013] The frequency of the ultrasound is 20~45 KHz, and the time for ultrasound-induced crystallization is 1~2 hours.

[0014] In step S2 above, the following preferred embodiments are available: During the continued addition of the remaining fumaric acid ethanol solution, a flow rate of 2-5 mL / h is effective. Excessive flow rate can also lead to a significant increase in the particle size of azithromycin fumarate.

[0015] The temperature of the reaction system was raised to 40-50 °C, and then concentrated under reduced pressure at a vacuum of -0.09 to -0.07 MPa. The concentrated reaction system was kept at 40-50 °C and stirred for 1.5-2.5 h. Then the temperature of the reaction system was reduced to 10 °C at a controlled rate of 2-4 h.

[0016] In the above-mentioned filtration and drying process, the filtration step is preferably carried out under conditions of isolation from water vapor, and the filtered wet product is vacuum dried at 70~80℃ and a vacuum degree of -0.09~-0.07 MPa for 6~9 hours.

[0017] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention first provides a low-solvent-residue, small-particle-size azithromycin fumarate crystallization process. This process uses fumaric acid and azithromycin as raw materials to achieve two technical objectives: the preparation of azithromycin fumarate and the acquisition of its crystal form. The above crystallization process does not require high temperature and pressure, the reaction raw materials are highly safe, and no toxic reagents are needed. For raw material manufacturers, it offers advantages such as cost-effectiveness, simple process, and ease of industrial production.

[0018] 2. Crystallization in ethanol solvent is a common practice in the field. However, azithromycin fumarate prepared by this method often leaves ethanol residue. While ethanol on the crystal surface can be removed by evaporation or adsorption, ethanol trapped inside the crystal particles is often difficult to remove, requiring further pulverization to remove the residual ethanol solvent. This invention provides a small-particle-size azithromycin fumarate that effectively reduces the residual ethanol space, making it easier to remove during vacuum drying. The ethanol residue in the product is as low as 0.5%, solving the problem of controlling ethanol residue in azithromycin fumarate.

[0019] 3. The particle size Dv(90) of azithromycin fumarate prepared by the process of the present invention is 15~30 μm, and the particle size distribution is normal. Such small-diameter crystals are easier to distribute evenly during the mixing process, reducing the risk of separation of drug components in the formulation. At the same time, it can improve the flowability and tableting performance of granules and can be directly used for formulation processing. Attached Figure Description

[0020] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0021] Figure 1 This is a laser particle size distribution diagram of azithromycin fumarate in Example 1; Figure 2 This is a microscopic image of the morphology of azithromycin fumarate in Example 1; Figure 3 This is the gas chromatographic spectrum of azithromycin fumarate in Example 1. Detailed Implementation

[0022] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0023] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0024] In the context of this specification, the word "including" is considered to mean "particularly including". It should not be interpreted as "consisting of only".

[0025] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0026] Example 1 In this embodiment, a crystallization process for small-particle-size azithromycin fumarate with low solvent residue is provided, comprising the following steps: (1) Add 10 g of azithromycin to 20 mL of anhydrous ethanol, stir and dissolve at 60 °C for 30 min, filter out insoluble matter and mechanical impurities, and then cool to 30 °C.

[0027] (2) Dissolve 1.55 g of fumaric acid in 15 mL of anhydrous ethanol, stir at 65 °C for 30 min, and filter out insoluble matter and mechanical impurities.

[0028] (3) Add 5 mL of the fumaric acid solution from step (2) to the azithromycin solution at a constant rate over 1 h, while stirring continuously and keeping the temperature at 30 °C.

[0029] (4) After the addition is complete, keep stirring, add 0.01 g of seed crystals, and turn on the ultrasonic wave at a frequency of 30 kHz for 2 h.

[0030] (5) Add the remaining fumaric acid solution to the azithromycin solution at a constant rate over 4 hours.

[0031] (6) Heat the system to 50 °C, then concentrate it to 20 mL under vacuum of -0.07 MPa, and then stir at a constant temperature for 2 h.

