A low-impurity cefozopran sodium crystal form and a preparation method thereof

Abstract

The application provides a low-impurity cefozopran sodium crystal form and a preparation method thereof, and belongs to the technical field of drug crystallization. The crystal form has specific X-ray powder diffraction characteristic peaks and thermal analysis characteristics, and the total impurity content is less than or equal to 0.5%. In the preparation, the cefozopran sodium solution is arranged in the pipe passage of the membrane module, and the anti-solvent is arranged in the shell passage; two-way diffusion is driven by the concentration difference on both sides of the membrane; local supersaturation is formed in the membrane holes to crystallize; the crystal nucleus is separated from the membrane holes by focused ultrasonic waves; and the crystal is obtained through the steps of nucleation, washing and drying. The application can realize efficient impurity removal and crystal form control simultaneously in the crystallization process through the cooperation of membrane hole limited crystallization, reverse diffusion mass transfer and ultrasonic waves, has high yield, is simple to operate, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug crystallization technology, and particularly relates to a low-impurity cefazolin sodium crystal form and its preparation method. Background Technology

[0002] Cefazolin sodium is a first-generation cephalosporin antibiotic, widely used clinically for respiratory tract infections, genitourinary tract infections, skin and soft tissue infections caused by susceptible bacteria, and for perioperative prophylaxis. Cefazolin sodium can react with water molecules to form various crystal forms, including the reported α-form (containing 5 molecules of water of crystallization), β-form (containing 3 / 2 molecules of water of crystallization), and γ-form (containing 1 molecule of crystalline ethanol). In addition, researchers have obtained other crystalline modifiers and amorphous products under different crystallization conditions. Regarding preparation methods, current techniques mainly employ solvent crystallization, where an antisolvent (such as ethanol or isopropanol) is added dropwise to a cefazolin sodium solution to induce crystallization. Some researchers have also used cooling crystallization or coupled crystallization processes to prepare the α-form cefazolin sodium. In recent years, there have been reports of combining supercritical fluid extraction technology with traditional crystallization techniques for the recrystallization of cefazolin sodium. Regarding impurity control, polymer impurities have always been an important aspect of the quality control of cephalosporin antibiotics. Researchers have used column-switching liquid chromatography-high-resolution mass spectrometry to analyze polymer impurities in cefazolin sodium.

[0003] However, the aforementioned existing technologies still have the following shortcomings. First, in conventional solvent crystallization, the antisolvent is directly added dropwise to the bulk solution. The mass transfer interface is limited by the macroscopic mixing scale, resulting in uneven distribution of local supersaturation, which easily leads to explosive nucleation and crystal agglomeration. Impurity molecules are easily captured by the crystal lattice or adsorbed onto the crystal surface during crystal growth, making them difficult to remove effectively. Although technologies such as supercritical fluid extraction can achieve a certain degree of impurity separation, their equipment is complex and the operating conditions are harsh, limiting their industrial application. Second, existing crystallization methods have limited control over crystal form, and inconsistent crystal forms can easily occur between different batches of products, affecting the quality controllability of the formulation. Third, polymer impurities and macromolecular degradation products are difficult to remove through simple solid-liquid separation in conventional crystallization processes. Additional purification steps (such as column chromatography adsorption) are usually required before crystallization, increasing process complexity and production costs. Fourth, the yields of existing crystallization methods are generally low, with wide crystal particle size distributions and significant agglomeration, affecting the subsequent processing performance of the product. Therefore, developing a novel crystallization technology that can simultaneously achieve efficient impurity removal, precise crystal control, and simple operation during the crystallization process is of great significance for improving the product quality of cefazolin sodium. Summary of the Invention

[0004] In order to overcome the above-mentioned defects of the prior art, the present invention provides a low-impurity cefazolin sodium crystal form and its preparation method, which solves the problems of impurity eutectic / adsorption, large batch-to-batch differences in crystal form, difficulty in removing polymer impurities, low yield and wide particle size distribution in conventional solvent crystallization in the prior art.

[0005] To achieve the above objectives, the present invention provides the following technical solution: A low-impurity cefazolin sodium crystal form exhibits characteristic peaks in its X-ray powder diffraction pattern measured using Cu-Kα rays at diffraction angles 2θ of 6.8°±0.2°, 11.5°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 19.5°±0.2°, 21.8°±0.2°, 24.1°±0.2°, and 27.3°±0.2°. The X-ray powder diffraction pattern of this crystal form is substantially as follows: Figure 1 As shown; the differential scanning calorimetry curve of the crystal form has an endothermic peak in the range of 180℃ to 195℃, and the weight loss in thermogravimetric analysis is less than or equal to 1.5%.

[0006] Preferably, the crystal form belongs to the orthorhombic crystal system, with space group P212121, and cell parameters a=11.24ű0.05Å, b=14.87ű0.05Å, c=18.56ű0.05Å, α=β=γ=90°.

[0007] Preferably, the average particle size of the crystals is 5 μm to 30 μm, and the particle size distribution span is less than 1.5; when detected by high performance liquid chromatography, the total impurity content is less than or equal to 0.5%, and the single largest unknown impurity is less than or equal to 0.1%.

