CN109553645A - A kind of method of low content Erythromycin A in extraction fermentation liquid - Google Patents
A kind of method of low content Erythromycin A in extraction fermentation liquid Download PDFInfo
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- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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Abstract
The present invention relates to pharmaceutical fields, and in particular to a method of extract low content Erythromycin A in fermentation liquid, which comprises (1) fermentation liquid ceramic membrane filter；(2) filtrate solvent extraction, saturated sodium-chloride wash light phase；(3) it is crystallized at salt: water being added in light phase, acid supplemented solution adjusts pH, adds rhodanate, react with thiocyanic acid, erythromycin thiocyanate is generated, is continued to adjust pH with acetum, erythromycin thiocyanate, filtering is precipitated, hot water washing, is filtered, dry, obtains erythromycin thiocyanate.Erythromycin A component is lower than 75% in fermentation liquid, after the method for the present invention is handled, obtains satisfactory erythromycin thiocyanate finished product, and yield reaches 80% or more.
Description
Technical field
The present invention relates to pharmaceutical fields, and in particular to a method of extract low content Erythromycin A in fermentation liquid.
Background technique
Erythromycin is a kind of macrolide antibiotic, mainly include Erythromycin A, berythromycin, Erythromycin C, Erythromycin D,
6 kinds of components such as Erythromycin E and erythromycin F, wherein the antibacterial activity with Erythromycin A is most strong.Erythromycin generallys use microorganism hair
The method of ferment is produced, during fermented and cultured, erythromycin impurity component in fermentation liquid, with main component erythromycin
A is generated simultaneously, and zymotechnique is different, and the Erythromycin Components content in fermentation liquid is different.When fermentation is abnormal, Erythromycin A component
Content is lower, is lower than 70%, main impurity composition berythromycin, C, D higher.Traditional extraction process cannot efficiently separate miscellaneous
Matter component.At present there are mainly two types of technique extract fermentation liquid in erythromycin: technique 1: fermentation liquid micro-filtration, filtrate resin removal of impurities,
Nanofiltration condensing crystallizing, recrystallization.Technique 2: fermentation liquid plate-frame filtering, solvent extraction, extract liquor removal of impurities, extract liquor crystallization.
Traditional erythromycin fermentation liquid filtering uses microfiltration membranes or sheet frame, and filtering accuracy is low, filtrate contain a large amount of albumen and
Pigment, need to use resin to carry out purified treatment, and it is big to produce wastewater flow rate for complex process.
Traditional extracting method, using solvent extraction, solvent mainly is butyl acetate or mixing containing butyl acetate
Solvent is closed, in erythromycin thiocyanate crystallization, obtained erythromycin thiocyanate A content is 80% hereinafter, impurity berythromycin+C is big
In 3.0%, crystallization process total recovery is less than 85%.
CN103044508B discloses a kind of crystallization of isolating macrolide class antibiotic from erythromycin fermentation liquid
Erythromycin thiocyanate extracting method, this method use ultrafiltration membrance filter, and filtrate is concentrated by nanofiltration, by stream plus sulphur cyanogen in concentrate
After sour erythromycin obtains crude salt, crude salt is dissolved in the pre- solvent such as amyl acetate or methylene chloride.Or it will be red mould in concentrate
Element is extracted under alkaline condition in pre- solvent, then will carry out active carbon decoloring, acetone is added in destainer, is eventually adding
Rhodanate is crystallized.The patent uses a variety of solvents, and solvent recycling separation is difficult, and decolourizes in solvent phase, solvent damage
It consumes larger.Using crystallizing twice, yield losses are big.
Patent CN105348340A discloses a kind of preparation method of erythromycin thiocyanate, the light phase of this method after the extraction
It after being dehydrated using saturated sodium-chloride, is decolourized using active carbon, thiocyanate salt solution is then added, with erythromycin at salt
Afterwards, double solvent is added, adjusts pH using acetum and crystallizes to obtain erythromycin thiocyanate.The patent uses activity in solvent
Charcoal should not recycle, and solvent loss is larger, and double solvent is added at salt when, and Vehicle Composition is more, and separation is difficult.
