A method for purifying erythromycin thiocyanate
By using membrane-assisted cooling coupled crystallization, the problems of large mother liquor volume and low production capacity in the purification of erythromycin thiocyanate were solved, realizing efficient and controllable production of erythromycin thiocyanate and improving product quality and yield.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- NINGXIA TAIYICIN BIOTECH CO LTD
- Filing Date
- 2024-12-31
- Publication Date
- 2026-06-30
AI Technical Summary
In the existing erythromycin thiocyanate refining process, the mother liquor volume is large and the content of erythromycin A component in the mother liquor is low, resulting in low efficiency in recovering effective components, low production capacity, and uncontrollable cooling crystallization process, making it difficult to control product quality.
A membrane-assisted cooling coupled crystallization method was adopted. Crude erythromycin thiocyanate was dissolved under alkaline conditions and thiocyanate was added. The crystallization was carried out under neutral to slightly alkaline conditions, followed by a second crystallization under membrane-assisted cooling. This method controls the nucleation rate and crystal size, and avoids explosive nucleation phenomena.
It significantly improved the yield and content of erythromycin A thiocyanate, shortened the production cycle, reduced the use of purified water, improved product quality and production efficiency, and achieved controllable crystal size and automated operation.
Smart Images
Figure BDA0005222077950000011
Abstract
Description
Technical Field
[0001] This invention belongs to the field of antibiotic extraction technology, specifically relating to a purification method for erythromycin thiocyanate. Background Technology
[0002] Erythromycin thiocyanate (abbreviated as erythromycin) is the thiocyanate of erythromycin, with the chemical structural formula shown in formula (I). It is a white or off-white crystalline powder and a macrolide antibiotic. Erythromycin thiocyanate is also used to synthesize semi-synthetic erythromycins that are popular both domestically and internationally, such as clarithromycin, roxithromycin, and azithromycin, making it an important pharmaceutical intermediate. Therefore, the quality of erythromycin thiocyanate as a pharmaceutical raw material is particularly crucial.
[0003]
[0004] Currently, the purification of erythromycin thiocyanate involves dissolving crude erythromycin thiocyanate in acetone, adding sodium thiocyanate, and adjusting the pH to 7.4–7.6 using acetic acid solution to generate erythromycin thiocyanate. Water is then added to the crystallization system to reduce the solubility of erythromycin thiocyanate in acetone through dissolution, causing crystallization. Cooling crystallization is then used to maximize the product yield. However, this water-based dissolution crystallization process requires a large amount of purified water, resulting in a large mother liquor volume and a low content of erythromycin A component in the mother liquor. This leads to low efficiency in recovering the active ingredient and low quality of the recovered product. Furthermore, the cooling crystallization process is slow, resulting in low production capacity, uncontrollable nucleation process, and difficulty in controlling product quality.
[0005] Therefore, there is an urgent need to develop a membrane-assisted cooling coupled crystallization method for purifying erythromycin thiocyanate. Summary of the Invention
[0006] The purpose of this invention is to provide a purification method for erythromycin thiocyanate, which replaces the traditional cooling crystallization method with a membrane-assisted cooling coupled crystallization method, successfully controls the nucleation rate, eliminates explosive nucleation phenomena, and significantly improves the content and yield of erythromycin thiocyanate A.
[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0008] A method for purifying erythromycin thiocyanate includes the following steps:
[0009] (1) Under alkaline conditions, crude erythromycin thiocyanate was dissolved in an ester solvent to obtain an erythromycin solution;
[0010] (2) Add thiocyanate to the erythromycin solution obtained in step (1) and crystallize it once under neutral to slightly alkaline conditions to obtain erythromycin thiocyanate crystallization solution.
[0011] (3) The erythromycin thiocyanate primary crystallization solution obtained in step (2) is subjected to membrane-assisted cooling for secondary crystallization to obtain erythromycin thiocyanate secondary crystallization solution;
[0012] (4) The secondary crystallization solution of erythromycin thiocyanate obtained in step (3) is filtered and dried to obtain high-quality erythromycin thiocyanate.
[0013] In step (1), the content of component A in the crude erythromycin thiocyanate is 70%-75%.
