CN109553645B - Method for extracting low-content erythromycin A in fermentation solution - Google Patents
Method for extracting low-content erythromycin A in fermentation solution Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Abstract
The invention relates to the field of pharmacy, in particular to a method for extracting low-content erythromycin A in a fermentation solution, which comprises the following steps: (1) filtering the fermentation liquor by using a ceramic membrane; (2) extracting the filtrate with solvent, and washing the light phase with saturated sodium chloride; (3) salifying and crystallizing: adding water into the light phase, adding an acid solution to adjust the pH, adding thiocyanate to react with thiocyanate to generate erythromycin thiocyanate, continuously adjusting the pH by using an acetic acid solution to separate out the erythromycin thiocyanate, filtering, washing with hot water, filtering, and drying to obtain the erythromycin thiocyanate. The erythromycin A component in the fermentation liquor is lower than 75 percent, and the erythromycin thiocyanate finished product meeting the requirements is obtained after the erythromycin A component is treated by the method, and the yield reaches more than 80 percent.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a method for extracting low-content erythromycin A in a fermentation solution.
Background
The erythromycin is a large-ring lactone antibiotic, mainly comprises 6 components of erythromycin A, erythromycin B, erythromycin C, erythromycin D, erythromycin E, erythromycin F and the like, wherein the antibacterial activity of the erythromycin A is strongest. Erythromycin is usually produced by a microbial fermentation method, and in the fermentation culture process, erythromycin impurity components in fermentation liquor and erythromycin A as a main component are produced simultaneously, and the content of the erythromycin components in the fermentation liquor is different due to different fermentation processes. When the fermentation is abnormal, the content of the erythromycin A component is lower than 70 percent, and the main impurity component erythromycin B, C, D is higher. The traditional extraction process cannot effectively separate impurity components. At present, two main processes are used for extracting erythromycin from fermentation liquor: the process 1 comprises the following steps: microfiltration of fermentation liquor, resin impurity removal of filtrate, nanofiltration, concentration, crystallization and recrystallization. And (2) a process: filtering the fermentation liquor by a plate frame, extracting by a solvent, removing impurities from the extract liquor, and crystallizing the extract liquor.
The traditional erythromycin fermentation liquor filtration uses a microfiltration membrane or a plate frame, the filtration precision is low, filtrate contains a large amount of protein and pigment, resin is required for purification treatment, the process is complex, and the amount of wastewater generated in production is large.
In the traditional extraction method, a solvent is used for extraction, the solvent mainly used is butyl acetate or a mixed solvent containing butyl acetate, when the erythromycin thiocyanate is crystallized, the content of the obtained erythromycin thiocyanate A is below 80%, the content of erythromycin B and C impurities is more than 3.0%, and the total yield in the crystallization process is less than 85%.
CN103044508B discloses a method for extracting crystallized erythromycin thiocyanate from an erythromycin fermentation broth, which comprises the steps of filtering with an ultrafiltration membrane, concentrating the filtrate by nanofiltration, adding erythromycin thiocyanate into the concentrated solution to obtain crude salt, and dissolving the crude salt in a pre-solvent such as amyl acetate or dichloromethane. Or extracting erythromycin in the concentrated solution into a pre-solvent under an alkaline condition, decolorizing with activated carbon, adding acetone into the decolorized solution, and finally adding thiocyanate for crystallization. The patent uses a plurality of solvents, the solvent recovery and separation are difficult, and the solvent phase is decolorized, and the solvent loss is large. Two crystallizations are used, with a large yield loss.
Patent CN105348340A discloses a preparation method of erythromycin thiocyanate, which comprises the steps of dehydrating the extracted light phase by using saturated sodium chloride, decoloring by using activated carbon, adding a thiocyanate solution, salifying with erythromycin, adding a composite solvent, and adjusting pH by using an acetic acid solution to crystallize to obtain the erythromycin thiocyanate. In the patent, activated carbon is used in a solvent, so that the solvent is not suitable for recovery, the solvent loss is large, and the compound solvent is added during salt formation, so that the solvent has more components and is difficult to separate.
