A novel hygroscopic crystalline form B of azithromycin fumarate and its preparation method

Abstract

This invention belongs to the technical field of azithromycin fumarate crystal form compounds, specifically relating to a novel hygroscopic azithromycin fumarate crystal form B with low hygroscopicity and its preparation method. Azithromycin fumarate itself has strong hygroscopicity, and improper storage will affect medication safety. To address the shortcomings of existing technologies, this invention provides a novel hygroscopic azithromycin fumarate crystal form B with low hygroscopicity and its preparation method. Using crude azithromycin fumarate as a raw material, it is dissolved in an alcohol solution and then subjected to ultrasonic induction and pressure treatment to form the novel crystal form B. Verification has shown that the novel crystal form B has lower hygroscopicity and higher temperature stability compared to existing crystal forms. Its preparation method has the advantages of being simple, reproducible, and easy for industrial production.

Description

Technical Field

[0001] This invention belongs to the technical field of azithromycin fumarate crystal form compounds, specifically relating to a novel azithromycin fumarate crystal form B with low hygroscopicity and its preparation method. 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 (CAS: 910239-90-6) is a salt compound formed from azithromycin and fumaric acid, belonging to the macrolide antibiotic class. Its chemical name is 9-deoxy-9α-aza-9α-methyl-9α-erythromycin A fumarate, and its chemical formula is C2. 42 H 76 N2O 16 Its chemical structure is as follows:

[0004]

[0005] As an improved salt-forming product, azithromycin fumarate specifically addresses the problems of poor solubility and low bioavailability of the original azithromycin. Related Chinese patents (CN101412740, CN1810253) both focus on the salt-forming improvement technology of azithromycin, providing theoretical support for the performance optimization of this drug. Azithromycin fumarate has gained widespread market recognition due to its outstanding advantages, and dosage forms such as capsules and dispersible tablets have been marketed.

[0006] However, since azithromycin fumarate itself has strong hygroscopicity, its moisture stability is not only directly related to the safety of the medicine, but also has a significant impact on the difficulty and cost control of transportation, storage and downstream formulation processing. Therefore, hygroscopicity has become a key technical indicator for measuring the performance of this product.

[0007] It is well known that the polymorphism of drug molecules significantly affects the physicochemical properties of active pharmaceutical ingredients (APIs). For azithromycin fumarate, the crystal form also has a significant impact on its hygroscopicity and stability. Currently, several crystal forms of azithromycin fumarate are known: Dezhou Deyao has protected a specific crystal form of azithromycin fumarate and its preparation method through patent CN119060109. This crystal form does not provide corresponding thermal analysis characterization, but based on the solvent selected in its technical solution, it is considered to be an anhydrous form. Liu Li disclosed the monohydrate, 2-hydrate, and pentahydrate of azithromycin fumarate in patent CN101412740. Experimental results show that the hydrate of azithromycin fumarate has significant advantages over the anhydrous form in terms of hygroscopicity and stability. However, even the pentahydrate, which has the best stability, is still not ideal; under accelerated experimental conditions, related substances still increase by 1.4 times, and the hygroscopic weight gain reaches 1.2%.

[0008] Extensive research has revealed that the preparation method described in this invention can yield azithromycin fumarate crystal form B, which exhibits significantly lower hygroscopicity and higher stability than existing products. These characteristics are more conducive to ensuring the safety and batch-to-batch consistency of azithromycin fumarate formulations, and are significantly more beneficial for the processing, storage, and transportation of downstream pharmaceutical preparations. Furthermore, this preparation method is simple to operate, has good reproducibility, high yield, high production efficiency, and uses an environmentally friendly solvent system, making it suitable for scale-up production. Summary of the Invention

[0009] In view of the shortcomings of existing azithromycin fumarate in terms of stability and hygroscopicity, the present invention first provides a new crystal form B of azithromycin fumarate, which has significantly reduced hygroscopicity compared to the existing crystal form, while also having good high-temperature stability.

[0010] In a first aspect, the present invention provides a novel crystalline form B of azithromycin fumarate with low hygroscopicity, wherein the novel crystalline form B is a hydrate of azithromycin fumarate, and its Cu-Kα radiation XRD diffraction pattern is within 2... θ Characteristic peaks are observed at 4.25±0.2°, 7.21±0.2°, 7.64±0.2°, 8.40±0.2°, 8.92±0.2°, 9.92±0.2°, 11.98±0.2°, 12.56±0.2°, 14.04±0.2°, 15.54±0.2°, 16.86±0.2°, 17.95±0.2°, and 19.31±0.2°.