[0008] Preferably, a method for preparing low-impurity cefazolin sodium crystal form includes the following steps: Step 1: Add cefazolin sodium to a solvent to prepare a cefazolin sodium solution; Step 2: Place the cefazolin sodium solution in the tube side of the membrane module and place the antisolvent in the shell side of the membrane module. The membrane pore size of the membrane module is 50 nm to 200 nm. Utilize the concentration difference across the membrane to drive the antisolvent to diffuse from the shell side through the membrane pores to the tube side, and the solvent to diffuse from the tube side through the membrane pores to the shell side, forming local supersaturation inside the membrane pores. Crystallize at a temperature of 0°C to 25°C for 30 to 120 minutes. Step 3: Turn on the focused ultrasonic device and align the focus of the focused ultrasonic device with the interface between the membrane surface of the membrane module and the bulk solution. Output ultrasonic waves in a pulse manner to cause the crystal nuclei formed in the membrane pores to detach from the membrane pores and enter the shell side. Step 4: Grow the crystal slurry in the shell at 0°C to 10°C for 1 to 4 hours; Step 5: Filter, wash with anti-solvent, and dry to obtain the low-impurity cefazolin sodium crystal form.

[0009] Preferably, the solvent in step one is a mixed solvent composed of an alcohol with 2 to 4 carbon atoms and water, wherein the volume ratio of the alcohol to water is 1:1 to 3:1; and the concentration of the cefazolin sodium solution is 0.1 g / mL to 0.5 g / mL.

[0010] Preferably, the membrane module in step two is a polymer hollow fiber membrane module or a flat sheet membrane module, wherein the polymer is selected from at least one of polytetrafluoroethylene, polyvinylidene fluoride, and polyethersulfone; the membrane pore size of the membrane module is 100 nm; the membrane surface of the membrane module is modified with a hydrophilic-hydrophobic gradient, with the tube side being hydrophilic and the shell side being hydrophobic.

[0011] Preferably, the antisolvent in step two is an alcohol with 2 to 4 carbon atoms; the volume ratio of the antisolvent to the solvent in step one is 2:1 to 6:1.

[0012] Preferably, the ultrasonic frequency of the focused ultrasonic device in step three is 20kHz to 80kHz, the power density is 0.5W / cm² to 5W / cm², and the pulse duty cycle is 30% to 70%; the pulse mode is to output ultrasonic waves for 1 to 10 minutes each time, then stop for 2 to 5 minutes, and repeat this cycle 3 to 10 times.

[0013] Preferably, the temperature of the antisolvent in step five is 0°C to 10°C, and the number of washing cycles is 2 to 3; the drying is vacuum drying at a temperature of 30°C to 50°C for 4 to 8 hours.

[0014] Preferably, an auxiliary ultrasonic wave with a frequency of 20 kHz is applied during the crystal growth process described in step four.

[0015] The technical effects and advantages of the low-impurity cefazolin sodium crystal form and its preparation method of this invention are as follows: 1. The cefazolin sodium crystal form provided by this invention, characterized by combined X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis, is a novel crystal form different from existing α, β, γ, and amorphous crystal forms. This crystal form has low total impurity content, low content of a single largest unknown impurity, and uniform crystal size distribution. When used as a pharmaceutical active ingredient, it is beneficial to improve the quality controllability and storage stability of the formulation.

[0016] 2. This invention employs a triple-mechanism synergistic impurity removal system. The membrane pore size exclusion effect intercepts polymer impurities and macromolecular degradation products; the steric hindrance effect of membrane pore-confined crystallization prevents impurities from entering the crystal lattice; and the cavitation effect of focused ultrasound strips away trace impurities adsorbed on the crystal surface. This triple mechanism provides multi-stage impurity interception throughout the entire process from nucleation and growth to separation, achieving a low-impurity crystal form without the need for additional impurity removers.

[0017] 3. The present invention offers strong controllability of crystal form. The membrane pores provide a highly uniform microenvironment for crystal growth, avoiding the mixed crystal phenomenon caused by uneven concentration gradients in traditional large-scale crystallization; the controllable intervention of ultrasound enables precise triggering of nucleation, avoiding uncontrollable burst nucleation and ensuring the stable acquisition of the target crystal form.

[0018] 4. The product yield of this invention is high. The continuous operation mode of the membrane module and the self-cleaning effect of ultrasound on the membrane pores enable the crystallization process to operate stably and sustainably, effectively reducing crystal adhesion losses on the vessel wall and membrane surface.

[0019] 5. This invention has wide applicability. The target crystal form can be stably obtained under different membrane materials, different alcohol solvent systems, and different ultrasonic parameters, proving that this method is highly tolerant to batch differences in raw materials and process fluctuations, and is easy to scale up industrially.