CN201610177576 discloses a preparation method of high-purity erythromycin A, which comprises the steps of dissolving erythromycin thiocyanate in two phases composed of an organic solvent and water by adding alkali, taking the organic phase, adding water for washing, separating out erythromycin A alkali in the organic phase, filtering, drying, and recrystallizing the dry powder by using water as a solvent to obtain high-purity erythromycin A. The method comprises the steps of taking erythromycin thiocyanate as raw powder, crystallizing erythromycin A alkali after dissolving, and recrystallizing to obtain erythromycin A.
Disclosure of Invention
Aiming at the technical current situation, the invention provides a method for extracting low-content erythromycin A in fermentation liquor, and the finished product obtained by the method has the advantages that the content of the erythromycin A is more than 80 percent, the content of erythromycin B and C is less than 3 percent, and the content of other impurities meets the pharmacopoeia standard. The method does not use active carbon, when solvent is recovered, purified water is added into mother liquor for washing, and light phase is obtained by phase separation, so that the method can be repeatedly used for extracting filtrate, and the recovery is convenient. The invention discloses a method for extracting low-content erythromycin A from a fermentation solution, which comprises the following steps:
(1) and (3) filtering: filtering the fermentation liquor by a filter membrane with the molecular weight cut-off of 3-100 ten thousand, and collecting the filtrate;
(2) and (3) extraction: extracting the filtrate with organic solvent, adjusting pH to 8.0-12 with alkali, stirring to separate phases, and washing the light phase with saturated sodium chloride to obtain light phase solution;
(3) and (3) crystallization: adding water into the light-phase solution, controlling the temperature, then adding an acid solution to adjust the pH value, then adding thiocyanate to react, continuing to react after the addition is finished, then continuously adjusting the pH value to 3.0-6.0 by using the acid solution, crystallizing, filtering and drying to obtain the erythromycin thiocyanate.
As one embodiment, in the step (1) of the invention, the molecular weight cut-off of the filter membrane is 3-100 ten thousand, preferably in the range of 3-10 ten thousand, and the filter membrane is preferably a ceramic filter membrane; the temperature during filtration is 5-20 deg.C, preferably 8-12 deg.C.
As one embodiment, the amount of the organic solvent used in step (2) of the present invention is that the concentration of erythromycin in the organic phase is 25000-45000u/ml, preferably 28000-32000 u/ml; preferably, the organic solvent is butyl acetate, butanol, octanol, kerosene, ethyl acetate, or one or more of the above; butyl acetate, octanol or kerosene are preferred.
As one embodiment, the alkali in step (2) of the present invention is sodium hydroxide, potassium hydroxide; the sodium hydroxide solution is preferred, and the concentration of the sodium hydroxide solution is more preferably 15 to 25%.
As one embodiment, the pH value in step (2) of the present invention is further in the range of 8.0 to 12, preferably 9.5 to 11.5; the extraction temperature is 20-40 deg.C, preferably 30-35 deg.C.
As one embodiment, the amount of the saturated sodium chloride solution used in step (2) of the present invention is 5 to 50% (v/v), preferably 10 to 30%.
As one embodiment, step (3) of the present invention further comprises: during crystallization, adding purified water into the light phase, wherein the using amount is 0.1-2 BV, and preferably 0.8-1.2 BV;
as one embodiment, step (3) of the present invention further comprises: the temperature is 20-60 ℃, and preferably 30-40 ℃;
as one embodiment, step (3) of the present invention further comprises: after adding purified water, the pH is adjusted to 6.5-7.5 with an acid solution.
As one embodiment, the concentration of the sodium thiocyanate solution in step (3) of the present invention is 10 to 40%, preferably 15 to 25%;
as one embodiment, step (3) of the present invention further comprises: the molar ratio of the sodium thiocyanate to the erythromycin A is 1.0-2.0: 1, preferably 1.1 to 1.3: 1;
as one embodiment, step (3) of the present invention further comprises: the adding time is 5min-2h, preferably 50-70 min.
As one embodiment, step (3) of the present invention further comprises: and after the thiocyanate is added, continuously reacting for 0.5-1 h.
As one embodiment, step (3) of the present invention further comprises: after the salt forming reaction is finished, adjusting the end point to a pH value of 3-6 by using an acetic acid solution, and preferably, adjusting the end point to a pH value of 5-6.