[0032] (7) Cool the system to 10 °C at a constant rate within 3 h.

[0033] (8) Filter under nitrogen protection and dry the wet product under vacuum at 80 °C and -0.09 MPa for 8 h to obtain the product.

[0034] The product yield was 87.3%, and its laser particle size distribution was as follows: Figure 1 As shown, Dv(90) is 18.055 μm, and the ethanol residue was 0.087% as determined by gas chromatography.

[0035] Example 2 In this embodiment, another crystallization process for small-particle-size azithromycin fumarate with low solvent residue is provided, comprising the following steps: (1) Add 10 g of azithromycin to 25 mL of anhydrous ethanol, stir and dissolve at 55 °C for 30 min, filter out insoluble matter and mechanical impurities, and then cool down to 20 °C.

[0036] (2) Dissolve 1.55 g of fumaric acid in 12.5 mL of anhydrous ethanol, stir at 70 °C for 30 min, and filter out insoluble matter and mechanical impurities.

[0037] (3) Add 6 mL of the fumaric acid solution from step (2) to the azithromycin solution at a constant rate over 1 h, while stirring continuously and keeping warm at 20 °C.

[0038] (4) After the addition is completed, keep stirring, add 0.01 g of seed crystals, and turn on the ultrasonic wave at a frequency of 20 kHz for 2 h.

[0039] (5) Add the remaining fumaric acid solution to the azithromycin solution at a constant rate over 3 hours.

[0040] (6) Heat the system to 40 °C, then concentrate it to 25 mL under vacuum of -0.08 MPa, and then stir at constant temperature for 1 h.

[0041] (7) Cool the system to 10 °C at a constant rate within 2 h.

[0042] (8) Filter under nitrogen protection and dry the wet product under vacuum at 75 °C and -0.08 MPa for 8 h to obtain the product.

[0043] The product yield was 86.0%, the Dv(90) was 22.313 μm, and the ethanol residue was 0.158% as determined by gas chromatography.

[0044] Example 3 In this embodiment, another crystallization process for small-particle-size azithromycin fumarate with low solvent residue is provided, comprising the following steps: (1) Add 10 g of azithromycin to 40 mL of anhydrous ethanol, stir and dissolve at 40 °C for 30 min, filter out insoluble matter and mechanical impurities, and then cool to 25 °C.

[0045] (2) Dissolve 1.55 g of fumaric acid in 18.5 mL of anhydrous ethanol, stir at 60 °C for 30 min, and filter out insoluble matter and mechanical impurities.

[0046] (3) Add 6 mL of the fumaric acid solution from step (2) to the azithromycin solution at a constant rate over 1 h, while stirring continuously and keeping the temperature at 25 °C.

[0047] (4) After the addition is complete, keep stirring, add 0.005 g of seed crystals, and turn on the ultrasonic wave at a frequency of 45 kHz for 2 h.

[0048] (5) Add the remaining fumaric acid solution to the azithromycin solution at a constant rate over 4 hours.

[0049] (6) Heat the system to 45 °C, then concentrate it to 20 mL under vacuum of -0.09 MPa, and then stir at a constant temperature for 2 h.

[0050] (7) Cool the system to 10 °C at a constant rate within 3 h.

[0051] (8) Filter under nitrogen protection and dry the wet product under vacuum at 70 °C and -0.09 MPa for 8 h to obtain the product.

[0052] The product yield was 88.5%, the Dv(90) was 29.166 μm, and the ethanol residue was 0.23% as determined by gas chromatography.

[0053] Example 4 In this embodiment, another crystallization process for small-particle-size azithromycin fumarate with low solvent residue is provided, comprising the following steps: (1) Add 10 g of azithromycin to 30 mL of anhydrous ethanol, stir and dissolve at 45 °C for 30 min, filter out insoluble matter and mechanical impurities, and then cool to 30 °C.