[0011] According to the thermogravimetric analysis results, the crystal structure of the new crystal form B of azithromycin fumarate contains 2.5 water molecules of crystallization.

[0012] It is well known in the field of crystallography that, for any given crystal form, the angular peak position may vary slightly due to factors such as sample preparation conditions, sample displacement, and the presence of an internal standard. In this invention, the variability of the angular peak position is ±0.2° in 2θ. Furthermore, the relative peak intensity of a given crystal form may vary due to differences in crystallite size and non-random crystallite orientation during sample preparation for XRD analysis. It is well known in the art that this variability can account for the above factors without hindering the definitive identification of the crystal form.

[0013] In some specific embodiments, the X-ray powder diffraction (XRD) is obtained from a copper radiation source (Cu-Kα) operating at 40V / 15mA with a scan rate of 10 ° / min. The resulting powder diffraction characteristics are shown in the table below:

[0014]

[0015] In a second aspect, the present invention provides a method for preparing the new crystal form B of azithromycin fumarate described in the first aspect, comprising the following steps:

[0016] S1: Add crude azithromycin fumarate and alcohol solution into a crystallizer, heat and stir to dissolve and reach equilibrium, filter while hot, and keep the filtrate warm.

[0017] S2: After cooling, turn on ultrasonic induction to induce crystallization. After stopping the ultrasonication, pressurize to 10~80 MPa and stir for a period of time.

[0018] S3: The solution obtained in S2 is concentrated under reduced pressure until the volume ratio of the solution to the crude azithromycin fumarate is 0.8~1.2mL:1g, then filtered and dried to obtain the final product.

[0019] The above S1 includes the following preferred embodiments:

[0020] The crude azithromycin fumarate described above has a chemical purity of ≥98%. In addition to meeting the purity requirements, it can be pharmaceutical grade, pharmaceutical intermediate grade, research grade or industrial grade, with pharmaceutical grade, pharmaceutical intermediate grade or research grade being preferred. Furthermore, the crude product can be any crystalline or amorphous form of azithromycin fumarate.

[0021] The aforementioned alcohol solution is an aqueous solution of a lower-carbon alcohol with a volume fraction of 97% or higher. Further examples of the volume fraction of the alcohol solution include 97%, 97.5%, 98%, 98.5%, 99%, and 99.5%. The lower-carbon alcohol is an alcohol reagent with four or fewer carbon atoms, including straight-chain alcohols and branched-chain alcohols. Specific examples are selected from one or more combinations of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.

[0022] The dosage ratio of the crude product to the alcohol solution is 1g:2~10mL; specifically, it is 1g:2mL, 1g:4mL, 1g:6mL, 1g:8mL or 1g:10mL.

[0023] The heating and stirring temperature is 50~65 ℃, and stirring is carried out continuously for 25~35 minutes until dissolution equilibrium is reached. In the hot filtration step, the solution system temperature is maintained at 50~65 ℃ for filtration, and the filtrate is kept warm after collection to prevent premature spontaneous precipitation caused by cooling.

[0024] The above S2 includes the following preferred embodiments:

[0025] The filtrate obtained from S1 is cooled to 30-40 °C and maintained at this temperature during the sonication process. The sonication frequency is 20-40 kHz. After crystals precipitate, sonication continues, and crystals are cultured at a constant temperature for 1-2 hours.

[0026] After stopping the ultrasound, maintain the temperature at 30-40 °C, increase the system pressure to 10-80 MPa, and continue stirring for 1-2 h. To achieve the above temperature and pressure conditions, in one embodiment verified by this invention, step S2 is placed in a sealed high-pressure reactor, gas is introduced, and mechanical hydraulic pressure is used to increase the pressure and maintain the temperature.

[0027] The above-mentioned S3 includes the following preferred embodiments:

[0028] Maintain the reaction temperature at 30~40 ℃, reduce the pressure to a vacuum of -0.05~-0.07 MPa for concentration, concentrate to the above dosage ratio, and continue stirring at a constant temperature for 1~2 h; filter, wash the filter cake and dry to obtain the final product.

[0029] Compared with the prior art, the beneficial effects of the present invention are:

[0030] 1. The present invention first provides a new crystal form B of azithromycin fumarate. According to thermogravimetric analysis, its crystal cell structure contains 2.5 molecules of water of crystallization. This structure helps to improve the solubility of azithromycin on the one hand, and also helps to improve the stability of azithromycin raw materials on the other hand. According to the results of hygroscopicity studies, the above-mentioned new crystal form B is less prone to moisture absorption and degeneration during storage compared with existing crystal forms.