As one embodiment, the acid in step (3) of the present invention is acetic acid; the concentration of acetic acid is preferably 15 to 25%, more preferably 20%.
As one embodiment, step (3) of the present invention further comprises: washing the filter cake with hot water at the temperature of 40-80 ℃, wherein the optimal temperature of the hot water is as follows: 45-55 ℃;
as one embodiment, step (3) of the present invention further comprises: filtering under vacuum of-0.08 MPa, and drying at 75-80 ℃ to obtain erythromycin thiocyanate meeting the specification.
As one embodiment, the method for extracting low-content erythromycin A from the fermentation solution comprises the following steps:
(1) filtration
Putting the erythromycin fermentation liquor into a tank, and then filtering the erythromycin fermentation liquor by a ceramic membrane, wherein the interception molecular weight of the ceramic membrane is 3-100 ten thousand, and the optimal interception range is 3-10 ten thousand; . The temperature of the feed liquid in the filtering process is 5-20 ℃, and the optimal temperature is 8-12 ℃;
(2) extraction of
Adding an extracting agent into the filtrate, wherein the extracting agent is one or more of butyl acetate, butanol, octanol, kerosene, ethyl acetate or the like, and preferably butyl acetate, octanol or kerosene; the dosage of the extractant is 25000 and 45000u/ml, preferably 28000 to 32000u/ml of the content of the erythromycin in the organic phase; adjusting pH to 8.0-12 with alkali solution, preferably pH 9.5-11.5; the temperature is 20-40 ℃, preferably 30-35 ℃; the alkali solution is sodium hydroxide and potassium hydroxide, preferably sodium hydroxide solution with the concentration of 15-25%; stirring for 10min, separating phase, and collecting light phase; washing the light phase with 5-50% (v/v) saturated sodium chloride solution, preferably 10-30%, stirring for 10min, separating phases, and collecting the light phase;
(3) crystallization of
Adding 0.1-2 BV of purified water, preferably 0.8-1.2BV, into the light phase at 20-60 ℃, preferably 30-40 ℃, and adjusting the pH value to 6.5-7.5 by using 15-25%, preferably 20% acetic acid aqueous solution; adding sodium thiocyanate solution with concentration of 10-40%, preferably 15-25%; the amount of sodium thiocyanate used was sodium thiocyanate: the molar ratio of erythromycin A is 1.0-2.0: 1, preferably 1.0 to 1.5: 1, further preferably 1.1 to 1.3: 1; the adding time is 5min-2h, preferably 50-70 min; after the addition is finished, continuing the reaction for 0.5-1 h, adjusting the end point to pH 3-6 by using 15-25%, preferably 20% acetic acid solution, preferably adjusting the end point to pH 5-6, and filtering; washing the filter cake with hot water at the temperature of 40-80 ℃, wherein the optimal temperature of the hot water is as follows: 45-55 ℃. Filtering, drying the wet powder for 2-3h at 75-80 ℃ under the vacuum of-0.08 MPa to obtain the erythromycin thiocyanate meeting the specification.
The method comprises the steps of filtering by a ceramic membrane, extracting by a solvent, washing by saturated sodium chloride, adding diluent purified water during crystallization, slowing down the crystallization speed, and obtaining the erythromycin thiocyanate finished product (a process flow chart is shown in figure 1). The method does not use activated carbon. When the solvent is recovered, purified water is added into the mother liquor for washing, and the light phase is obtained by phase separation, so that the method can be repeatedly applied to the extraction of the filtrate, and is convenient to recover.
The content of the erythromycin A in the finished product obtained by the method is more than 80 percent, the content of the erythromycin B and C is less than 3 percent, and the content of other impurities meets the pharmacopoeia standard.
Drawings
FIG. 1: the invention relates to a process flow chart.
Detailed Description
The invention is further illustrated by the following examples, which do not in any way limit the effective scope of the invention.