[0054] (2) Dissolve 1.55 g of fumaric acid in 15 mL of anhydrous ethanol, stir at 65 °C for 30 min, and filter out insoluble matter and mechanical impurities.

[0055] (3) Add 7 mL of the fumaric acid solution from step (2) to the azithromycin solution at a constant rate over 2 h, while stirring continuously and keeping the temperature at 30 °C.

[0056] (4) After the addition is complete, keep stirring, add 0.01 g of seed crystals, and turn on the ultrasonic wave at a frequency of 35 kHz for 2 h.

[0057] (5) Add the remaining fumaric acid solution to the azithromycin solution at a constant rate over 2 hours.

[0058] (6) Heat the system to 40 °C, then concentrate it to 30 mL under vacuum of -0.08 MPa, and then stir at constant temperature for 2 h.

[0059] (7) Cool the system to 10 °C at a constant rate within 3 h.

[0060] (8) Filter under nitrogen protection and dry the wet product under vacuum at 75 °C and -0.09 MPa for 6 h to obtain the product.

[0061] The product yield was 85.8%, and its laser particle size distribution diagram is as follows: Figure 2 As shown, Dv(90) is 16.128 μm, and the ethanol residue was 0.123% as determined by gas chromatography.

[0062] Example 5 In this embodiment, another crystallization process for small-particle-size azithromycin fumarate with low solvent residue is provided, comprising the following steps: (1) Add 10 g of azithromycin to 30 mL of anhydrous ethanol, stir and dissolve at 50 °C for 30 min, filter out insoluble matter and mechanical impurities, and then cool to 25 °C.

[0063] (2) Dissolve 1.55 g of fumaric acid in 14 mL of anhydrous ethanol, stir at 70 °C for 30 min, and filter out insoluble matter and mechanical impurities.

[0064] (3) Add 7 mL of the fumaric acid solution from step (2) to the azithromycin solution at a constant rate over 2 h, stirring continuously and keeping the temperature at 25 °C.

[0065] (4) After the addition is completed, keep stirring, add 0.005 g of seed crystals, and turn on the ultrasonic wave at a frequency of 40 kHz for 1 h.

[0066] (5) Add the remaining fumaric acid solution to the azithromycin solution at a constant rate over 3 hours.

[0067] (6) Heat the system to 50 °C, then concentrate it to 20 mL under vacuum of -0.08 MPa, and then stir at a constant temperature for 2 h.

[0068] (7) Cool the system to 10 °C at a constant rate within 3 h.

[0069] (8) Filter under nitrogen protection and dry the wet product under vacuum at 80 °C and -0.08 MPa for 8 h to obtain the product.

[0070] The product yield was 88.1%, the Dv(90) was 19.237 μm, and the ethanol residue was 0.156% as determined by gas chromatography.

[0071] Example 6 In this embodiment, another crystallization process for small-particle-size azithromycin fumarate with low solvent residue is provided, comprising the following steps: (1) Add 10 g of azithromycin to 40 mL of anhydrous ethanol, stir and dissolve at 40 °C for 30 min, filter out insoluble matter and mechanical impurities, and then cool down to 20 °C.

[0072] (2) Dissolve 1.55 g of fumaric acid in 16 mL of anhydrous ethanol, stir at 65 °C for 30 min, and filter out insoluble matter and mechanical impurities.

[0073] (3) Add 6 mL of the fumaric acid solution from step (2) to the azithromycin solution at a constant rate over 2 h, stirring continuously and keeping warm at 20 °C.

[0074] (4) After the addition is complete, keep stirring, add 0.005 g of seed crystals, and turn on the ultrasonic wave at a frequency of 25 kHz for 2 h.

[0075] (5) Add the remaining fumaric acid solution to the azithromycin solution at a constant rate over 2 hours.

[0076] (6) Heat the system to 50 °C, then concentrate it to 25 mL under vacuum of -0.07 MPa, and then stir at constant temperature for 2 h.

[0077] (7) Cool the system to 10 °C at a constant rate within 2 h.