[0020] 6. This invention is green and environmentally friendly. The antisolvent can be recycled and reused, the consumption of organic solvent is low, and the entire crystallization process does not require the addition of crystal form control agents or surfactants, thus avoiding the risk of introducing new impurities. Attached Figure Description

[0021] Figure 1 This is a schematic diagram of the process flow for the preparation method of low-impurity cefazolin sodium crystal form according to the present invention; Figure 2 This is a schematic diagram illustrating the synergistic effect of the membrane module and the focused ultrasonic device of the present invention. Figure 3 This is a schematic diagram of the X-ray powder diffraction characteristic peak positions of the low-impurity cefazolin sodium crystal form of the present invention. Detailed Implementation

[0022] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all 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.

[0023] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include," "contain," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase "includes..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes the element.

[0024] refer to Figure 1-3This invention provides a low-impurity cefazolin sodium crystal form and its preparation method. The X-ray powder diffraction pattern of this crystal form, measured using Cu-Kα rays, exhibits characteristic peaks at diffraction angles 2θ of 6.8°±0.2°, 11.5°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 19.5°±0.2°, 21.8°±0.2°, 24.1°±0.2°, and 27.3°±0.2°. The differential scanning calorimetry curve shows an endothermic peak in the range of 180℃ to 195℃. The thermogravimetric analysis shows a weight loss of less than or equal to 1.5%. This crystal form belongs to the orthorhombic crystal system. The space group is P212121, the cell parameters are a = 11.24 Å ± 0.05 Å, b = 14.87 Å ± 0.05 Å, c = 18.56 Å ± 0.05 Å, α = β = γ = 90°, the average crystal size is 5 μm to 30 μm, the particle size distribution span is less than 1.5, the total impurity content is less than or equal to 0.5%, and the largest single unknown impurity is less than or equal to 0.1%. The preparation method for this crystal form includes: adding cefazolin sodium to a mixed solvent of alcohol and water with 2 to 4 carbon atoms to prepare a solution with a concentration of 0.1 g / mL to 0.5 g / mL; placing the resulting solution in a membrane module... In the membrane module, an alcohol with 2 to 4 carbon atoms is placed as the antisolvent in the tube side and in the shell side. The membrane pore size of the module is 50 nm to 200 nm, and the membrane surface is modified with a hydrophilic-hydrophobic gradient, with the tube side being hydrophilic and the shell side being hydrophobic. The volume ratio of antisolvent to solvent is 2:1 to 6:1. At 0°C to 25°C, the concentration difference across the membrane drives the antisolvent to diffuse from the shell side through the membrane pores to the tube side, and the solvent to diffuse from the tube side through the membrane pores to the shell side. Local supersaturation is formed inside the membrane pores, and crystallization occurs for 30 to 120 minutes. Then, a focused ultrasonic device is turned on, and its focus is aligned with the membrane surface of the membrane module and the main... At the interface of the bulk solution, ultrasonic waves with a frequency of 20kHz to 80kHz, a power density of 0.5W / cm² to 5W / cm², and a pulse duty cycle of 30% to 70% are output in a pulsed manner. Each output lasts for 1 to 10 minutes, followed by a 2 to 5 minute pause, and is repeated 3 to 10 times. This causes the crystal nuclei formed in the membrane pores to detach from the membrane pores and enter the shell side. Subsequently, the crystal slurry in the shell side is cultured at 0°C to 10°C for 1 to 4 hours. After filtration, the crystals are washed 2 to 3 times with an anti-solvent at 0°C to 10°C, and then vacuum dried at 30°C to 50°C for 4 to 8 hours to obtain the low-impurity cefazolin sodium crystal form.

[0025] Example 1 Purpose of implementation: The product quality and yield of cefazolin sodium crystal form prepared by this method were verified using a polytetrafluoroethylene hollow fiber membrane module, a water-ethanol solvent system, anhydrous ethanol as an antisolvent, and 40kHz focused ultrasound.

[0026] Implementation System: A polytetrafluoroethylene (PTFE) hollow fiber membrane module with a pore size of 100 nm is used. The membrane surface is modified with a hydrophilic-hydrophobic gradient, with the tube-side being hydrophilic and the shell-side being hydrophobic. A focused ultrasonic device operates at a frequency of 40 kHz, a power density of 2 W / cm², and a pulse duty cycle of 50%. A jacketed temperature control system maintains a crystallization temperature of 10°C and a growth temperature of 5°C. The circulation and delivery system includes a peristaltic pump, a storage tank, piping, and valves.

[0027] Implementation steps: Step 1: Preparation of cefazolin sodium solution. Add 20g of cefazolin sodium to 80mL of a water-ethanol mixed solvent, with a water to ethanol volume ratio of 2:1. Stir and dissolve at 30℃ and a stirring speed of 300r / min to prepare a cefazolin sodium solution with a concentration of 0.25g / mL. Filter the solution through a 0.22μm microporous membrane.

[0028] Step 2: Reverse diffusion crystallization. The cefazolin sodium solution obtained in Step 1 is placed in the tube side of the membrane module, and anhydrous ethanol is placed in the shell side of the membrane module as the antisolvent. The volume ratio of the antisolvent to the solvent in Step 1 is 3:1. The system temperature is controlled at 10°C. The concentration difference across the membrane drives the anhydrous ethanol to diffuse from the shell side through the membrane pores to the tube side, and the water-ethanol solvent to diffuse from the tube side through the membrane pores to the shell side, forming local supersaturation inside the membrane pores. Crystallization takes 60 minutes.