[0014] The ester solvent in step (1) is selected from at least one of ethyl acetate, butyl acetate, propyl acetate, isobutyl acetate, and octyl acetate.
[0015] In step (1), the alkaline conditions are set to pH 9.0 to 9.3.
[0016] Preferably, the pH is adjusted using a 30% sodium hydroxide solution under alkaline conditions.
[0017] The dissolution temperature in step (1) is 45-50℃.
[0018] In step (2), the thiocyanate has a mass fraction of 40% NaSCN, and the amount of NaSCN added is 20% to 28% of the weight of crude erythromycin thiocyanate.
[0019] In step (2), the pH of the center is set to 7.4 to 7.7.
[0020] Preferably, glacial acetic acid with a mass fraction of 15% is used to adjust the pH to be neutral to slightly alkaline.
[0021] The crystallization time in step (2) is 20-30 min.
[0022] In step (3), the cooling temperature during the membrane-assisted cooling secondary crystallization is 10-20°C.
[0023] In step (3), the membrane-assisted cooling secondary crystallization time is 20-30 min.
[0024] In step (3), the membrane used in the membrane-assisted cooling secondary crystallization is a polytetrafluoroethylene (PTFE) hollow fiber membrane.
[0025] The technical solution of the present invention has at least the following beneficial technical effects:
[0026] (1) The present invention eliminates the water addition and precipitation process by using membrane-assisted cooling coupled crystallization method, which effectively shortens the production cycle and improves production efficiency. At the same time, it reduces the use of purified water and greatly improves product quality.
[0027] (2) Compared with traditional batch coolers, the membrane-assisted cooling crystallization method of this invention can induce heterogeneous nucleation at low supersaturation, reduce the temperature gradient during the nucleation process, and improve heat transfer efficiency and controllability by introducing hollow fiber membranes. This avoids secondary nucleation in the system, greatly improves crystal quality, and enables automatic seed input for automated operation. Furthermore, the coupled crystallization process not only shortens the time required for a single crystallization process but also has lower energy consumption, successfully controlling the nucleation rate without explosive nucleation, resulting in controllable crystal size and high-quality erythromycin thiocyanate product.
[0028] (3) Experiments show that by improving the purification method of erythromycin thiocyanate, the present invention significantly improves the content and yield of erythromycin thiocyanate product, with the yield of erythromycin thiocyanate A reaching over 90.5% and the content of erythromycin thiocyanate A component reaching over 85.9%. Detailed Implementation
[0029] The embodiments of the present invention will be clearly and completely described below with reference to the examples. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.
[0030] Example 1
[0031] Add butyl acetate to the crystallizer, the amount being 1.4 times the weight of the crude erythromycin thiocyanate. Start stirring and heat after adding the crude erythromycin thiocyanate. When the system temperature reaches 45°C, add a 30% sodium hydroxide solution, ultimately controlling the system pH to 9.0. After the crude erythromycin thiocyanate is completely dissolved, remove insoluble matter by filtration, collect the butyl acetate phase, and maintain the temperature at 45°C. Slowly add a 40% NaSCN solution at 20% of the weight of the crude erythromycin. After the NaSCN solution is completely added, continue stirring for 5 minutes. Then, add a 15% glacial acetic acid solution to the crystallizer. Stop adding the glacial acetic acid solution when the pH of the material reaches 7.4, and allow crystals to grow for 30 minutes. The crystallization system described above was pumped into the tube layer of a polytetrafluoroethylene (PTFE) hollow fiber membrane module via a peristaltic pump. Heat exchange occurred between the system and the coolant within the membrane module. Once a sufficient amount of seed crystals appeared in the solution, the erythromycin thiocyanate crystallization system was returned to the original crystallizer for further crystal growth for 30 minutes. After filtration and drying, a high-quality erythromycin thiocyanate product was obtained, with a yield of 90.5% for erythromycin A and a erythromycin A component content of 86.7%.