CN201610177576 discloses a kind of preparation method of high-purity Erythromycin A, and this method takes erythromycin thiocyanate,
In the two-phase that organic solvent and water form, add alkali soluble solution, take organic phase, water is added and is washed, is precipitated in organic phase red
Mycin A alkali after filtration drying, then dry powder is taken water as a solvent and is recrystallized, obtains the Erythromycin A of high-purity.This method with
Erythromycin thiocyanate is original powder, after dissolution, crystallizes out Erythromycin A alkali, then recrystallized, obtains Erythromycin A.
Summary of the invention
For the above state of the art, the present invention provides a kind of method for extracting low content Erythromycin A in fermentation liquid, this method
The content of obtained finished product, Erythromycin A is greater than 80%, and for the content of berythromycin+C less than 3%, other impurity contents meet medicine
Allusion quotation standard.This method does not use active carbon, when solvent recycles, purifying water washing is added to mother liquor, split-phase takes light phase, i.e., repeatable
For the extraction of filtrate, recycling is convenient.The method of the present invention that low content Erythromycin A is extracted from fermentation liquid comprising:
(1) filter: fermentation liquid collects filtrate by 30,000-100 ten thousand membrane filtration of molecular cut off；
(2) extract: filtrate is extracted with organic solvent, then adjusts pH value 8.0-12, stirring to split-phase with alkali, and light phase is used full
And NaCl, obtain light phase solution；
(3) it crystallizes: water being added into light phase solution, control temperature, acid solution is then added and adjusts pH, adds thiocyanic acid
Reactant salt, the reaction was continued after adding, and then continues to adjust pH value to 3.0-6.0, crystallization, filtering, drying using acid solution, obtains
Erythromycin thiocyanate.
As one of embodiment, membrane retention molecular weight is 30,000-100 ten thousand, preferably model in step (1) of the present invention
Enclosing is 30,000-10 ten thousand, and preferably filter membrane is ceramic filtration membrane；Temperature is 5-20 DEG C, preferably 8-12 DEG C when filtering.
As one of embodiment, the dosage of organic solvent is that erythromycin is dense in organic phase in step (2) of the present invention
Degree is in 25000-45000u/ml, preferably 28000-32000u/ml；It is preferred that organic solvent is butyl acetate, butanol, octanol, coal
Oil, ethyl acetate or they one of or it is several；Preferably butylacetate, octanol or kerosene.
As one of embodiment, alkali is sodium hydroxide, potassium hydroxide in step (2) of the present invention；Preferably hydrogen-oxygen
Change sodium solution, further preferred concentration of sodium hydroxide solution is 15-25%.
As one of embodiment, further pH value is in 8.0-12, the preferred 9.5- of pH in step (2) of the present invention
11.5；Temperature is 20-40 DEG C, preferably 30-35 DEG C when extraction.
As one of embodiment, the dosage of step (2) saturated sodium chloride solution of the present invention is 5-50% (v/v),
Preferably 10-30%.
As one of embodiment, step (3) of the present invention further comprises: when crystallization, being added in light phase pure
Change water, dosage is 0.1~2BV, preferably 0.8-1.2BV；
As one of embodiment, step (3) of the present invention further comprises: temperature is 20~60 DEG C, preferably 30-
40℃；
As one of embodiment, step (3) of the present invention further comprises: after purified water is added, using acid solution
Adjust pH to 6.5-7.5.
As one of embodiment, the concentration of sodium thiocyanate solution is 10-40% in step (3) of the present invention, preferably
15-25%；
As one of embodiment, step (3) of the present invention further comprises: the sodium sulfocyanate and Erythromycin A
Molar ratio be 1.0~2.0:1, preferably 1.1~1.3:1；
As one of embodiment, step (3) of the present invention further comprises: the addition time is 5min-2h, preferably
50-70min。
As one of embodiment, step (3) of the present invention further comprises: after adding rhodanate, continuing anti-
Answer 0.5~1h.
As one of embodiment, step (3) of the present invention further comprises: salt-forming reaction is finished, molten with acetic acid
It is 3~6 that liquid, which adjusts terminal to pH value, and preferably endpoint pH is 5-6.