[0029] Step 3: Focused Ultrasonic Treatment. Turn on the focused ultrasonic device and align its focal point with the interface between the membrane surface of the membrane module and the bulk solution. Output ultrasonic waves in pulse mode. The ultrasonic frequency is 40kHz, the power density is 2W / cm², and the pulse duty cycle is 50%. Each ultrasonic output lasts 5 minutes, followed by a 3-minute pause, and this cycle is repeated 5 times.

[0030] Step 4: Crystal growth. The crystal slurry in the shell is grown at 5°C for 2 hours.

[0031] Step 5: Separation, washing, and drying. Filter the crystal slurry after crystal growth. Wash the filter cake three times with anhydrous ethanol at 5°C. Vacuum dry the washed filter cake at 40°C for 6 hours to obtain 18.2g of low-impurity cefazolin sodium crystal product.

[0032] Implementation results: The yield of cefazolin sodium crystalline product was 91.0%. X-ray powder diffraction patterns showed characteristic peaks at diffraction angles 2θ of 6.8°, 11.5°, 13.9°, 16.2°, 19.5°, 21.8°, 24.1°, and 27.3°. Differential scanning calorimetry (DSC) showed an endothermic peak at 185℃. Thermogravimetric analysis showed a weight loss of 1.2%. High-performance liquid chromatography (HPLC) analysis revealed a total impurity content of 0.38% and a single largest unknown impurity of 0.06%. The average crystal size was 18 μm, and the particle size distribution span was 1.2.

[0033] Example 2 Purpose of implementation: The product quality and yield of cefazolin sodium crystal form prepared by this method were verified using polyvinylidene fluoride hollow fiber membrane module, water-isopropanol solvent system, isopropanol antisolvent, and 60kHz focused ultrasound.

[0034] Implementation System: A polyvinylidene fluoride hollow fiber membrane module with a pore size of 150 nm is used. The membrane surface is modified with a hydrophilic-hydrophobic gradient, with the tube-side being hydrophilic and the shell-side being hydrophobic. A focused ultrasonic device operates at a frequency of 60 kHz, a power density of 3 W / cm², and a pulse duty cycle of 60%. A jacketed temperature control system maintains a crystallization temperature of 15°C and a growth temperature of 8°C. The circulation and delivery system includes a peristaltic pump, a storage tank, piping, and valves.

[0035] Implementation steps: Step 1: Preparation of cefazolin sodium solution. Add 30g of cefazolin sodium to 100mL of a water-isopropanol mixed solvent, with a water to isopropanol volume ratio of 1:1. Dissolve by stirring at 35℃ and a stirring speed of 400r / min to prepare a cefazolin sodium solution with a concentration of 0.30g / mL. Filter the solution through a 0.22μm microporous membrane.

[0036] Step 2: Reverse diffusion crystallization. The cefazolin sodium solution obtained in Step 1 is placed in the tube side of the membrane module, and isopropanol is placed in the shell side of the membrane module as the antisolvent. The volume ratio of the antisolvent to the solvent in Step 1 is 4:1. The system temperature is controlled at 15°C. The concentration difference across the membrane drives the isopropanol to diffuse from the shell side through the membrane pores to the tube side, and the water-isopropanol solvent to diffuse from the tube side through the membrane pores to the shell side, forming local supersaturation inside the membrane pores. Crystallization takes 90 minutes.

[0037] Step 3: Focused Ultrasonic Treatment. Turn on the focused ultrasonic device and align its focal point with the interface between the membrane surface of the membrane module and the bulk solution. Output ultrasonic waves in pulse mode. The ultrasonic frequency is 60kHz, the power density is 3W / cm², and the pulse duty cycle is 60%. Each ultrasonic output lasts 3 minutes, followed by a 2-minute pause, and is repeated 8 times.

[0038] Step 4: Crystal growth. The crystal slurry in the shell is grown at 8°C for 3 hours.

[0039] Step 5: Separation, washing, and drying. Filter the crystal slurry after crystal growth. Wash the filter cake three times with isopropanol at 8°C. Vacuum dry the washed filter cake at 45°C for 5 hours to obtain 27.0g of low-impurity cefazolin sodium crystal product.

[0040] Implementation results: The yield of the obtained cefazolin sodium crystalline product was 90.0%. X-ray powder diffraction patterns showed characteristic peaks at diffraction angles 2θ of 6.8°, 11.5°, 13.9°, 16.2°, 19.5°, 21.8°, 24.1°, and 27.3°. Differential scanning calorimetry (DSC) showed an endothermic peak at 188℃. Thermogravimetric analysis showed a weight loss of 1.0%. High-performance liquid chromatography (HPLC) analysis revealed a total impurity content of 0.42% and a single largest unknown impurity of 0.08%. The average crystal size was 22 μm, and the particle size distribution span was 1.1.