[0032] Example 2
[0033] Add ethyl acetate to the crystallizer, the amount being 2.0 times the weight of the crude erythromycin thiocyanate. Start stirring and heat after adding the crude erythromycin thiocyanate. When the system temperature reaches 45°C, add a 30% sodium hydroxide solution, ultimately controlling the system pH to 9.1. After the crude erythromycin thiocyanate is completely dissolved, remove insoluble matter by filtration, collect the ethyl acetate phase, and maintain the temperature at 45°C. Slowly add a 40% NaSCN solution at 22% of the weight of the crude erythromycin. After the NaSCN solution is completely added, continue stirring for 5 minutes. Then, add a 15% glacial acetic acid solution to the crystallizer. Stop adding the glacial acetic acid solution when the pH of the material reaches 7.5, and allow crystals to grow for 30 minutes. The above crystallization system was pumped into the tubular layer of a polytetrafluoroethylene (PTFE) hollow fiber membrane module via a peristaltic pump. Heat exchange occurred between the system and the coolant within the membrane module. Once a sufficient amount of seed crystals appeared in the solution, the erythromycin thiocyanate crystallization system was returned to the original crystallizer for further crystal growth for 30 minutes. After filtration and drying, the refined erythromycin thiocyanate product was obtained. The yield of erythromycin thiocyanate A was 91.2%, and the erythromycin A component content was 88.5%.
[0034] Example 3
[0035] Add propyl acetate to the crystallizer, the amount being 2.5 times the weight of the crude erythromycin thiocyanate. Start stirring and raise the temperature after adding the crude erythromycin thiocyanate. When the system temperature reaches 46°C, add a 30% sodium hydroxide solution, ultimately controlling the pH of the system to 9.2. After the crude erythromycin thiocyanate is completely dissolved, remove insoluble matter by filtration, collect the propyl acetate phase, and maintain the temperature at 46°C. Slowly add a 40% NaSCN solution at 24% of the weight of the crude erythromycin. After the NaSCN solution is completely added, continue stirring for 5 minutes. Then, add a 15% glacial acetic acid solution dropwise to the crystallizer. Stop adding the glacial acetic acid solution when the pH of the material is controlled at 7.6, and allow crystals to grow for 30 minutes. The above crystallization system was pumped into the tubular layer of a polytetrafluoroethylene (PTFE) hollow fiber membrane module via a peristaltic pump. Heat exchange occurred between the system and the coolant within the membrane module. Once a sufficient amount of seed crystals appeared in the solution, the erythromycin thiocyanate crystallization system was returned to the original crystallizer for further crystal growth for 30 minutes. After filtration and drying, the refined erythromycin thiocyanate product was obtained. The yield of erythromycin thiocyanate A was 91.5%, and the erythromycin A component content was 88.8%.
[0036] Example 4
[0037] Isobutyl acetate was added to the crystallizer at a rate 1.4 times the weight of the crude erythromycin thiocyanate. Stirring was started, and the temperature was raised after the addition of the crude erythromycin thiocyanate. When the system temperature reached 48°C, a 30% sodium hydroxide solution was added dropwise, ultimately controlling the system pH to 9.2. After the crude erythromycin thiocyanate was completely dissolved, insoluble matter was removed by filtration, and the isobutyl acetate phase was collected. The temperature was maintained at 48°C, and a 40% NaSCN solution was slowly added dropwise at 26% of the weight of the crude erythromycin. After the NaSCN solution was completely added, stirring was continued for 5 minutes. Then, a 15% glacial acetic acid solution was added dropwise to the crystallizer. When the pH of the material was controlled at 7.6, the addition of the glacial acetic acid solution was stopped, and crystallization was allowed to continue for 30 minutes. The above crystallization system was pumped into the tubular layer of a polytetrafluoroethylene (PTFE) hollow fiber membrane module via a peristaltic pump. Heat exchange occurred between the system and the coolant within the membrane module. Once a sufficient amount of seed crystals appeared in the solution, the erythromycin thiocyanate crystallization system was returned to the original crystallizer for further crystal growth for 30 minutes. After filtration and drying, the refined erythromycin thiocyanate product was obtained. The yield of erythromycin thiocyanate A was 92.4%, and the erythromycin A component content was 89.3%.