[0031] Furthermore, the aforementioned novel crystalline form B exhibits excellent high-temperature stability. Its chemical properties remain largely unchanged after long-term storage at 40°C, and it melts upon heating to 80°C, yet its chemical structure remains unchanged. Based on this high-temperature stability, the novel crystalline form B provided by this invention can meet the formulation processing requirements under various operating conditions.

[0032] 2. The present invention also provides a method for preparing the above-mentioned new crystal form B, which uses crude azithromycin fumarate as raw material, dissolves it in an alcohol solution, and then induces crystallization by ultrasound and concentrates it under pressure to re-precipitate crystals. The method has the advantages of simple process, good reproducibility, and easy industrial scale-up production. Attached Figure Description

[0033] 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.

[0034] Figure 1 The X-ray powder diffraction pattern of azithromycin fumarate crystal form B described in Example 1;

[0035] Figure 2 Thermogravimetric analysis of azithromycin fumarate crystal form B as described in Example 1;

[0036] Figure 3 Differential scanning calorimetry (DSC) of azithromycin fumarate crystal form B as described in Example 1;

[0037] Figure 4 This is a micrograph of azithromycin fumarate crystal form B as described in Example 1;

[0038] Figure 5 The image shows the X-ray powder diffraction pattern of azithromycin fumarate described in Comparative Example 1. Detailed Implementation

[0039] 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.

[0040] 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.

[0041] In the context of this specification, the word "including" is considered to mean "particularly including". It should not be interpreted as "consisting of only".

[0042] 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.

[0043] Example 1

[0044] In this embodiment, a novel crystalline form B of azithromycin fumarate is provided, and the preparation method of the novel crystalline form B is as follows:

[0045] (1) Add 10 g of crude azithromycin fumarate and 20 mL of 99.5% methanol to a crystallizer, heat to 60 °C and stir to dissolve for 30 min;

[0046] (2) Filter while hot, collect the filtrate and keep it at 60 ℃;

[0047] (3) Cool the system to 35 °C, then turn on the ultrasonic induction crystallization at a frequency of 35 KHz. After crystals precipitate, continue to stir under ultrasonic constant temperature for 2 h.

[0048] (4) Stop the ultrasound, maintain 35 ℃, increase the system pressure to 50 MPa, and continue stirring for 2 h;

[0049] (5) Maintain 35 °C and concentrate the system to 10 mL under a vacuum of -0.07 MPa, and continue stirring for 1 h;

[0050] (6) Filter, rinse the filter cake with an appropriate amount of methanol, and dry the wet product under vacuum at 40 °C for 8 h.

[0051] The obtained product, as determined by XRD, was a novel crystalline form B of azithromycin fumarate, with a yield of 83.5%. Using Cu-Kα radiation at a scan rate of 10 ° / min, the novel crystalline form B exhibited the following characteristics: Figure 1 The XRD diffraction patterns shown are illustrated in Table 1 below.

[0052] Table 1. XRD diffraction characteristic peak information of the new crystal form B

[0053]

[0054] The thermogravimetric results of the above-mentioned new crystal form B of azithromycin fumarate are as follows: Figure 2 As shown, the crystal form B exhibits a step-like weight change at around 100°C, indicating that crystal form B contains 2.5 water molecules of crystallization.

[0055] according to Figure 3 The differential scanning calorimetry (DSC) curve shows that the new crystal form B exhibits two endothermic peaks at 80°C and 140°C, losing 2 water molecules at 80°C and 0.5 water molecules at 140°C. Furthermore, the absorption peak heights are essentially consistent, indicating that the composition of the new crystal form B remains unchanged after melting and dehydration.

[0056] Example 2

[0057] In this embodiment, another method for preparing the new crystal form B of azithromycin fumarate described in Example 1 is provided, and the specific steps are as follows:

[0058] (1) Add 10 g of crude azithromycin fumarate and 40 mL of 97% ethanol to a crystallizer, heat to 50 °C and stir to dissolve for 30 min.

[0059] (2) Filter while hot and keep the filtrate at 50 ℃.

[0060] (3) Cool the system to 30 °C, then turn on the ultrasonic induction crystallization at a frequency of 40 KHz. After crystals precipitate, continue to stir under constant temperature for 1 h under ultrasonication.

[0061] (4) Stop the ultrasound, maintain 30 ℃, increase the system pressure to 80 MPa, and continue stirring for 2 h.