As one of embodiment, the acid in step (3) of the present invention is acetic acid；It is preferred that the concentration of acetic acid is 15-
25%, further preferably 20%.
As one of embodiment, step (3) of the present invention further comprises: 40~80 DEG C of hot water wash of filter cake
It washs, hot water optimum temperature are as follows: 45-55 DEG C；
As one of embodiment, step (3) of the present invention further comprises: filtering vacuum -0.08MPa with
Under, 75~80 DEG C of dryings must meet defined erythromycin thiocyanate.
As one of embodiment, the method that the present invention extracts low content Erythromycin A from fermentation liquid includes:
(1) it filters
After erythromycin fermentation liquid puts tank, into ceramic membrane filter, ceramic membrane interception molecular weight is 30,000~1,000,000, optimal section
Staying range is 30,000-10 ten thousand；.Filter process feed liquid temperature is 5-20 DEG C, preferably 8-12 DEG C；
(2) it extracts
Be added extractant in filtrate, the extractant be butyl acetate, butanol, octanol, kerosene, ethyl acetate or they in
One or several kinds, preferably butylacetate, octanol or kerosene；Solvent quantity is that erythromycin content is 25000- in organic phase
45000u/ml, preferably 28000~32000u/ml；PH is adjusted in 8.0-12, the preferred 9.5-11.5 of pH with lye；Temperature is 20-
40 DEG C, preferably 30-35 DEG C；The aqueous slkali is sodium hydroxide, potassium hydroxide, it is preferable to use sodium hydroxide solution, concentration 15-
25%；Split-phase after stirring 10min, takes light phase；Light phase is washed using the saturated sodium chloride solution of 5-50% (v/v), dosage
Preferably 10-30%, stirs 10min, and split-phase takes light phase；
(3) it crystallizes
The purified water of 0.1~2BV, preferably 0.8-1.2BV are added in light phase, temperature is 20~60 DEG C, preferably 30-40
DEG C, with 15-25%, preferably 20% aqueous acetic acid, adjust pH=6.5~7.5；Sodium thiocyanate solution is added, sodium sulfocyanate is molten
The concentration of liquid is 10-40%, preferably 15-25%；The dosage of sodium sulfocyanate is sodium sulfocyanate: Erythromycin A molar ratio be 1.0~
2.0:1, preferably 1.0~1.5:1, further preferred 1.1-1.3:1；The addition time is 5min-2h, preferably 50-70min；It adds
The reaction was continued afterwards 0.5~1h, with 15-25%, preferably 20% acetum adjusts terminal to pH=3~6, and preferably terminal pH is
5-6, filtering；Filter cake is washed with 40~80 DEG C of hot water, hot water optimum temperature are as follows: 45-55 DEG C.Filtering, wet-milling at 75~80 DEG C,
Vacuum -0.08MPa must meet defined erythromycin thiocyanate hereinafter, dry 2-3h.
Diluent purifying is added in crystallization by ceramic membrane filter, solvent extraction, saturated sodium-chloride washing for this method
Water slows down brilliant speed out, obtained erythromycin thiocyanate finished product (process flow chart is referring to attached drawing 1), present invention gained Erythromycin A
Content is high, and impurity composition content is low, and for the extract yield of erythromycin 80% or more, other impurity contents meet standards of pharmacopoeia.
This method does not use active carbon.When solvent recycles, purifying water washing is added to mother liquor, split-phase takes light phase, i.e., repeatable to be suitable for
The extraction of filtrate, recycling are convenient.
The finished product that the method for the present invention obtains, the content of Erythromycin A are greater than 80%, the content of berythromycin+C less than 3%,
Its impurity content meets standards of pharmacopoeia.
Detailed description of the invention
Fig. 1: process flow chart of the invention.
Specific embodiment
The present invention for the present invention is further explained, but is not limited of the invention in any manner by following embodiment
Effective range.
