CN109081844A - A method of extracting spectinomycin from fermentation culture medium - Google Patents
A method of extracting spectinomycin from fermentation culture medium Download PDFInfo
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- CN109081844A CN109081844A CN201811175836.XA CN201811175836A CN109081844A CN 109081844 A CN109081844 A CN 109081844A CN 201811175836 A CN201811175836 A CN 201811175836A CN 109081844 A CN109081844 A CN 109081844A
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Abstract
The method that the present invention provides a kind of to extract spectinomycin from fermentation culture medium.The present invention extracts spectinomycin using liquid ion exchanger, and sulfonic group and spectinomycin have good binding ability in the liquid ion exchanger, selectively can fast and accurately extract spectinomycin from the system contained a large amount of impurities.Using method provided by the invention, spectinomycin yield may be up to 65% or more, and up to 98%, good product quality meets EP, USP quality standard, and has the advantages such as the period is short, blowdown flow rate is few, production cost is low purity.
Description
Technical field
The present invention relates to spectinomycin extractive technique fields, and in particular to one kind extracts spectinomycin from fermentation culture medium
Method.
Background technique
Spectinomycin (Spectinomycin) is a kind of logical by streptomyces spectabilis (Streptomyces spectabilis)
Most gram-positive bacterias and Gram-negative bacteria are all had antibacterial by the aminoglycosides antibiotics that everfermentation extraction method generates
Activity, it is highly effective to current domestic popular Neisseria gonorrhoeae separation strains, penicillin resistant, tetracycline gonococcus to it also
There is high susceptibility, in terms of the infection caused by clinical treatment Neisseria gonorrhoeae etc., with curative effect is prominent, side reaction is few and makes
With it is safe the features such as, it has also become China treatment stranguria syndrome one of choice drug.In addition the hypotoxicity and broad-spectrum antiseptic of spectinomycin
Property keep its application in agricultural and the fields such as animal husbandry also more and more extensive.
Currently, the traditional extraction process of spectinomycin is usually resin adsorption analytic method, yield is lower, and extracting cycle compared with
Length generates a large amount of acidic and alkaline waste water.
Summary of the invention
The method that the purpose of the present invention is to provide a kind of to extract spectinomycin from fermentation culture medium, it is provided by the invention
Method spectinomycin yield and purity is high, good product quality meet EP, USP quality standard；And have the period is short, blowdown flow rate is few,
The low advantage of production cost.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The method that the present invention provides a kind of to extract spectinomycin from fermentation culture medium, comprising the following steps:
It is separated by solid-liquid separation after the pH value of spectinomycin fermentation liquid is adjusted to 3.0~4.0 using acid reagent, using alkali
The pH value of gained liquid material is adjusted to 6.0~7.0 by property reagent, obtains precursor solution；
Ion exchange is carried out after the precursor solution is mixed with liquid ion exchanger and organic solvent, it is isolated
Organic phase containing spectinomycin；Contain sulfonic group in the liquid ion exchanger；
Water is carried out after the organic phase containing spectinomycin is mixed with aqueous extraction agent to mention, it is isolated to contain grand sight
The water phase of mycin；
It will be crystallized after the water phase decoloration containing spectinomycin, obtain spectinomycin.
Preferably, the acid reagent includes hydrochloric acid, sulfuric acid or oxalic acid, and the concentration of the acid reagent is 1.5~
2.5mol/L。
Preferably, the alkaline reagent includes sodium hydroxide solution, potassium hydroxide solution or ammonium hydroxide, the alkaline reagent
Concentration is 5~15wt.%.
Preferably, the liquid ion exchanger include propylnaphthalenesulfonic acid or nonyl how sulfonic acid.
Preferably, the organic solvent includes ethyl acetate, butyl acetate, propyl acetate, toluene or n-butanol.
Preferably, the volume ratio of the spectinomycin fermentation liquid, liquid ion exchanger and organic solvent be 5:(0.15~
0.25): (0.75~0.85).
Preferably, the aqueous extraction agent includes hydrochloric acid, ammonium chloride solution or sodium chloride solution, the aqueous extraction agent
Concentration is 1.5~2.5wt.%.
Preferably, the organic phase containing spectinomycin and the volume ratio of aqueous extraction agent are (4~6): 1.
Preferably, it is described crystallization the following steps are included:
Gained destainer after decoloration is concentrated, cooling processing is carried out when until there is crystal precipitation, obtains spectinomycin；Its
In, the temperature of the concentration is 65~75 DEG C；The time of the cooling processing is 3.5~4.5h, and the cooling handles final
Temperature is 5~10 DEG C.