[0041] Example 3 Purpose of implementation: The product quality and yield of cefazolin sodium crystal form prepared by this method were verified using a polyethersulfone flat sheet membrane module, a water-n-propanol solvent system, n-propanol antisolvent, and 30kHz focused ultrasound.

[0042] Implementation System: A polyethersulfone flat sheet membrane module with an 80nm pore size is used. The membrane surface is modified with a hydrophilic-hydrophobic gradient, with the tube-side being hydrophilic and the shell-side being hydrophobic. A focused ultrasonic device operates at a frequency of 30kHz, a power density of 1.5W / cm², and a pulse duty cycle of 40%. A jacketed temperature control system maintains a crystallization temperature of 8℃ and a growth temperature of 3℃. The circulation system includes a peristaltic pump, a storage tank, piping, and valves.

[0043] Implementation steps Step 1: Preparation of cefazolin sodium solution. Add 25g of cefazolin sodium to 90mL of a water-n-propanol mixed solvent, with a water to n-propanol volume ratio of 1.5:1. Dissolve by stirring at 25℃ and a stirring speed of 250r / min to prepare a cefazolin sodium solution with a concentration of 0.28g / mL. Filter the solution through a 0.22μm microporous membrane.

[0044] Step 2: Reverse diffusion crystallization. The cefazolin sodium solution obtained in Step 1 is placed in the tube side of the membrane module, and n-propanol is placed in the shell side of the membrane module as the antisolvent. The volume ratio of the antisolvent to the solvent in Step 1 is 5:1. The system temperature is controlled at 8°C. The concentration difference across the membrane drives n-propanol to diffuse from the shell side through the membrane pores to the tube side, and the water-n-propanol solvent diffuses from the tube side through the membrane pores to the shell side, forming local supersaturation inside the membrane pores. Crystallization takes 45 minutes.

[0045] Step 3: Focused Ultrasonic Treatment. Turn on the focused ultrasonic device and align its focal point with the interface between the membrane surface of the membrane module and the bulk solution. Output ultrasonic waves in pulse mode. The ultrasonic frequency is 30kHz, the power density is 1.5W / cm², and the pulse duty cycle is 40%. Each ultrasonic output lasts 8 minutes, followed by a 4-minute pause, and this cycle is repeated 4 times.

[0046] Step 4: Crystal growth. The crystal slurry in the shell is used to grow crystals at 3°C ​​for 2.5 hours. An auxiliary ultrasonic wave with a frequency of 20kHz is applied during the crystal growth process.

[0047] Step 5: Separation, washing, and drying. Filter the crystal slurry after crystal growth. Wash the filter cake twice with n-propanol at 3°C. Vacuum dry the washed filter cake at 35°C for 7 hours to obtain 22.6g of low-impurity cefazolin sodium crystal product.

[0048] Implementation results: The yield of the obtained cefazolin sodium crystalline product was 90.4%. X-ray powder diffraction patterns showed characteristic peaks at diffraction angles 2θ of 6.8°, 11.5°, 13.9°, 16.2°, 19.5°, 21.8°, 24.1°, and 27.3°. Differential scanning calorimetry (DSC) showed an endothermic peak at 182℃. Thermogravimetric analysis showed a weight loss of 1.4%. High-performance liquid chromatography (HPLC) analysis revealed a total impurity content of 0.35% and a single largest unknown impurity of 0.05%. The average crystal size was 15 μm, and the particle size distribution span was 1.3.

[0049] Example 4 Purpose of implementation: The product quality and yield of cefazolin sodium crystals prepared by this method were verified under conditions of higher crystallization temperature (20℃), longer crystallization time (120 minutes), and higher ultrasonic frequency (80kHz).

[0050] Implementation System: A polytetrafluoroethylene (PTFE) hollow fiber membrane module with a pore size of 120 nm is used. The membrane surface is modified with a hydrophilic-hydrophobic gradient, with the tube-side being hydrophilic and the shell-side being hydrophobic. A focused ultrasonic device operates at 80 kHz with a power density of 4 W / cm² and a pulse duty cycle of 70%. A jacketed temperature control system maintains a crystallization temperature of 20°C and a growth temperature of 10°C. The circulation system includes a peristaltic pump, a storage tank, piping, and valves.

[0051] Implementation steps: Step 1: Preparation of cefazolin sodium solution. Add 40g of cefazolin sodium to 130mL of a water-ethanol mixed solvent, with a water to ethanol volume ratio of 3:1. Stir and dissolve at 40℃ and a stirring speed of 500r / min to prepare a cefazolin sodium solution with a concentration of 0.31g / mL. Filter the solution through a 0.22μm microporous membrane.

[0052] Step 2: Reverse diffusion crystallization. The cefazolin sodium solution obtained in Step 1 is placed in the tube side of the membrane module, and anhydrous ethanol is placed in the shell side of the membrane module as the antisolvent. The volume ratio of the antisolvent to the solvent in Step 1 is 2:1. The system temperature is controlled at 20°C. The concentration difference across the membrane drives the anhydrous ethanol to diffuse from the shell side through the membrane pores to the tube side, and the water-ethanol solvent to diffuse from the tube side through the membrane pores to the shell side, forming local supersaturation inside the membrane pores. Crystallization takes 120 minutes.