Example 1
200L of erythromycin fermentation liquor, wherein the chemical valence of the erythromycin is about 8000u/ml, the content of the component erythromycin A is 70%, the content of the erythromycin B is 3%, and the content of the erythromycin C is 6%. The temperature was 12 ℃ and filtration was carried out using a ceramic membrane with a molecular weight cut-off of 3 ten thousand. Adding 50L of compound solvent into the filtrate, adjusting pH to 10.0 with 20% NaOH solution at 35 deg.C, stirring for 10min, and centrifuging. Adding 10L saturated sodium chloride solution into the light phase, stirring at 30 deg.C for 10min, standing, and phase separating. The light phase was taken. Adding 1.0BV of purified water into the light phase, adjusting the pH to 6.5 by using 20% acetic acid at the temperature of 30 ℃, adding 20% sodium thiocyanate solution, wherein the dosage of the sodium thiocyanate is sodium thiocyanate: the molar ratio of erythromycin A is 1.2: 1, adjusting the pH value to 5.0 by using acetic acid, filtering, washing a filter cake by using hot water at 50 ℃, filtering, drying for 2 hours at 75-80 ℃ under vacuum of-0.085 MPa to obtain a finished erythromycin thiocyanate product meeting the requirements, wherein the content is as follows: 826u/g of the total weight of the components,
the obtained product comprises the following components in percentage by weight: the content of erythromycin A is 81.5%, and the content of erythromycin B is 1.4%. The content of erythromycin C is 2.6%, the content of erythromycin impurity is 0.7%, erythromycin enol ether is 0.3%, and other impurities are all in accordance with the requirements of pharmacopoeia. The yield of erythromycin A is more than 80%.
Example 2
500L of erythromycin fermentation liquor, the chemical valence of the erythromycin is about 8000u/ml, the content of the component erythromycin A is 65%, the content of the erythromycin B is 4%, and the content of the erythromycin C is 10%. The temperature was 8 ℃ and filtration was carried out using a ceramic membrane with a molecular weight cut-off of 5 ten thousand. Adding 120L of composite solvent into the filtrate, adjusting pH to 11.0 with 20% NaOH solution at 30 deg.C, stirring for 10min, and centrifuging. Adding 35L saturated sodium chloride solution into the light phase, stirring at 30 deg.C for 10min, standing, and phase separating. The light phase was taken. Adding 0.8BV of purified water into the light phase, adjusting the pH to 7.0 by using 20% acetic acid at the temperature of 30 ℃, adding 20% sodium thiocyanate solution, wherein the dosage of the sodium thiocyanate is sodium thiocyanate: the molar ratio of the erythromycin A is 1.1: 1, adjusting the pH value to 5.5 by using acetic acid, filtering, washing a filter cake by using hot water at 50 ℃, filtering, drying for 3 hours at 75-80 ℃ under vacuum of-0.085 MPa to obtain a finished erythromycin thiocyanate product meeting the requirements, wherein the content is as follows: 806u/g of the total weight of the rubber,
the obtained product comprises the following components in percentage by weight: the content of erythromycin A is 81.0%, and the content of erythromycin B is 1.7%. The content of erythromycin C is 2.1%, the content of erythromycin impurity is 1.1%, erythromycin enol ether is 0.4%, and other impurities are all in accordance with the requirements of pharmacopoeia. The yield of erythromycin A is more than 80%.
Example 3
1000L of erythromycin fermentation liquor, wherein the chemical valence of the erythromycin is about 8000u/ml, the content of the erythromycin A is 76%, the content of the erythromycin B is 3%, and the content of the erythromycin C is 5%. The temperature was 12 ℃ and filtration was carried out using a ceramic membrane with a molecular weight cut-off of 10 ten thousand. Adding 120L of composite solvent into the filtrate, adjusting pH to 11.0 with 20% NaOH solution at 35 deg.C, stirring for 10min, and centrifuging. Adding 35L saturated sodium chloride solution into the light phase, stirring at 30 deg.C for 10min, standing, and phase separating. The light phase was taken. Adding 1.2BV of purified water into the light phase, adjusting the pH to 7.5 by using 20% acetic acid at the temperature of 30 ℃, adding 20% sodium thiocyanate solution, wherein the dosage of the sodium thiocyanate is sodium thiocyanate: the molar ratio of the erythromycin A is 1.1: 1, adjusting the pH value to 5.0 by using acetic acid, filtering, washing a filter cake by using hot water at 50 ℃, filtering, drying for 3 hours at 75-80 ℃ under vacuum of-0.085 MPa to obtain a finished erythromycin thiocyanate product meeting the requirements, wherein the content is as follows: 785 u/g.