Preferably, after the crystallization further include:
Gained system after crystallization is separated by solid-liquid separation, obtained solid material is dried, spectinomycin is obtained.
The method that the present invention provides a kind of to extract spectinomycin from fermentation culture medium, it is using acid reagent that grand sight is mould
The pH value of plain fermentation liquid is separated by solid-liquid separation after being adjusted to 3.0~4.0, using alkaline reagent by the pH value tune of gained liquid material
Section obtains precursor solution to 6.0~7.0；After the precursor solution is mixed with liquid ion exchanger and organic solvent
Carry out ion exchange, the isolated organic phase containing spectinomycin；Contain sulfonic group in the liquid ion exchanger；By institute
It states progress water after the organic phase containing spectinomycin is mixed with aqueous extraction agent to mention, the isolated water phase containing spectinomycin；
It will be crystallized after the water phase decoloration containing spectinomycin, obtain spectinomycin.The present invention uses liquid ion exchanger
Spectinomycin is extracted, sulfonic group and spectinomycin have good binding ability, energy in the liquid ion exchanger
It is enough selectively fast and accurately to extract spectinomycin from the system contained a large amount of impurities；In addition, proposing processing by water
Afterwards, the liquid ion exchanger can activity recovery, may be reused.Using method provided by the invention, grand sight is mould
Plain yield may be up to 65% or more, and purity meets EP, USP quality standard up to 98%, good product quality, and, row short with the period
The advantages such as dirt is measured less, production cost is low.
Specific embodiment
The method that the present invention provides a kind of to extract spectinomycin from fermentation culture medium, comprising the following steps:
It is separated by solid-liquid separation after the pH value of spectinomycin fermentation liquid is adjusted to 3.0~4.0 using acid reagent, using alkali
The pH value of gained liquid material is adjusted to 6.0~7.0 by property reagent, obtains precursor solution；
Ion exchange is carried out after the precursor solution is mixed with liquid ion exchanger and organic solvent, it is isolated
Organic phase containing spectinomycin；Contain sulfonic group in the liquid ion exchanger；
Water is carried out after the organic phase containing spectinomycin is mixed with aqueous extraction agent to mention, it is isolated to contain grand sight
The water phase of mycin；
It will be crystallized after the water phase decoloration containing spectinomycin, obtain spectinomycin.
The present invention is separated by solid-liquid separation after the pH value of spectinomycin fermentation liquid is adjusted to 3.0~4.0 using acid reagent,
The pH value of gained liquid material is adjusted to 6.0~7.0 using alkaline reagent, obtains precursor solution.In the present invention, described
Spectinomycin fermentation liquid is preferably obtained by streptomyces spectabilis by Spawn incubation and fermentation；The present invention to the Spawn incubation and
The concrete operation method of fermentation does not have special restriction, using method well known to those skilled in the art.In the present invention,
The content of spectinomycin is preferably 3000~4500u/mL in the spectinomycin fermentation liquid, more preferably 3500~4000u/
mL。
The present invention does not have the acid reagent special restriction, using it is well known to those skilled in the art can be by institute
The pH value for stating spectinomycin fermentation liquid is adjusted to 3.0~4.0 reagent；In the present invention, the acid reagent preferably wraps
Hydrochloric acid, sulfuric acid or oxalic acid are included, the concentration of the acid reagent is preferably 1.5~2.5mol/L, more preferably 2mol/L.The present invention
The pH value of spectinomycin fermentation liquid is adjusted to 3.0~4.0 using acid reagent, is to improve subsequent fermentation liquid and be separated by solid-liquid separation
Yield improves separating effect.
The present invention does not have the mode of the separation of solid and liquid special restriction, using side well known to those skilled in the art
Method is specific as filtered or being centrifuged.The present invention is obtained by being separated by solid-liquid separation the solid impurities such as bacteria residue in removal system containing big
The liquid material of miromycin.
The present invention does not have the alkaline reagent special restriction, can will be consolidated using well known to those skilled in the art
The pH value of gained liquid material is adjusted to 6.0~7.0 reagent after liquid separation；In the present invention, the alkaline reagent is excellent
Choosing includes sodium hydroxide solution, potassium hydroxide solution or ammonium hydroxide, and the concentration of the alkaline reagent is preferably 5~15wt.%, more excellent
It is selected as 10wt.%.The pH value of gained liquid material after separation of solid and liquid is adjusted to 6.0~7.0 using alkaline reagent by the present invention, is had
Conducive to the progress of subsequent ion exchange.