[0053] Step 3: Focused Ultrasonic Treatment. Turn on the focused ultrasonic device and align its focal point with the interface between the membrane surface of the membrane module and the bulk solution. Output ultrasonic waves in pulse mode. The ultrasonic frequency is 80kHz, the power density is 4W / cm², and the pulse duty cycle is 70%. Each ultrasonic output lasts for 2 minutes, followed by a 5-minute pause, and is repeated 10 times.

[0054] Step 4: Crystal growth. The crystal slurry in the shell is grown at 10°C for 4 hours.

[0055] Step 5: Separation, washing, and drying. Filter the crystal slurry after crystal growth. Wash the filter cake three times with anhydrous ethanol at 10°C. Vacuum dry the washed filter cake at 50°C for 4 hours to obtain 36.0g of low-impurity cefazolin sodium crystal product.

[0056] Implementation results: The yield of the obtained cefazolin sodium crystalline product was 90.0%. X-ray powder diffraction patterns showed characteristic peaks at diffraction angles 2θ of 6.8°, 11.5°, 13.9°, 16.2°, 19.5°, 21.8°, 24.1°, and 27.3°. Differential scanning calorimetry (DSC) showed an endothermic peak at 190℃. Thermogravimetric analysis showed a weight loss of 0.9%. High-performance liquid chromatography (HPLC) analysis revealed a total impurity content of 0.45% and a single largest unknown impurity of 0.09%. The average crystal size was 25 μm, and the particle size distribution span was 1.4.

[0057] Example 5 Purpose of implementation: The product quality and yield of cefazolin sodium crystals prepared by this method were verified under conditions of lower crystallization temperature (5℃), shorter crystallization time (30 minutes), and lower ultrasonic frequency and power density (20kHz, 0.5W / cm²).

[0058] Implementation System: A polyvinylidene fluoride hollow fiber membrane module with a pore size of 60 nm is used. The membrane surface is modified with a hydrophilic-hydrophobic gradient, with the tube-side being hydrophilic and the shell-side being hydrophobic. A focused ultrasonic device with a frequency of 20 kHz, a power density of 0.5 W / cm², and a pulse duty cycle of 30% is used. A jacketed temperature control device controls the crystallization temperature at 5℃ and the growth temperature at 2℃. The circulation and delivery system includes a peristaltic pump, a storage tank, piping, and valves.

[0059] Implementation steps: Step 1: Preparation of cefazolin sodium solution. Add 15g of cefazolin sodium to 60mL of a water-isopropanol mixed solvent, with a water to isopropanol volume ratio of 1.2:1. Dissolve by stirring at 20℃ and a stirring speed of 200r / min to prepare a cefazolin sodium solution with a concentration of 0.25g / mL. Filter the solution through a 0.22μm microporous membrane.

[0060] Step 2: Reverse diffusion crystallization. The cefazolin sodium solution obtained in Step 1 is placed in the tube side of the membrane module, and isopropanol is placed in the shell side of the membrane module as the antisolvent. The volume ratio of the antisolvent to the solvent in Step 1 is 6:1. The system temperature is controlled at 5°C. The concentration difference across the membrane drives the isopropanol to diffuse from the shell side through the membrane pores to the tube side, and the water-isopropanol solvent to diffuse from the tube side through the membrane pores to the shell side, forming local supersaturation inside the membrane pores. Crystallization is carried out for 30 minutes.

[0061] Step 3: Focused Ultrasonic Treatment. Turn on the focused ultrasonic device and align its focal point with the interface between the membrane surface of the membrane module and the bulk solution. Output ultrasonic waves in pulse mode. The ultrasonic frequency is 20kHz, the power density is 0.5W / cm², and the pulse duty cycle is 30%. Each ultrasonic output lasts 10 minutes, followed by a 2-minute pause, and this cycle is repeated 3 times.

[0062] Step 4: Crystal growth. The crystal slurry in the shell is used to grow crystals at 2°C for 1 hour. An auxiliary ultrasonic wave with a frequency of 20kHz is applied during the crystal growth process.

[0063] Step 5: Separation, washing, and drying. Filter the crystal slurry after crystal growth. Wash the filter cake twice with isopropanol at 2°C. Vacuum dry the washed filter cake at 30°C for 8 hours to obtain 13.5g of low-impurity cefazolin sodium crystal product.

[0064] Implementation results: The yield of the obtained cefazolin sodium crystalline product was 90.0%. X-ray powder diffraction patterns showed characteristic peaks at diffraction angles 2θ of 6.8°, 11.5°, 13.9°, 16.2°, 19.5°, 21.8°, 24.1°, and 27.3°. Differential scanning calorimetry (DSC) showed an endothermic peak at 184℃. Thermogravimetric analysis showed a weight loss of 1.5%. High-performance liquid chromatography (HPLC) analysis revealed a total impurity content of 0.40% and a single largest unknown impurity of 0.07%. The average crystal size was 12 μm, and the particle size distribution span was 1.0.