[0062] (5) Keep at 30 °C and concentrate the system to 8 mL under a vacuum of -0.06 Mpa, and continue stirring for 2 h.

[0063] (6) Filter the filter cake with an appropriate amount of anhydrous ethanol and dry the wet product under vacuum at 40 °C for 8 h.

[0064] The obtained product was identified by XRD as a new crystal form B of azithromycin fumarate, with a yield of 85.2%.

[0065] Example 3

[0066] In this embodiment, another method for preparing the new crystal form B of azithromycin fumarate described in Example 1 is provided, and the specific steps are as follows:

[0067] (1) Add 10 g of crude azithromycin fumarate and 50 mL of 99% ethanol to a crystallizer, heat to 65 °C and stir to dissolve for 30 min.

[0068] (2) Filter while hot and collect the filtrate and keep it at 65 ℃.

[0069] (3) Cool the system to 30 °C, then turn on the ultrasonic induction crystallization at a frequency of 30 KHz. After crystals precipitate, continue to stir under constant temperature for 2 h under ultrasonication.

[0070] (4) Stop the ultrasound, maintain 30 ℃, increase the system pressure to 40 MPa, and continue stirring for 2 h.

[0071] (5) Keep at 30 °C and concentrate the system to 10 mL under a vacuum of -0.05 MPa, and continue stirring for 2 h.

[0072] (6) Filter the filter cake with an appropriate amount of anhydrous ethanol and dry the wet product under vacuum at 40 °C for 8 h.

[0073] The obtained product was identified by XRD as a new crystal form B of azithromycin fumarate, with a yield of 85.5%.

[0074] Example 4

[0075] In this embodiment, another method for preparing the new crystal form B of azithromycin fumarate described in Example 1 is provided, and the specific steps are as follows:

[0076] (1) Add 10 g of crude azithromycin fumarate and 70 mL of 98% isopropanol to a crystallizer, heat to 60 °C and stir to dissolve for 30 min.

[0077] (2) Filter while hot and keep the filtrate at 60 ℃.

[0078] (3) Cool the system to 35 °C, then turn on the ultrasonic induction crystallization at a frequency of 20 KHz. After crystals precipitate, continue to stir under constant temperature for 2 h under ultrasonication.

[0079] (4) Stop the ultrasound, maintain 35 ℃, increase the system pressure to 10 MPa, and continue stirring for 2 h.

[0080] (5) Keep at 35 °C and concentrate the system to 9 mL under a vacuum of -0.06 Mpa, and continue stirring for 1 h.

[0081] (6) Filter the filter cake with an appropriate amount of isopropanol and dry the wet product under vacuum at 40 °C for 8 h.

[0082] The obtained product was identified by XRD as a new crystal form B of azithromycin fumarate, with a yield of 86.1%.

[0083] Example 5

[0084] In this embodiment, another method for preparing the new crystal form B of azithromycin fumarate described in Example 1 is provided, and the specific steps are as follows:

[0085] (1) Add 10 g of crude azithromycin fumarate and 60 mL of 97.5% n-propanol to a crystallizer, heat to 55 °C and stir to dissolve for 30 min.

[0086] (2) Filter while hot and collect the filtrate and keep it at 55 ℃.

[0087] (3) Cool the system to 40 °C, then turn on the ultrasonic induction crystallization at a frequency of 25 KHz. After crystals precipitate, continue to stir under constant temperature for 1 h under ultrasonication.

[0088] (4) Stop the ultrasound, maintain 35 ℃, increase the system pressure to 50 MPa, and continue stirring for 1 h.

[0089] (5) Keep at 35 °C and concentrate the system to 12 mL under a vacuum of -0.07 Mpa, and continue stirring for 2 h.

[0090] (6) Filter the filter cake with an appropriate amount of n-propanol and dry the wet product under vacuum at 40 °C for 8 h.

[0091] The obtained product was identified by XRD as a new crystal form B of azithromycin fumarate, with a yield of 86.0%.

[0092] Example 6

[0093] In this embodiment, another method for preparing the new crystal form B of azithromycin fumarate described in Example 1 is provided, and the specific steps are as follows:

[0094] (1) Add 10 g of crude azithromycin fumarate and 80 mL of 97% n-butanol to a crystallizer, heat to 65 °C and stir to dissolve for 30 min.

[0095] (2) Filter while hot and collect the filtrate and keep it at 65 ℃.

[0096] (3) Cool the system to 40 °C, then turn on the ultrasonic induction crystallization at a frequency of 30 KHz. After crystals precipitate, continue to stir under ultrasonic constant temperature for 2 h.