After obtaining precursor solution, the present invention mixes the precursor solution with liquid ion exchanger and organic solvent
After carry out ion exchange, the isolated organic phase containing spectinomycin；Contain sulfonic group in the liquid ion exchanger.?
In the present invention, the liquid ion exchanger preferably include propylnaphthalenesulfonic acid or nonyl how sulfonic acid；The organic solvent preferably wraps
Include ethyl acetate, butyl acetate, propyl acetate, toluene or n-butanol.In the present invention, the spectinomycin fermentation liquid, liquid
The volume ratio of ion-exchanger and organic solvent is preferably 5:(0.15~0.25): (0.75~0.85), more preferably 5:0.2:
0.8。
In the present invention, the precursor solution mixed with liquid ion exchanger and organic solvent preferably will be described before
Liquid solution is driven to mix with the organic solution of liquid ion exchanger.
In the present invention, the time of the ion exchange is preferably 25~35min, more preferably 30min；Temperature is preferably
20~30 DEG C, more preferably 25 DEG C.In the present invention, the ion exchange preferably carries out under agitation；The present invention for
The rate of the stirring does not have special restriction, using stirring rate well known to those skilled in the art.
The present invention carries out ion exchange, the liquid ions exchange to the precursor solution using liquid ion exchanger
In agent sulfonic group and spectinomycin have good binding ability, can be selectively by spectinomycin from containing a large amount of impurities
It is fast and accurately extracted in system；In addition, the liquid ion exchanger can restore living after subsequent water proposes processing
Property, it may be reused.
The present invention restriction not special for the separation, using isolated technical side well known to those skilled in the art
Case, the present invention are separated after preferably passing through stratification or are separated using high speed dish type centrifuge.
After obtaining the organic phase containing spectinomycin, the present invention is by the organic phase and aqueous extraction containing spectinomycin
It carries out water after agent mixing to mention, the isolated water phase containing spectinomycin.In the present invention, the aqueous extraction agent preferably includes
The concentration of hydrochloric acid, ammonium chloride solution or sodium chloride solution, the aqueous extraction agent is preferably 1.5~2.5wt.%, more preferably
2wt.%.In the present invention, the organic phase containing spectinomycin and the volume ratio of aqueous extraction agent are preferably (4~6): 1,
More preferably 5:1.
In the present invention, the time that the water mentions is preferably 25~35min, more preferably 30min；Temperature is preferably 20~
30 DEG C, more preferably 25 DEG C.In the present invention, the water mentions preferably carries out under agitation；The present invention is for the stirring
Rate there is no special restriction, using stirring rate well known to those skilled in the art.
The present invention carries out water to the organic phase containing spectinomycin using aqueous extraction agent and mentions, and is in order to which grand sight is mould
Element, which is transferred in water phase, carries out subsequent purification, while also making liquid ion exchanger activity recovery, uses convenient for following cycle.
The present invention restriction not special for the separation, using isolated technical side well known to those skilled in the art
Case, the present invention separate after preferably passing through stratification.
After obtaining the water phase containing spectinomycin, the present invention ties after the water phase containing spectinomycin is decolourized
Crystalline substance obtains spectinomycin.In the present invention, decoloration reagent used by the decoloration is preferably active carbon, specifically will be described
Water phase containing spectinomycin is decolourized after mixing with active carbon, then gained destainer is carried out later crystallization by filtering.This
Invention does not have special restriction for the concrete operations condition of the decoloration, using the skill of decoloration well known to those skilled in the art
Art scheme.
In the present invention, the crystallization preferably includes following steps:
Gained destainer after decoloration is concentrated, cooling processing is carried out when until there is crystal precipitation, obtains spectinomycin；Its
In, the temperature of the concentration is 65~75 DEG C；The time of the cooling processing is 3.5~4.5h, and the cooling handles final
Temperature is 5~10 DEG C.
In the present invention, the concentration is preferably concentrated in vacuo, and the temperature of the vacuum concentration is preferably 65~75 DEG C, more
Preferably 70 DEG C.
In the present invention, it is described cooling processing for by slow cooling realize crystallization process, it is described cooling processing when
Between preferably 3.5~4.5h, more preferably 4h；The final temperature of the cooling processing is preferably 5~10 DEG C.The present invention is for institute
The rate of temperature fall stated in cooling treatment process does not have special restriction, through 3.5~4.5h by 65~75 DEG C of uniform decrease in temperature to 5~10
DEG C.