[0038] Example 5
[0039] Octyl acetate was added to the crystallizer at a rate 2.0 times the weight of the crude erythromycin thiocyanate. Stirring was started, and the temperature was raised after adding the crude erythromycin thiocyanate. When the system temperature reached 48°C, a 30% sodium hydroxide solution was added dropwise, ultimately controlling the system pH to 9.3. After the crude erythromycin thiocyanate was completely dissolved, insoluble matter was removed by filtration, and the octyl acetate phase was collected. The temperature was maintained at 48°C, and a 40% NaSCN solution was slowly added dropwise at 26% of the crude erythromycin weight. After the NaSCN solution was completely added, stirring was continued for 5 minutes. Then, a 15% glacial acetic acid solution was added dropwise to the crystallizer. When the pH of the material reached 7.6, the addition of the glacial acetic acid solution was stopped, and crystallization was allowed to continue for 30 minutes. The above crystallization system was pumped into the tubular layer of a polytetrafluoroethylene (PTFE) hollow fiber membrane module via a peristaltic pump. Heat exchange occurred between the system and the coolant within the membrane module. Once a sufficient amount of seed crystals appeared in the solution, the erythromycin thiocyanate crystallization system was returned to the original crystallizer for further crystal growth for 30 minutes. After filtration and drying, the refined erythromycin thiocyanate product was obtained. The yield of erythromycin thiocyanate A was 91.7%, and the erythromycin A component content was 85.9%.
[0040] Example 6
[0041] Add butyl acetate to the crystallizer, the amount being 2.5 times the weight of the crude erythromycin thiocyanate. Start stirring. After adding the crude erythromycin thiocyanate, raise the temperature. When the system temperature reaches 50°C, add a 30% sodium hydroxide solution, ultimately controlling the system pH to 9.3. After the crude erythromycin thiocyanate is completely dissolved, remove insoluble matter by filtration, collect the butyl acetate phase, and maintain the temperature at 50°C. Slowly add a 40% NaSCN solution at 28% of the weight of the crude erythromycin. After the NaSCN solution is completely added, continue stirring for 5 minutes. Then, add a 15% glacial acetic acid solution to the crystallizer. Stop adding the glacial acetic acid solution when the pH of the material reaches 7.6, and allow crystals to grow for 30 minutes. The above crystallization system was pumped into the tubular layer of a polytetrafluoroethylene (PTFE) hollow fiber membrane module via a peristaltic pump. Heat exchange occurred between the system and the coolant within the membrane module. Once a sufficient amount of seed crystals appeared in the solution, the erythromycin thiocyanate crystallization system was returned to the original crystallizer for further crystal growth for 30 minutes. After filtration and drying, the refined erythromycin thiocyanate product was obtained. The yield of erythromycin thiocyanate A was 92.1%, and the erythromycin A component content was 87.3%.
[0042] Comparative Example 1
[0043] Butyl acetate was added to the crystallizer at a rate 2.2 times the weight of the crude erythromycin thiocyanate. Stirring was started, and the temperature was raised after the addition of crude erythromycin thiocyanate. When the system temperature reached 45°C, a 30% sodium hydroxide solution was added dropwise, ultimately controlling the system pH to 9.5. After the crude erythromycin thiocyanate was completely dissolved, insoluble matter was removed by filtration, and the butyl acetate phase was collected. The temperature was maintained at 45°C, and a 40% NaSCN solution was slowly added dropwise at 28% of the weight of the crude erythromycin. After the NaSCN solution was completely added, stirring continued for 5 minutes. Then, a 15% glacial acetic acid solution was added dropwise to the crystallizer. When the pH of the material reached 7.4, the addition of glacial acetic acid was stopped, and crystallization was allowed to continue for 5 minutes. After filtration and drying, erythromycin thiocyanate was obtained, with a yield of 82.1% and a erythromycin A component content of 76.5%.
[0044] Comparative Example 2
[0045] Add butyl acetate to the crystallizer, the amount being 2.2 times the weight of the crude erythromycin thiocyanate. Start stirring and heat after adding the crude erythromycin thiocyanate. When the system temperature reaches 45℃, add a 30% sodium hydroxide solution, ultimately controlling the system pH to 9.5. After the crude erythromycin thiocyanate is completely dissolved, remove insoluble matter by filtration, collect the butyl acetate phase, and maintain the temperature at 45℃. Slowly add a 40% NaSCN solution at 28% of the weight of the crude erythromycin. After the NaSCN solution is completely added, continue stirring for 5 minutes. Then, add a 15% glacial acetic acid solution to the crystallizer. Stop adding the glacial acetic acid solution when the pH of the material reaches 7.4, and allow crystals to grow for 5 minutes. Finally, add 0.3 times the volume of purified water to adjust the pH to 7.4, and allow crystals to grow for 20 minutes. After crystallization, the product was obtained by filtration and drying, with a yield of erythromycin thiocyanate A of 84.5% and a content of 78.6% for erythromycin A component.