[0065] Comparative Example 1 Purpose of implementation: The conventional solution-crystallization method was used to prepare cefazolin sodium crystal form, and the method of the present invention was compared with that of the present invention to verify the superiority of the present invention in terms of impurity control, yield, and crystal particle size distribution.

[0066] Implementation System: A jacketed crystallization reactor with a top-mounted agitator is used. The temperature control device is a jacketed circulating water bath. Conventional filtration, washing, and drying equipment are also included.

[0067] Implementation steps Step 1: Preparation of cefazolin sodium solution. Add 20g of cefazolin sodium to 80mL of a water-ethanol mixed solvent, with a water to ethanol volume ratio of 2:1. Stir and dissolve at 30℃ and a stirring speed of 300r / min to prepare a cefazolin sodium solution with a concentration of 0.25g / mL.

[0068] Step 2: Dissolution and crystallization. The cefazolin sodium solution obtained in Step 1 is transferred to a jacketed crystallization reactor. Anhydrous ethanol is added dropwise to the solution under stirring conditions. The stirring speed is 300 r / min, and the dropping rate is 5 mL / min. The total volume ratio of anhydrous ethanol added to the solvent mentioned in Step 1 is 3:1. After the addition is complete, the temperature is lowered to 5°C.

[0069] Step 3: Crystal growth, grow crystals at 5℃ for 2 hours.

[0070] Step 4: Separation, washing, and drying. Filter the crystal slurry after crystal growth. Wash the filter cake three times with anhydrous ethanol at 5°C. Vacuum dry the washed filter cake at 40°C for 6 hours to obtain 17.0g of cefazolin sodium crystal product.

[0071] Implementation results: The yield of the obtained cefazolin sodium crystalline product was 85.0%. The X-ray powder diffraction pattern differed from the characteristic peaks of the products obtained in Examples 1 to 5. High-performance liquid chromatography (HPLC) analysis revealed a total impurity content of 1.35% and a single largest unknown impurity of 0.28%. The average crystal size was 45 μm, with a particle size distribution span of 2.1. The crystal morphology was irregular, and significant agglomeration was observed.

[0072] Compared with Examples 1-5 and Comparative Example 1, and comparing the preparation results of Examples 1-5 and Comparative Example 1, the method of the present invention is significantly superior to the conventional dissolution crystallization method in terms of product quality and process performance. Regarding impurity control, the total impurity content of Examples 1-5 was 0.35% to 0.45%, and the single largest unknown impurity was 0.05% to 0.09%, while the total impurity content of Comparative Example 1 was 1.35%, and the single largest unknown impurity was 0.28%. The method of the present invention reduced the total impurities by 66.7% to 74.1%, and the reduction in the largest single impurity by 67.9% to 82.1%. Regarding yield, the yield of Examples 1-5 was 90.0% to 91.4%, and the yield of Comparative Example 1 was 85.0%. The method of the present invention improved the yield by 5.0% to 6.4 percentage points. Regarding crystal particle size distribution, the average particle size of Examples 1-5 ranged from 12 μm to 25 μm, with a span of 1.0 to 1.4, and the crystals were short rod-shaped or spherical. Comparative Example 1 had an average particle size of 45 μm and a span of 2.1, with irregular crystal morphology and significant agglomeration, indicating that the crystals obtained by the method of this invention have more uniform particle size and better dispersibility. Regarding crystal form consistency, the X-ray powder diffraction patterns of the products obtained in Examples 1-5 all showed characteristic peaks at diffraction angles 2θ of 6.8°, 11.5°, 13.9°, 16.2°, 19.5°, 21.8°, 24.1°, and 27.3°, and the differential scanning calorimetry curves all showed an endothermic peak in the range of 180°C to 195°C, with thermogravimetric analysis weight loss of less than 1.5%. In contrast, the characteristic peaks of the X-ray powder diffraction pattern of the product obtained in Comparative Example 1 were significantly different from those of Examples 1-5, indicating a known different crystal form.

[0073] The fundamental reason for the above differences lies in the reverse diffusion-ultrasound synergistic crystallization mechanism within the confined space of the membrane microreactor used in this invention. In conventional dissolution crystallization methods, the antisolvent is directly added dropwise to the bulk solution. The mass transfer interface is limited by the macroscopic mixing scale, resulting in uneven distribution of local supersaturation, which easily leads to explosive nucleation and crystal aggregation. Impurity molecules are easily captured by the crystal lattice or adsorbed onto the crystal surface during crystal growth, making them difficult to remove effectively. In the method of this invention, the membrane pores serve as the only physical space for crystallization, with a pore size of 50 nm to 200 nm, smaller than the hydrodynamic radius of cefazolin sodium polymer impurities, thus achieving physical interception of impurities. The reverse diffusion process forms highly localized supersaturation within the membrane pores, making the nucleation kinetics more mild and controllable. The microjets generated by the cavitation effect of focused ultrasound act on the membrane pore outlet, peeling the newly formed crystal nuclei from the membrane pore opening and dispersing them in the receiving phase. At the same time, the mechanical oscillation of the ultrasound effectively inhibits the aggregation between crystal nuclei. The close coupling of membrane-confined crystallization, reverse diffusion mass transfer, and ultrasonic synergistic exfoliation enables multiple interceptions and eliminations of impurities throughout the entire process from nucleation and growth to separation. This results in a significant reduction in impurity content, a substantial increase in yield, and a marked improvement in crystal size distribution. The target crystal form can be stably obtained under different membrane materials (PTFE, PVC, polyethersulfone), different solvent systems (water-ethanol, water-isopropanol, water-n-propanol), and different ultrasonic parameters, indicating that the method of this invention has broad applicability and good reproducibility, and possesses clear prospects for industrial application.