[0097] (4) Stop the ultrasound, maintain 40 ℃, increase the system pressure to 30 MPa, and continue stirring for 1 h.

[0098] (5) Keep at 35 °C and concentrate the system to 12 mL under a vacuum of -0.06 Mpa, and continue stirring for 2 h.

[0099] (6) Filter the filter cake with an appropriate amount of n-butanol and dry the wet product under vacuum at 40 °C for 8 h.

[0100] The obtained product was identified by XRD as a new crystal form B of azithromycin fumarate, with a yield of 85.3%.

[0101] Example 7

[0102] In this embodiment, another method for preparing the new crystal form B of azithromycin fumarate described in Example 1 is provided, and the specific steps are as follows:

[0103] (1) Add 10 g of crude azithromycin fumarate and 100 mL of 97% tert-butanol to a crystallizer, heat to 60 °C and stir to dissolve for 30 min.

[0104] (2) Filter while hot and keep the filtrate at 60 ℃.

[0105] (3) Cool the system to 35 °C, then turn on the ultrasonic induction crystallization at a frequency of 35 KHz. After crystals precipitate, continue to stir under ultrasonic constant temperature for 2 h.

[0106] (4) Stop the ultrasound, maintain 35 ℃, increase the system pressure to 20 MPa, and continue stirring for 2 h.

[0107] (5) Keep at 35 °C and concentrate the system to 10 mL under a vacuum of -0.05 MPa, and continue stirring for 1 h.

[0108] (6) Filter, rinse the filter cake with an appropriate amount of methanol, and dry the wet product under vacuum at 40 °C for 8 h.

[0109] The obtained product was identified by XRD as a new crystal form B of azithromycin fumarate, with a yield of 85.9%.

[0110] Comparative Example 1

[0111] This embodiment provides a method for preparing the crystal form of azithromycin fumarate. The difference from Example 1 is that step (3) does not use ultrasonic induction. The specific operation is as follows: cool the system to 30 °C, then continue stirring. After crystals precipitate, continue stirring for 1 h. The rest of the settings are the same as in Example 1.

[0112] The XRD diffraction results of the obtained product are as follows Figure 5 As shown, the crystal form is consistent with that disclosed in patent CN119060109, with a yield of 76.5%.

[0113] Comparative Example 2

[0114] This embodiment provides a method for preparing the crystal form of azithromycin fumarate. The difference from Example 1 is that high-pressure treatment is not used in step (4). The specific operation is as follows: stop sonication, maintain 30 °C, concentrate the system to 8 mL under a vacuum of -0.06 MPa, and continue stirring for 2 h. The remaining settings are the same as in Example 1. The resulting product, as determined by XRD, has a crystal form consistent with that disclosed in patent CN119060109, with a yield of 80.7%.

[0115] Comparative Example 3

[0116] This embodiment provides a method for preparing the crystal form of azithromycin fumarate. The difference from Example 1 is that vacuum concentration is not used in step (5). The specific steps are as follows: filtration; washing the filter cake with an appropriate amount of anhydrous ethanol; and vacuum drying the wet product at 40 °C for 8 h. The remaining settings are the same as in Example 1. The obtained product was XRD-detected as the new crystal form B of azithromycin fumarate, with a yield of 60.1%.

[0117] Comparing the results of Example 1 with those of Comparative Examples 1-2, ultrasonication and high-pressure growth play a crucial role in obtaining crystal form B; the aforementioned new crystal form B cannot be obtained without either ultrasonication or high pressure. Vacuum concentration is also significant for improving product yield.

[0118] Comparative Example 4

[0119] Azithromycin fumarate was obtained by referring to the preparation method in Example 1 of patent CN 119060109, and TGA showed no weight loss.

[0120] Performance testing

[0121] 1. Hygroscopicity test

[0122] Following the method described in patent CN101412740, the samples prepared in the above examples and comparative examples were exposed in a constant temperature and humidity chamber at 40 ℃ and 75% humidity for 2 days. The results are as follows:

[0123] Table 2. Hygroscopicity test results of azithromycin fumarate in the examples and comparative examples.

[0124]

[0125] Hygroscopicity test results show that the azithromycin fumarate crystal form B described in this invention has a significant advantage in hygroscopicity compared to existing crystal forms. This not only effectively ensures the safety and batch-to-batch consistency of azithromycin fumarate preparations, but also benefits the downstream pharmaceutical preparations in processing, storage and transportation.