Embodiment 1
Erythromycin fermentation liquid 200L, erythromycin chemical titer are about 8000u/ml, and the content of component Erythromycin A is 70%,
Berythromycin is 3%, Erythromycin C 6%.Temperature is filtered at 12 DEG C using the ceramic membrane that molecular cut off is 30,000.Filtrate
Middle addition 50L's uses double solvent, and temperature adjusts pH to 10.0 at 35 DEG C, using 20% NaOH solution, stirs 10min, warp
Centrifuge is separated.The saturated sodium chloride solution of 10L is added in light phase, 30 DEG C of temperature, stirs 10 minutes, stands split-phase.It takes
Light phase.In light phase, the purified water of 1.0BV is added, 30 DEG C of temperature, with 20% vinegar acid for adjusting pH to 6.5, adding concentration is 20%
Sodium thiocyanate solution, the dosage of sodium sulfocyanate are sodium sulfocyanate: Erythromycin A molar ratio is 1.2:1, extremely using vinegar acid for adjusting pH
5.0, filtering, filter cake is washed with 50 DEG C of hot water, is filtered, and at 75~80 DEG C, vacuum -0.085MPa, dry 2h must meet the requirements
Erythromycin thiocyanate finished product, content: 826u/g,
In products obtained therefrom, the content that each component content is respectively as follows: Erythromycin A is 81.5%, and berythromycin content is 1.4%.
The content of Erythromycin C is 2.6%, 1 content 0.7% of erythromycin impurity, number of erythromycin enol ether 0.3%, other equal composite medicines of impurity
Allusion quotation requirement.The yield of Erythromycin A is greater than 80%.
Embodiment 2
Erythromycin fermentation liquid 500L, erythromycin chemical titer are about 8000u/ml, and the content of component Erythromycin A is 65%,
Berythromycin is 4%, Erythromycin C 10%.Temperature is filtered at 8 DEG C using the ceramic membrane that molecular cut off is 50,000.Filtrate
Middle addition 120L's uses double solvent, and temperature adjusts pH to 11.0 at 30 DEG C, using 20% NaOH solution, stirs 10min, warp
Centrifuge is separated.The saturated sodium chloride solution of 35L is added in light phase, 30 DEG C of temperature, stirs 10 minutes, stands split-phase.It takes
Light phase.In light phase, the purified water of 0.8BV is added, 30 DEG C of temperature, with 20% vinegar acid for adjusting pH to 7.0, adding concentration is 20%
Sodium thiocyanate solution, the dosage of sodium sulfocyanate are sodium sulfocyanate: Erythromycin A molar ratio is 1.1:1, extremely using vinegar acid for adjusting pH
5.5, filtering, filter cake is washed with 50 DEG C of hot water, is filtered, and at 75~80 DEG C, vacuum -0.085MPa, dry 3h must meet the requirements
Erythromycin thiocyanate finished product, content: 806u/g,
In products obtained therefrom, the content that each component content is respectively as follows: Erythromycin A is 81.0%, and berythromycin content is 1.7%.
The content of Erythromycin C is 2.1%, 1 content 1.1% of erythromycin impurity, number of erythromycin enol ether 0.4%, other equal composite medicines of impurity
Allusion quotation requirement.The yield of Erythromycin A is greater than 80%.
Embodiment 3
Erythromycin fermentation liquid 1000L, erythromycin chemical titer are about 8000u/ml, and the content of component Erythromycin A is 76%,
Berythromycin is 3%, Erythromycin C 5%.Temperature is filtered at 12 DEG C using the ceramic membrane that molecular cut off is 100,000.Filter
120L is added in liquid uses double solvent, and temperature adjusts pH to 11.0 at 35 DEG C, using 20% NaOH solution, stirs 10min,
It is separated through centrifuge.The saturated sodium chloride solution of 35L is added in light phase, 30 DEG C of temperature, stirs 10 minutes, stands split-phase.
Take light phase.In light phase, the purified water of 1.2BV is added, 30 DEG C of temperature, with 20% vinegar acid for adjusting pH to 7.5, adding concentration is 20%
Sodium thiocyanate solution, the dosage of sodium sulfocyanate is sodium sulfocyanate: Erythromycin A molar ratio is 1.1:1, extremely using vinegar acid for adjusting pH
5.0, filtering, filter cake is washed with 50 DEG C of hot water, is filtered, and at 75~80 DEG C, vacuum -0.085MPa, dry 3h must meet the requirements
Erythromycin thiocyanate finished product, content: 785u/g.