Spectinomycin in system is precipitated sufficiently by crystallization in the present invention, wherein can be to avoid crystal using slow cooling
It is precipitated too fast and makes in product comprising impurity, and product stable crystal form can be made uniform, improve product quality.
After completing the crystallization, gained system after crystallization is preferably separated by solid-liquid separation by the present invention, by obtained solid material
It is dried, obtains spectinomycin, obtain spectinomycin.The present invention does not have the mode of the separation of solid and liquid special limit
It is fixed, it is specific as filtered using the technical solution of separation of solid and liquid well known to those skilled in the art.The present invention is for described dry
Dry not special restriction using the technical solution of drying well known to those skilled in the art, guarantees that material is sufficiently dry.
Below in conjunction with the embodiment in the present invention, the technical solution in the present invention is clearly and completely described.It is aobvious
So, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the reality in the present invention
Example is applied, every other embodiment obtained by those of ordinary skill in the art without making creative efforts all belongs to
In the scope of protection of the invention.
Embodiment 1
Take spectinomycin fermentation liquid (spectinomycin content is 3780u/mL) 5L, the salt acid for adjusting pH for being 2mol/L with concentration
Value is separated by solid-liquid separation to 3.5, collects filtrate 4.8L；The sodium hydroxide solution that filtrate is 10wt.% with concentration adjusts pH value to 6.5,
The ethyl acetate solution that propylnaphthalenesulfonic acid is added (is formulated) 1L by volume by propylnaphthalenesulfonic acid and ethyl acetate for 1:4,
Ion exchange 30min is carried out under agitation, and stratification collects the organic phase containing spectinomycin；Concentration, which is added, is
The ammonium chloride solution 200mL of 2wt.% carries out water under agitation and mentions 30min, stratification, and collection contains spectinomycin
Water phase 450mL；Active carbon is added to decolourize, filters, gained destainer is concentrated in vacuo under the conditions of 70 DEG C, until there is crystal
It carries out cooling processing (through 4h uniform decrease in temperature to 10 DEG C), filters when precipitation, gained crystal is dry, obtain spectinomycin
18.60g, yield 63.6%, purity 97.6%.
Embodiment 2
Spectinomycin fermentation liquid (spectinomycin content is 3960u/mL) 100L is taken, is adjusted with the sulfuric acid that concentration is 2mol/L
PH value is separated by solid-liquid separation to 4.0, collects filtrate 97L；Filtrate with concentration be 10wt.% potassium hydroxide solution adjust pH value to
7.0, the butanol solution of nonyl naphthalene sulfonic acids is added (union base naphthalene sulfonic acids and ethyl acetate are formulated by volume for 1:4)
20L, carries out ion exchange 30min under agitation, and stratification collects the organic phase containing spectinomycin；Concentration is added
For the hydrochloric acid solution 4L of 2wt.%, water is carried out under agitation and mentions 30min, stratification collects the water containing spectinomycin
Phase 9L；Active carbon is added to decolourize, filters, gained destainer is concentrated in vacuo under the conditions of 75 DEG C, until there is crystal precipitation
Shi Jinhang cooling handles (through 4h uniform decrease in temperature to 15 DEG C), filtering, and gained crystal is dry, obtains spectinomycin 363.20g, produces
Rate is 64.3, purity 97.8%.
Embodiment 3
Spectinomycin fermentation liquid (spectinomycin content is 4060u/mL) 500L is taken, is adjusted with the sulfuric acid that concentration is 2mol/L
PH value is separated by solid-liquid separation to 3.0, collects filtrate 480L；The ammonia spirit that filtrate is 10wt.% with concentration adjusts pH value to 5.0, adds
Butyl acetate solution (union base naphthalene sulfonic acids and ethyl acetate are formulated by volume for the 1:4) 96L for entering nonyl naphthalene sulfonic acids,
Ion exchange 30min is carried out under stirring condition, stratification collects the organic phase containing spectinomycin；Concentration, which is added, is
The sodium chloride solution 20L of 2wt.% carries out water under agitation and mentions 30min, and stratification collects the water containing spectinomycin
Phase 46L；Active carbon is added to decolourize, filters, gained destainer is concentrated in vacuo under the conditions of 65 DEG C, until there is crystal precipitation
Shi Jinhang cooling handles (through 4h uniform decrease in temperature to 5 DEG C), filtering, and gained crystal is dry, obtains spectinomycin 1.81kg, yield
It is 65.2%, purity 98.1%.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of method for extracting spectinomycin from fermentation culture medium, comprising the following steps:
It is separated by solid-liquid separation after the pH value of spectinomycin fermentation liquid is adjusted to 3.0~4.0 using acid reagent, is tried using alkalinity
The pH value of gained liquid material is adjusted to 6.0~7.0 by agent, obtains precursor solution；
Carry out ion exchange after the precursor solution is mixed with liquid ion exchanger and organic solvent, it is isolated containing
The organic phase of spectinomycin；Contain sulfonic group in the liquid ion exchanger；
Water is carried out after the organic phase containing spectinomycin is mixed with aqueous extraction agent to mention, it is isolated to contain spectinomycin
Water phase；
It will be crystallized after the water phase decoloration containing spectinomycin, obtain spectinomycin.