The obtained product comprises the following components in percentage by weight: the content of erythromycin A is 80.2%, and the content of erythromycin B is 1.5%. The content of erythromycin C is 2.8%, the content of erythromycin impurity is 1.5%, erythromycin enol ether is 0.4%, and other impurities are all in accordance with the requirements of pharmacopoeia. The yield of erythromycin A is more than 80%.
Claims (34)
1. A method for extracting low-content erythromycin A in a fermentation solution, which is characterized by comprising the following steps:
(1) and (3) filtering: filtering the fermentation liquor by a filter membrane with the molecular weight cut-off of 3-10 ten thousand, and collecting the filtrate; the temperature during filtration is 5-20 ℃, and the filter membrane is a ceramic filter membrane;
(2) and (3) extraction: extracting the filtrate with organic solvent, and adjusting pH to 8.0-12 with alkali at 20-40 deg.C; stirring to separate phases, washing the light phase with 5-50% saturated sodium chloride to obtain a light phase solution, wherein the organic solvent is butyl acetate, butanol, octanol, kerosene or ethyl acetate, or a combination of two or more of the above; the dosage of the organic solvent is that the concentration of the erythromycin in the organic phase is 25000-45000 u/ml; the alkali is sodium hydroxide or potassium hydroxide;
(3) and (3) crystallization: adding water into the light phase solution, controlling the temperature to be 20-60 ℃, then adding an acid solution to adjust the pH value to 6.5-7.5, then adding sodium thiocyanate to react, continuing to react for 0.5-1 h after the addition is finished, then using the acid solution to continue to adjust the pH value to 3.0-6.0, filtering, washing a filter cake with hot water at the temperature of 40-80 ℃, filtering, and drying for 2-3h at the temperature of 75-80 ℃ under the vacuum pressure of-0.08 MPa to obtain erythromycin thiocyanate; the acid is acetic acid; the sodium thiocyanate: the molar ratio of the erythromycin A is 1.0-2.0: 1.
2. the method according to claim 1, wherein the temperature during the filtration in the step (1) is 8-12 ℃.
3. The method as claimed in claim 1, wherein the organic solvent is used in the step (2) in an amount such that the concentration of erythromycin in the organic phase is 28000-32000 u/ml.
4. The method of claim 1, wherein the organic solvent in step (2) is butyl acetate, octanol or kerosene, or a combination of two or more thereof.
5. The method according to claim 1, wherein the base in the step (2) is a sodium hydroxide solution.
6. The method of claim 5, wherein the sodium hydroxide solution is at a concentration of 15-25%.
7. The method according to claim 1, wherein the pH value in the step (2) is 9.5 to 11.5.
8. The method of claim 1, wherein the temperature during the extraction is 30-35 ℃.
9. The method according to claim 1, wherein the saturated sodium chloride solution used in step (2) is used in an amount of 10 to 30%.
10. The method of claim 1, wherein the step (3) further comprises: and during crystallization, purified water is added into the light phase, and the using amount is 0.1-2 BV.
11. The method of claim 10, wherein the purified water is used in an amount of 0.8 to 1.2 BV.
12. The method according to claim 1, wherein the temperature in the step (3) is 30-40 ℃.
13. The method according to claim 1, wherein the concentration of the sodium thiocyanate solution in step (3) is 10-40%.
14. The method according to claim 13, wherein the concentration of the sodium thiocyanate solution in step (3) is 15-25%.
15. The process according to claim 1, wherein the molar ratio of sodium thiocyanate to erythromycin a in step (3) is 1.1-1.3: 1.
16. the method according to claim 1, wherein the sodium thiocyanate is added in step (3) for a period of 5min to 2 h.
17. The method as claimed in claim 16, wherein the sodium thiocyanate is added in step (3) for 50-70 min.
18. The method of claim 1, wherein the step (3) further comprises: and after the salt forming reaction is finished, adjusting the end point to pH 3-6 by using an acetic acid solution.