In products obtained therefrom, the content that each component content is respectively as follows: Erythromycin A is 80.2%, and berythromycin content is 1.5%.
The content of Erythromycin C is 2.8%, 1 content 1.5% of erythromycin impurity, number of erythromycin enol ether 0.4%, other equal composite medicines of impurity
Allusion quotation requirement.The yield of Erythromycin A is greater than 80%.
Claims (18)
1. a kind of method for extracting low content Erythromycin A in fermentation liquid, which is characterized in that the described method includes:
(1) filter: fermentation liquid collects filtrate by 30,000-100 ten thousand membrane filtration of molecular cut off；
(2) extract: filtrate is extracted with organic solvent, then adjusts pH value 8.0-12, stirring to split-phase, light phase saturation chlorine with alkali
Change sodium washing, obtains light phase solution；
(3) it crystallizes: water being added into light phase solution, control temperature, acid solution is then added and adjusts pH value, adds rhodanate
Reaction, the reaction was continued after adding, and then continues adjusting pH value using acid solution and is washed to 3.0-6.0, filtering, filter cake with hot water,
Filtering, it is dry, obtain erythromycin thiocyanate.
2. the method according to claim 1, wherein membrane retention molecular weight is 30,000-100 in the step (1)
Ten thousand, preferred scope is 30,000-10 ten thousand, and preferably filter membrane is ceramic filtration membrane；Temperature is 5-20 DEG C, preferably 8-12 DEG C when filtering.
3. the method according to claim 1, wherein the dosage of organic solvent is organic to make in the step (2)
Erythromycin concentration is 25000-45000u/ml, preferably 28000~32000u/ml in phase；It is preferred that organic solvent be butyl acetate,
Butanol, octanol, kerosene or ethyl acetate or two or more combination in them；Preferably butylacetate, octanol or coal
Oil or two or more combination in them.
4. the method according to claim 1, wherein alkali is sodium hydroxide or hydroxide in the step (2)
Potassium；Preferably sodium hydroxide solution；The concentration of sodium hydroxide solution is preferably 15-25%.
5. the method according to claim 1, wherein the step (2) further comprise pH value be 8.0-12,
Preferable ph is 9.5-11.5；Temperature is 20-40 DEG C, preferably 30-35 DEG C when extraction.
6. the method according to claim 1, wherein the dosage of the step (2) saturated sodium chloride solution is 5-
50% (v/v)；Preferably 10-30%.
7. the method according to claim 1, wherein the step (3) further comprises: when crystallization, light
Purified water is incorporated as in phase, dosage is 0.1~2BV, preferably 0.8-1.2BV.
8. the method according to claim 1, wherein the step (3) further comprises: temperature is 20~60
DEG C, preferably 30-40 DEG C.
9. the method according to claim 1, wherein the step (3) further comprises: purified water is added
Afterwards, pH to 6.5-7.5 is adjusted with acid solution.
10. the method according to claim 1, wherein the concentration of sodium thiocyanate solution is in the step (3)
10-40%, preferably 15-25%.
11. the method according to claim 1, wherein sodium sulfocyanate and Erythromycin A described in the step (3)
Molar ratio be 1.0~2.0:1, preferably 1.1-1.3:1.
12. the method according to claim 1, wherein it is 5min-2h that the time is added in the step (3), preferably
50-70min。
13. the method according to claim 1, wherein the step (3) further comprises: adding thiocyanic acid
After salt, the reaction was continued 0.5~1h.
14. the method according to claim 1, wherein the step (3) further comprises: salt-forming reaction is complete
Finish, adjusts terminal to pH=3~6 with acetum, preferably terminal pH is 5-6.
15. the method according to claim 1, wherein the acid in the step (3) is acetic acid；It is preferred that acetic acid
Concentration is 15-25%, further preferred 20%.