[0078] (8) Filter under nitrogen protection and dry the wet product under vacuum at 75 °C and -0.08 MPa for 8 h to obtain the product.

[0079] The product yield was 86.9%, the Dv(90) was 25.545 μm, and the ethanol residue was 0.099% as determined by gas chromatography.

[0080] Example 7 In this embodiment, another crystallization process for small-particle-size azithromycin fumarate with low solvent residue is provided, comprising the following steps: (1) Add 10 g of azithromycin to 25 mL of anhydrous ethanol, stir and dissolve at 55 °C for 30 min, filter out insoluble matter and mechanical impurities, and then cool down to 20 °C.

[0081] (2) Dissolve 1.55 g of fumaric acid in 17.5 mL of anhydrous ethanol, stir at 60 °C for 30 min, and filter out insoluble matter and mechanical impurities.

[0082] (3) Add 6 mL of the fumaric acid solution from step (2) to the azithromycin solution at a constant rate over 1 h, while stirring continuously and keeping warm at 20 °C.

[0083] (4) After the addition is complete, keep stirring, add 0.01 g of seed crystals, and turn on the ultrasonic wave at a frequency of 30 kHz for 2 h.

[0084] (5) Add the remaining fumaric acid solution to the azithromycin solution at a constant rate over 3 hours.

[0085] (6) Heat the system to 40 °C, then concentrate it to 25 mL under vacuum of -0.09 MPa, and then stir at constant temperature for 2 h.

[0086] (7) Cool the system to 10 °C at a constant rate within 3 h.

[0087] (8) Filter under nitrogen protection and dry the wet product under vacuum at 70 °C and -0.09 MPa for 8 h to obtain the product.

[0088] The product yield was 87.3%, the Dv(90) was 28.396 μm, and the ethanol residue was 0.112% as determined by gas chromatography.

[0089] Comparative Example 1 In this embodiment, a small-particle-size azithromycin fumarate crystallization process is provided, which differs from Example 1 in that: ultrasonic operation is not used in step (4). The specific steps are as follows: after the addition is completed, keep stirring, add 0.005 g of seed crystals, and continue stirring for 1 h. The remaining settings are the same as in Example 1.

[0090] The product yield was 84.7%, the Dv(90) was 109.440 μm, and the ethanol residue was 1.45% as determined by gas chromatography.

[0091] Comparative Example 2 In this embodiment, a small-particle-size azithromycin fumarate crystallization process is provided, which differs from Example 1 in that: the specific steps of step (3) are as follows: 10 mL of the fumarate solution in step (2) is added to the azithromycin solution at a uniform rate within 2 h, and the mixture is continuously stirred and kept at 25°C.

[0092] In this embodiment, the initial dosage of fumaric acid was doubled compared to Example 1, while the other settings were the same as in Example 1. The product yield was 86.6%, the Dv(90) was 94.543 μm, and the ethanol residue was 0.99% as determined by gas chromatography.

[0093] Comparative Example 3 In this embodiment, a small-particle-size azithromycin fumarate crystallization process is provided, which differs from Example 1 in that the specific steps of step (5) are as follows: the remaining fumaric acid solution is added to the azithromycin solution at a uniform rate over 30 min. In this embodiment, the dropping rate of the fumaric acid solution is 8 times that of Example 1.

[0094] The product yield was 85.1%, the Dv(90) was 110.277 μm, and the ethanol residue was 0.93% as determined by gas chromatography.

[0095] Comparative Example 4 Azithromycin fumarate was obtained according to the preparation method in Example 4 of patent CN119060109. The ethanol residue of the sample was 1.71% and the Dv(90) was 93.346 μm as determined by gas chromatography.

[0096] The azithromycin fumarate products obtained in Examples 1-7 above have an ethanol residue distribution of 0.087-0.23%, which effectively reduces ethanol solvent residue and improves the quality of azithromycin fumarate raw materials compared with the prior art method (Comparative Example 4).