19. The method of claim 18, wherein the endpoint pH is 5-6.
20. The method of claim 1, wherein the concentration of acetic acid is 15-25%.
21. The method of claim 20, wherein the acetic acid is at a concentration of 20%.
22. The method according to claim 1, wherein the hot water temperature in step (3) is: 45-55 ℃.
23. A method for extracting low-content erythromycin A in a fermentation solution, which is characterized by comprising the following steps:
(1) and (3) filtering: putting the erythromycin fermentation liquor into a tank, and then filtering the erythromycin fermentation liquor by a ceramic membrane, wherein the molecular weight cut-off of the ceramic membrane is 3-10 ten thousand; the temperature of feed liquid in the filtering process is 5-20 ℃;
(2) and (3) extraction: adding an extracting agent into the filtrate, wherein the extracting agent is one or more of butyl acetate, butanol, octanol, kerosene, ethyl acetate; the dosage of the extractant is that the content of the erythromycin in the organic phase is 25000-45000 u/ml; adjusting pH to 8.0-12 with alkali solution; the temperature is 20-40 ℃; the alkali solution is sodium hydroxide and potassium hydroxide; stirring for 10min, separating phase, and collecting light phase; washing the light phase with 5-50% saturated sodium chloride solution by volume percentage, stirring for 10min, separating phases, and taking the light phase;
(3) and (3) crystallization: adding 0.1-2 BV of purified water into the light phase at 20-60 ℃, and adjusting the pH value to 6.5-7.5 by using a 15-25% acetic acid aqueous solution; adding a sodium thiocyanate solution, wherein the concentration of the sodium thiocyanate solution is 10-40%; the amount of sodium thiocyanate used was sodium thiocyanate: the molar ratio of erythromycin A is 1.0-2.0: 1; the adding time of the sodium thiocyanate is 5min-2h, and after the sodium thiocyanate is added, the sodium thiocyanate is continuously stirred and reacts for 0.5-1 h; then adjusting the end point to pH 3-6 with 15-25% acetic acid solution, crystallizing and filtering; washing the filter cake with hot water at the temperature of 40-80 ℃, wherein the temperature of the hot water is as follows: 45-55 ℃; filtering, and drying for 2-3h at the temperature of 75-80 ℃ under the vacuum of-0.08 MPa to obtain the erythromycin thiocyanate meeting the specification.
24. The method according to claim 23, wherein the temperature of the feed liquid during the filtration in the step (1) is 8-12 ℃.
25. The method of claim 23, wherein the extractant in step (2) is butyl acetate, octanol or kerosene.
26. The method as claimed in claim 23, wherein the amount of the extractant used in step (2) is such that the content of erythromycin in the organic phase is 28000-32000 u/m.
27. The method as claimed in claim 23, wherein the pH value in step (2) is adjusted to 9.5-11.5 with alkali solution.
28. The method according to claim 23, wherein the temperature in step (2) is 30-35 ℃.
29. The method as claimed in claim 23, wherein the alkali solution in the step (2) is sodium hydroxide solution with a concentration of 15-25%.
30. The method as claimed in claim 23, wherein the light phase in step (2) is washed with 10-30% by volume of saturated sodium chloride solution.
31. The method according to claim 23, wherein the purified water is added to the light phase at 0.8-1.2BV in step (3) at a temperature of 30-40 ℃.
32. The method as claimed in claim 23, wherein the concentration of the sodium thiocyanate solution in step (3) is 15-25%.
33. The method as claimed in claim 23, wherein the sodium thiocyanate is added in step (3) for 50-70 min.
34. The method according to claim 23, wherein the end point is adjusted to pH 5-6 with 20% acetic acid solution in the step (3).
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| CN110950918A (en) * | 2019-12-31 | 2020-04-03 | 伊犁川宁生物技术有限公司 | Method for recovering erythromycin thiocyanate from erythromycin thiocyanate secondary crystallization mother liquor |
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Non-Patent Citations (2)
| Title |
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| Combined UF–NF membrane system for filtering erythromycin fermentation broth and concentrating the filtrate to improve the downstream efficiency;Yasan He，et al.;《Separation and Purification Technology》;20091231;第66卷;第390-396页 * |
| Nanofiltration-based diafiltration process for solvent exchange in pharmaceutical manufacturing;Jignesh P. Sheth，et al;《Journal of Membrane Science》;20031231;第211卷;第251-261页 * |
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