16. the method according to claim 1, wherein the step (3) further comprises: filter cake with 40~
80 DEG C of hot water washing, hot water optimum temperature are as follows: 45-55 DEG C.
17. the method according to claim 1, wherein the step (3) further comprises: at 75~80 DEG C,
Vacuum -0.08MPa must meet defined erythromycin thiocyanate hereinafter, dry 2-3h.
18. any method according to claim 1~17, which is characterized in that the described method includes:
(1) filter: after erythromycin fermentation liquid puts tank, into ceramic membrane filter, ceramic membrane interception molecular weight is 30,000~1,000,000, most
Excellent retention range is 30,000-10 ten thousand；Filter process feed liquid temperature is 5-20 DEG C, preferably 8-12 DEG C；
(2) extract: being added extractant in filtrate, the extractant be butyl acetate, butanol, octanol, kerosene, ethyl acetate or it
One of or several, preferably butylacetate, octanol or kerosene；Solvent quantity is to make erythromycin content in organic phase
25000-45000u/ml, preferably 28000~32000u/ml；Adjusting pH value with lye is 8.0-12, preferable ph 9.5-
11.5；Temperature is 20-40 DEG C, preferably 30-35 DEG C；The aqueous slkali is sodium hydroxide, potassium hydroxide, it is preferable to use hydroxide
Sodium solution, concentration 15-25%；Split-phase after stirring 10min, takes light phase；Light phase is molten using the saturated sodium-chloride of 5-50% (v/v)
Liquid is washed, and dosage is preferably 10-30%, stirs 10min, and split-phase takes light phase；
(3) it crystallizes: the purified water of 0.1~2BV, preferably 0.8-1.2BV being added in light phase, temperature is 20~60 DEG C, preferably 30-
40 DEG C, with 15-25%, further preferably 20% aqueous acetic acid, adjust pH=6.5~7.5；Sodium thiocyanate solution is added,
The concentration of sodium thiocyanate solution is 10-40%, preferably 15-25%；The dosage of sodium sulfocyanate is sodium sulfocyanate: Erythromycin A mole
Than for 1.0~2.0:1, preferably 1.1-1.3:1；The addition time is 5min-2h, preferably 50-70min, and after adding, it is anti-to continue stirring
Answer 0.5~1h；Then 15-25% is used, further preferred 20% acetum adjusts terminal to pH=3~6, preferably terminal pH
For 5-6, crystallization and filtration；Filter cake is washed with 40~80 DEG C of hot water, hot water optimum temperature are as follows: 45-55 DEG C；Filtering, 75~
80 DEG C, vacuum -0.08MPa must meet defined erythromycin thiocyanate hereinafter, dry 2-3h.
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| CN109942655A (en) * | 2019-04-29 | 2019-06-28 | 宜昌东阳光药业股份有限公司 | A kind of continuous crystallisation process of erythromycin thiocyanate crude product |
| 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 |
| CN114113365A (en) * | 2021-10-25 | 2022-03-01 | 伊犁川宁生物技术股份有限公司 | Liquid chromatography-tandem mass spectrometry detection method for antibiotic substances in erythromycin fermentation wastewater |
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| CN103044508A (en) * | 2013-01-09 | 2013-04-17 | 宁夏启元药业有限公司 | Method for extracting crystallized erythromycin thiocyanate from fermentation liquid |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109942655A (en) * | 2019-04-29 | 2019-06-28 | 宜昌东阳光药业股份有限公司 | A kind of continuous crystallisation process of erythromycin thiocyanate crude product |
| CN109942655B (en) * | 2019-04-29 | 2020-05-12 | 宜昌东阳光药业股份有限公司 | Continuous crystallization method of erythromycin thiocyanate crude product |
| 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 |
| CN114113365A (en) * | 2021-10-25 | 2022-03-01 | 伊犁川宁生物技术股份有限公司 | Liquid chromatography-tandem mass spectrometry detection method for antibiotic substances in erythromycin fermentation wastewater |
| CN114113365B (en) * | 2021-10-25 | 2023-09-29 | 伊犁川宁生物技术股份有限公司 | Liquid chromatography-tandem mass spectrometry detection method for antibiotics in erythromycin fermentation wastewater |
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