[0046] Comparative Example 3
[0047] Add butyl acetate to the crystallizer, the amount being 2.2 times the weight of the crude erythromycin thiocyanate. Start stirring. After adding the crude erythromycin thiocyanate, raise the temperature. When the system temperature reaches 45°C, add a 30% sodium hydroxide solution, ultimately controlling the system pH to 9.5. After the crude erythromycin thiocyanate is completely dissolved, remove insoluble matter by filtration, collect the butyl acetate phase, and maintain the temperature at 45°C. Slowly add a 40% NaSCN solution at 28% of the weight of the crude erythromycin. After the NaSCN solution is completely added, continue stirring for 5 minutes. Then, add a 15% glacial acetic acid solution to the crystallizer. Stop adding the glacial acetic acid solution when the pH of the material reaches 7.4, and allow crystals to grow for 5 minutes. Add purified water at 0.3 times the volume of the crystallization liquid, adjust the pH to maintain at 7.4, then turn on the chilled water to cool down to 5°C at a cooling rate of 10°C / h. Filter the material and rinse with purified water for 5 minutes to obtain erythromycin thiocyanate product. The yield of erythromycin thiocyanate A is 86.3%, and the content of erythromycin A component is 80.5%.
Claims
1. A method for purifying erythromycin thiocyanate, comprising the following steps: (1) Under alkaline conditions, crude erythromycin thiocyanate was dissolved in an ester solvent to obtain an erythromycin solution; (2) Add thiocyanate to the erythromycin solution obtained in step (1) and crystallize it once under neutral to slightly alkaline conditions to obtain erythromycin thiocyanate crystallization solution. (3) The erythromycin thiocyanate primary crystallization solution obtained in step (2) is subjected to membrane-assisted cooling for secondary crystallization to obtain erythromycin thiocyanate secondary crystallization solution; (4) The secondary crystallization solution of erythromycin thiocyanate obtained in step (3) is filtered and dried to obtain high-quality erythromycin thiocyanate.
2. The purification method of erythromycin thiocyanate according to claim 1, characterized in that... The content of component A in the crude erythromycin thiocyanate described in step (1) is 70%-75%.
3. The purification method of erythromycin thiocyanate according to claim 1, characterized in that... The ester solvent in step (1) is selected from at least one of ethyl acetate, butyl acetate, propyl acetate, isobutyl acetate and octyl acetate.
4. The purification method of erythromycin thiocyanate according to claim 1, characterized in that... The alkaline conditions described in step (1) are adjusted to pH 9.0 to 9.
3. Preferably, the pH is adjusted using a 30% sodium hydroxide solution.
5. The purification method of erythromycin thiocyanate according to claim 1, characterized in that... The dissolution temperature in step (1) is 45-50℃.
6. The purification method of erythromycin thiocyanate according to claim 1, characterized in that... The thiocyanate in step (2) is NaSCN with a mass fraction of 40%, and the amount of NaSCN added is 20% to 28% of the weight of crude erythromycin thiocyanate.
7. The purification method of erythromycin thiocyanate according to claim 1, characterized in that... In step (2), the pH of the neutral to slightly alkaline condition is set to 7.4 to 7.
7. Preferably, the pH is adjusted by using 15% glacial acetic acid.
8. The purification method of erythromycin thiocyanate according to claim 1, characterized in that... The primary crystallization time in step (2) is 20-30 minutes.
9. The purification method of erythromycin thiocyanate according to claim 1, characterized in that... In step (3), the cooling temperature during membrane-assisted cooling secondary crystallization is 10-20°C, and the membrane-assisted cooling secondary crystallization time is 20-30 min.
10. The purification method of erythromycin thiocyanate according to claim 1, characterized in that... In step (3), the membrane used in the membrane-assisted cooling secondary crystallization is a polytetrafluoroethylene (PTFE) hollow fiber membrane.