[0097] Comparing the examples and comparative examples, the results show that the azithromycin fumarate prepared by the method of the present invention has significant advantages in terms of ethanol residue and particle size. The research of this invention indicates that ultrasound has a crucial effect on reducing the particle size of azithromycin fumarate; in addition, the ratio of fumaric acid to azithromycin and the dosing rate also have a significant impact on the morphology of azithromycin fumarate.

[0098] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A crystallization process for small-particle-size azithromycin fumarate with low solvent residue, characterized in that, Includes the following steps: S1: Add the ethanol solution of fumaric acid to the ethanol solution of azithromycin at a uniform rate, and stop when the molar ratio of fumaric acid to azithromycin is 1:2~3; add fumaric acid-azithromycin seed crystals, introduce ultrasonic waves to induce crystallization for a period of time, and then stop. The reaction temperature is controlled at 20~30℃ during the above stages. S2: Continue adding an ethanol solution of fumaric acid until the molar ratio of fumaric acid to azithromycin in the system reaches 0.9~1.1:

1. Heat and concentrate under reduced pressure until the total liquid-solid ratio in the reaction system is 2~3:

1. Maintain constant temperature for crystal growth, filter and dry to obtain the above-mentioned small-particle azithromycin fumaric acid.

2. The low solvent residue, small particle size azithromycin fumarate crystallization process as described in claim 1, characterized in that, In step S1: The fumaric acid ethanol solution is an anhydrous ethanol solution of fumaric acid. To prepare it, fumaric acid is added to anhydrous ethanol at a dosage ratio of 1g:8~12mL, stirred and dissolved at 60~70℃ for 25~35 minutes, filtered to remove insoluble matter, and then set aside.

3. The low solvent residue, small particle size azithromycin fumarate crystallization process as described in claim 1, is characterized in that... In step S1: The azithromycin ethanol solution is an anhydrous azithromycin ethanol solution. To prepare it, azithromycin is added to anhydrous ethanol at a dosage ratio of 1g:2~4mL, stirred and dissolved at 40~60℃ for 25~35min, and the insoluble matter is removed by filtration to obtain the azithromycin solution. Then, the solution is cooled to 20~30℃ for later use.

4. The low solvent residue, small particle size azithromycin fumarate crystallization process as described in claim 1, characterized in that, In step S1: the ethanol solution of fumaric acid is fed at a rate of 3.5~6 mL / h. During the feeding process, the reaction system is continuously stirred and the reaction temperature is controlled within the range of 20~30℃.

5. The low solvent residue, small particle size azithromycin fumarate crystallization process as described in claim 1, characterized in that, In step S1: the particle size Dv(90) of the azithromycin fumarate seed crystals is 10~15 μm; the amount of seed crystals added is 0.05%~0.1%.

6. The low solvent residue, small particle size azithromycin fumarate crystallization process as described in claim 1, characterized in that, In step S1: the frequency of the ultrasound is 20~45 KHz, and the time for ultrasound-induced crystallization is 1~2 hours.

7. The low solvent residue, small particle size azithromycin fumarate crystallization process as described in claim 1, characterized in that, In step S2: During the continued addition of the remaining fumaric acid ethanol solution, the addition rate is 2~5 mL / h.

8. The low solvent residue, small particle size azithromycin fumarate crystallization process as described in claim 1, characterized in that, In step S2: the temperature of the reaction system is raised to 40~50 ℃, and the concentration is carried out under reduced pressure under vacuum conditions of -0.09~-0.07 MPa; the concentrated reaction system is kept at 40~50 ℃ and stirred at a constant temperature for 1.5~2.5h, and then the temperature of the reaction system is reduced to 10℃ by controlling the rate within the range of 2~4h.

9. The low solvent residue, small particle size azithromycin fumarate crystallization process as described in claim 1, characterized in that, In step S2: During the filtration and drying process, the filtration step is carried out under the condition of isolating water vapor, and the wet product obtained by filtration is vacuum dried at 70~80℃ and vacuum degree of -0.09~-0.07 MPa for 6~9 hours.

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