[0126] 2. Stability test

[0127] Following the methods outlined in the Stability Guidelines for Active Pharmaceutical Ingredients (APIs) of the 2025 edition of the Chinese Pharmacopoeia (9001), samples were sealed in vials and subjected to accelerated testing at 40°C to assess their chemical stability. Samples were taken on days 0, 5, 10, and 30 of the experiment, and their chemical purity was determined using HPLC. The results are as follows:

[0128] Table 3. Results of crystal form stability tests for azithromycin fumarate in the examples and comparative examples.

[0129]

[0130] Chemical stability test results show that the azithromycin fumarate crystal form B obtained in the embodiments of the present invention has higher chemical stability under high temperature accelerated test conditions, and has a greater stability advantage compared with products processed by other methods.

[0131] 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 novel crystalline form B of azithromycin fumarate with low hygroscopicity, characterized in that, The novel crystalline form B is a hydrate of azithromycin fumarate, and its Cu-Kα radiation XRD diffraction pattern is in the range of 2. θ Characteristic peaks are observed at 4.25±0.2°, 7.21±0.2°, 7.64±0.2°, 8.40±0.2°, 8.92±0.2°, 9.92±0.2°, 11.98±0.2°, 12.56±0.2°, 14.04±0.2°, 15.54±0.2°, 16.86±0.2°, 17.95±0.2°, and 19.31±0.2°.

2. The novel crystalline form B of azithromycin fumarate with low hygroscopicity as described in claim 1, characterized in that, The novel crystal form B of azithromycin fumarate contains 2.5 water molecules of crystallization in its crystal structure.

3. The novel crystalline form B of azithromycin fumarate with low hygroscopicity as described in claim 1, characterized in that, The XRD diffraction was obtained from a copper radiation source operating at 40V / 15mA at a scan rate of 10 ° / min.

4. The method for preparing the new crystal form B of azithromycin fumarate according to any one of claims 1-3, characterized in that, Includes the following steps: S1: Add crude azithromycin fumarate and alcohol solution into a crystallizer, heat and stir to dissolve and reach equilibrium, filter while hot, and keep the filtrate warm. S2: After cooling, turn on ultrasonic induction to induce crystallization. After stopping the ultrasonication, pressurize to 10~80 MPa and stir for a period of time. S3: The solution obtained in S2 is concentrated under reduced pressure until the volume ratio of the solution to the crude azithromycin fumarate is 0.8~1.2mL:1g, then filtered and dried to obtain the final product.

5. The method for preparing the new crystal form B of azithromycin fumarate as described in claim 4, characterized in that, In S1, the crude azithromycin fumarate has a chemical purity of ≥98% and is either crystalline or amorphous azithromycin fumarate.

6. The method for preparing the new crystal form B of azithromycin fumarate as described in claim 4, characterized in that, In S1, the alcohol solution is an aqueous solution of a low-carbon alcohol with a volume fraction of 97% or higher; The lower alcohol is selected from one or a combination of several of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.

7. The method for preparing the new crystal form B of azithromycin fumarate as described in claim 4, characterized in that, In S1, the dosage ratio of the crude product to the alcohol solution is 1g:2~10mL.

8. The method for preparing the new crystal form B of azithromycin fumarate as described in claim 4, characterized in that, In S1, the temperature for heating and stirring is 50~65 ℃, and stirring is carried out continuously for 25~35 min until dissolution equilibrium is reached; In the hot filtration step, the solution system temperature is maintained at 50~65 ℃ for filtration, and the filtrate is kept warm after collection.

9. The method for preparing the new crystal form B of azithromycin fumarate as described in claim 4, characterized in that, In S2, the filtrate obtained in S1 is cooled to 30-40 ℃ and the temperature of the filtrate is maintained during the ultrasonic process; the frequency of the ultrasonication is 20-40 KHz, and ultrasonication is continued after crystals precipitate, and crystals are grown at a constant temperature for 1-2 h. After stopping the ultrasound, maintain the temperature at 30-40 ℃, increase the system pressure to 10-80 MPa, and continue stirring for 1-2 h.

10. The method for preparing the new crystal form B of azithromycin fumarate as described in claim 4, characterized in that, In S3, the reaction temperature is maintained at 30~40 ℃, and the pressure is reduced to a vacuum degree of -0.05~-0.07 MPa for concentration. After concentration to the stated dosage ratio, the mixture is stirred at a constant temperature for 1~2 h. The mixture is then filtered, the filter cake is washed and dried to obtain the final product.

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