[0074] The above are merely specific embodiments of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of protection of the claims.

[0075] In conclusion, the above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A low-impurity cefazolin sodium crystal form, characterized in that, The X-ray powder diffraction pattern obtained using Cu-Kα rays exhibits characteristic peaks at diffraction angles 2θ of 6.8°±0.2°, 11.5°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 19.5°±0.2°, 21.8°±0.2°, 24.1°±0.2°, and 27.3°±0.2°. The X-ray powder diffraction pattern of the crystal form is essentially as shown in Figure 1. The differential scanning calorimetry curve of the crystal form has an endothermic peak in the range of 180℃ to 195℃, and the weight loss in thermogravimetric analysis is less than or equal to 1.5%.

2. The low-impurity cefazolin sodium crystal form according to claim 1, characterized in that, The crystal form belongs to the orthorhombic crystal system, with space group P212121 and unit cell parameters a=11.24ű0.05Å, b=14.87ű0.05Å, c=18.56ű0.05Å, α=β=γ=90°.

3. The low-impurity cefazolin sodium crystal form according to claim 1, characterized in that, The average particle size of the crystals is 5 μm to 30 μm, and the particle size distribution span is less than 1.

5. The total impurity content is less than or equal to 0.5% and the single largest unknown impurity is less than or equal to 0.1% when detected by high performance liquid chromatography.

4. A method for preparing the low-impurity cefazolin sodium crystal form as described in any one of claims 1 to 3, characterized in that, Includes the following steps: Step 1: Add cefazolin sodium to a solvent to prepare a cefazolin sodium solution; Step 2: Place the cefazolin sodium solution in the tube side of the membrane module and place the antisolvent in the shell side of the membrane module. The membrane pore size of the membrane module is 50 nm to 200 nm. Utilize the concentration difference across the membrane to drive the antisolvent to diffuse from the shell side through the membrane pores to the tube side, and the solvent to diffuse from the tube side through the membrane pores to the shell side, forming local supersaturation inside the membrane pores. Crystallize at a temperature of 0°C to 25°C for 30 to 120 minutes. Step 3: Turn on the focused ultrasonic device and align the focus of the focused ultrasonic device with the interface between the membrane surface of the membrane module and the bulk solution. Output ultrasonic waves in a pulse manner to cause the crystal nuclei formed in the membrane pores to detach from the membrane pores and enter the shell side. Step 4: Grow the crystal slurry in the shell at 0°C to 10°C for 1 to 4 hours; Step 5: Filter, wash with anti-solvent, and dry to obtain the low-impurity cefazolin sodium crystal form.

5. The preparation method according to claim 4, characterized in that, The solvent mentioned in step one is a mixed solvent composed of alcohol with 2 to 4 carbon atoms and water, wherein the volume ratio of alcohol to water is 1:1 to 3:1; and the concentration of cefazolin sodium solution is 0.1 g / mL to 0.5 g / mL.

6. The preparation method according to claim 4, characterized in that, The membrane module mentioned in step two is a polymer hollow fiber membrane module or a flat sheet membrane module. The polymer is selected from at least one of polytetrafluoroethylene, polyvinylidene fluoride, and polyethersulfone. The membrane pore size of the membrane module is 100 nm. The membrane surface of the membrane module is modified with a hydrophilic-hydrophobic gradient, with the tube side being hydrophilic and the shell side being hydrophobic.

7. The preparation method according to claim 4, characterized in that, The antisolvent in step two is an alcohol with 2 to 4 carbon atoms; the volume ratio of the antisolvent to the solvent in step (1) is 2:1 to 6:

1.

8. The preparation method according to claim 4, characterized in that, The ultrasonic frequency of the focused ultrasonic device in step three is 20kHz to 80kHz, the power density is 0.5W / cm² to 5W / cm², and the pulse duty cycle is 30% to 70%. The pulse mode is to output ultrasonic waves for 1 to 10 minutes each time, then stop for 2 to 5 minutes, and repeat this cycle 3 to 10 times.

9. The preparation method according to claim 4, characterized in that, The temperature of the antisolvent in step five is 0°C to 10°C, and the number of washing cycles is 2 to 3; the drying is vacuum drying at a temperature of 30°C to 50°C for 4 to 8 hours.

10. The preparation method according to claim 4, characterized in that, In step four, an auxiliary ultrasonic wave with a frequency of 20 kHz is applied during the crystal growth process.

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