2. described the method according to claim 1, wherein the acid reagent includes hydrochloric acid, sulfuric acid or oxalic acid
The concentration of acid reagent is 1.5~2.5mol/L.
3. the method according to claim 1, wherein the alkaline reagent includes sodium hydroxide solution, hydroxide
Potassium solution or ammonium hydroxide, the concentration of the alkaline reagent are 5~15wt.%.
4. the method according to claim 1, wherein the liquid ion exchanger includes propylnaphthalenesulfonic acid or nonyl
Base how sulfonic acid.
5. the method according to claim 1, wherein the organic solvent includes ethyl acetate, butyl acetate, second
Propyl propionate, toluene or n-butanol.
6. according to claim 1, method described in 4 or 5, which is characterized in that the spectinomycin fermentation liquid, liquid ions exchange
The volume ratio of agent and organic solvent is 5:(0.15~0.25): (0.75~0.85).
7. the method according to claim 1, wherein the aqueous extraction agent include hydrochloric acid, ammonium chloride solution or
Sodium chloride solution, the concentration of the aqueous extraction agent are 1.5~2.5wt.%.
8. the method according to the description of claim 7 is characterized in that the organic phase containing spectinomycin and aqueous extraction agent
Volume ratio be (4~6): 1.
9. the method according to claim 1, wherein it is described crystallization the following steps are included:
Gained destainer after decoloration is concentrated, cooling processing is carried out when until there is crystal precipitation, obtains spectinomycin；Wherein,
The temperature of the concentration is 65~75 DEG C；The time of the cooling processing is 3.5~4.5h, the final temperature of the cooling processing
It is 5~10 DEG C.
10. according to claim 1 or method described in 9, which is characterized in that after the crystallization further include:
Gained system after crystallization is separated by solid-liquid separation, obtained solid material is dried, spectinomycin is obtained.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111705092A (en) * | 2020-07-20 | 2020-09-25 | 山东齐发药业有限公司 | Feed supplement for improving fermentation titer of spectinomycin and preparation method and use method thereof |
| CN112390806A (en) * | 2020-10-27 | 2021-02-23 | 河北圣雪大成制药有限责任公司 | Method for improving extraction yield of spectinomycin |
| CN113861212A (en) * | 2021-10-11 | 2021-12-31 | 河北圣雪大成唐山制药有限责任公司 | Method for improving turbidity of spectinomycin hydrochloride product |
| CN115594687A (en) * | 2021-06-28 | 2023-01-13 | 黑龙江联顺生物科技有限公司（Cn） | Method for extracting and purifying spectinomycin |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111705092A (en) * | 2020-07-20 | 2020-09-25 | 山东齐发药业有限公司 | Feed supplement for improving fermentation titer of spectinomycin and preparation method and use method thereof |
| CN111705092B (en) * | 2020-07-20 | 2022-03-08 | 山东齐发药业有限公司 | Feed supplement for improving fermentation titer of spectinomycin and preparation method and use method thereof |
| CN112390806A (en) * | 2020-10-27 | 2021-02-23 | 河北圣雪大成制药有限责任公司 | Method for improving extraction yield of spectinomycin |
| CN115594687A (en) * | 2021-06-28 | 2023-01-13 | 黑龙江联顺生物科技有限公司（Cn） | Method for extracting and purifying spectinomycin |
| CN113861212A (en) * | 2021-10-11 | 2021-12-31 | 河北圣雪大成唐山制药有限责任公司 | Method for improving turbidity of spectinomycin hydrochloride product |
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