CN105272992A - Method for extracting nemadectin from fermentation liquor - Google Patents
Method for extracting nemadectin from fermentation liquor Download PDFInfo
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- CN105272992A CN105272992A CN201410358600.5A CN201410358600A CN105272992A CN 105272992 A CN105272992 A CN 105272992A CN 201410358600 A CN201410358600 A CN 201410358600A CN 105272992 A CN105272992 A CN 105272992A
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Abstract
The invention relates to a method for extracting nemadectin from fermentation liquor, especially relates to a method for extracting nemadectin from fermentation liquor by using a ceramic membrane, a macroporous absorption resin column and other equipments and organic solvents, and the yield is extremely high.
Description
Technical field
The present invention relates to medicinal chemistry art.Specifically, the present invention relates to a kind of method extracting nimoctin from fermented liquid, more specifically, the present invention relates to and be a kind ofly combined ceramic membrane, resin column be combined the method that the nimoctin in fermented liquid extracts with abnormal high yield by organic solvent.
Background technology
Nimoctin (Nemadectin) is a kind of ten hexa-atomic macrolide antibiotics, is produced through fermenting process by cyaneogriseus streptomyces (Streptomycescyaneogriseussp.Noncyanogenus).As a member of mibemycin race, nimoctin is mainly used in synthesis mosictin (Moxidectin), and the latter is a kind of agricultural antibiotic of Macrolide, is mainly used in treating the parasitosis in the animal bodies such as cattle and sheep.
European patent EP 0170006A2 discloses a kind of productive culture base and zymotechnique of nimoctin, first cyaneogriseus streptomyces is inoculated in containing glucose 1.0%, dextrin 2.0%, yeast extract 0.5%, in the substratum of NZ amine (caseic enzymically hydrolyse thing) 0.5% and calcium carbonate 0.1%, (the percentage composition unit of each material is g/mL, such as 0.1% i.e. 0.001g/mL, refer in 100mL solution containing 0.1g solute, this is concentration method for expressing general when solid matter being mixed with in biochemistry solution reagent), cultivate 48-72h for 28 DEG C, as first order seed, first order seed is accessed same substratum, cultivates 48h, as secondary seed for 28 DEG C, then the access of 1L secondary seed solution is contained in the substratum 30L of dextrin 1.0%, soy peptone 1.0%, molasses 1.0%, calcium carbonate 0.1%, in 30 DEG C of fermentation culture, the air flow quantity 30L/min of fermentor tank, tank pressure 8 pounds, stir 500rpm, after cultivating 91h, put tank.This invention also discloses fermented liquid and comprises nimoctin and analog thereof the separation purification method at interior tunning: adding diatomite to fermented liquid is that filter aid obtains wet mycelia slag; To wet mycelia slag with methanol extraction; Extraction liquid uses dichloromethane extraction again after concentrated; Collect methylene dichloride through anhydrous sodium sulfate drying, concentrate, then obtain nimoctin through silica gel column chromatography.The defect of the method is, employs a large amount of flocculating aids, produce a large amount of filtered wastewater, cause environmental pollution due to filtering fermentating liquid difficulty; Use methanol extraction to wet mycelia slag, the consumption of methyl alcohol is excessive; And using disposable silica gel to be separated nimoctin, extraction cost is higher.
Substantially to be (1) realize being separated of mycelium and aqueous phase with plate-and-frame filter press or whizzer to the method extracting at present nimoctin from fermented liquid, soaks mycelium extract fat-soluble target components with organic solvent.The shortcoming of aforesaid method is the mounting or dismounting of sheet frame, material to draw off with the cleaning of filter cloth be all manual operations, and non-cutting time is long, and greatly, production efficiency is low, thus affects the progress of whole production for labour intensity; The part fat-soluble target components be free in aqueous phase enters in waste water when mycelium and aqueous phase separation with aqueous phase; Operate unfriendly to environment, organic solvent consumption is large; Because of complicated component in mycelium, in organic solvent extraction process, easily cause a large amount of emulsification, and then affect yield and quality.(2) with organic solvent directly lixiviate nimoctin in fermented liquid.The shortcoming of aforesaid method is solvent consumption large (such as ethanol, methyl alcohol etc.), easy emulsification; Need to use a large amount of flocculating aidss simultaneously, both increased cost and also increased hand labor intensity, also can cause environmental pollution simultaneously.After aforesaid method process, often product filtrate is of low quality, increases technical load below, as increased the treatment time of resin column, increasing the regeneration frequency of pillar, reducing its work-ing life etc.
Modern Membrane Technology originates from the sixties in 20th century, is a kind of novel fluid separation element operative technique.It take polymeric membrane for separation as separating medium, with pressure difference, concentration difference, potential difference etc. for mass transfer driving force, the difference of the different substances in fluid to be separated according to molecular weight, particle or electric charge is separated.Because membrane separation technique has the features such as energy-efficient, since first set industrial equipment is introduced to the market, obtain fast development, at present throughout nearly all industrial circle.According to the different principle of membrane sepn, film can be divided into the different sortses such as microfiltration membrane, ultra-filtration membrane, nanofiltration membrane, reverse osmosis membrane, dialysis membrane, electrodialytic membranes, infiltrating and vaporizing membrane and gas separation membrane.
Not yet find that there is employing membrane separation technique at present, particularly ceramic membrane carrys out concentrated broth, and then extracts the report of nimoctin.
The technology that application macroporous adsorbent resin carries out being separated is one of separation technology after ion exchange resin grown up late 1960s.Macroporous adsorbent resin is a kind of not containing the cancellated high molecular polymer sorbent material of ionic group, have that adsorptivity is strong, desorption is easy, physical strength is good, can the advantage such as Reusability, fluid resistance be little, its separation performance is relevant with resin nature, solvent factor and separated compound property etc.Along with the further application in pharmaceutical chemistry constituents extraction, separation, enrichment, macroporous adsorbent resin will be conducive to the improvement of pharmaceutical preparation technology, is conducive to the process promoting medicine Study on Modernization.
Do not find that macroporous adsorbent resin is combined the report extracting nimoctin from fermented liquid with membrane separation technique at present yet.
Summary of the invention
The present invention be devoted to provide a kind of simpler effectively, environmental protection, the method for extracting nimoctin from fermented liquid with high yield that cost is low, even if the poor quality of fermented liquid.
Method of the present invention for extracting nimoctin from fermented liquid comprises:
A) ceramic membrane concentrated broth is used, optionally, then
B) continue to add in fermented liquid concentrated solution or interval adds the mixture that one or several are selected from alcohol, glycol, ketone, ester class, carboxylic-acid organic solvent or above-mentioned solvent and water, and use ceramic membrane lixiviate, acquisition nimoctin vat liquor.
According to method of the present invention, also comprise:
C) nimoctin concentrated solution is obtained with macroporous adsorbing resin for purification nimoctin vat liquor.
The present invention relates to a kind of method extracting nimoctin from fermented liquid, more specifically, the present invention relates to one and be combined the equipment such as ceramic membrane, macroporous adsorptive resins, the method nimoctin in fermented liquid extracted with abnormal high yield with organic solvent.
Generally speaking, the method extracting nimoctin from fermented liquid comprises uses ceramic membrane concentrated broth, continue to add in fermented liquid concentrated solution one or several be selected from alcohol, glycol, ketone, ester class, carboxylic-acid organic solvent or above-mentioned solvent and water mixture and after using ceramic membrane lixiviate nimoctin vat liquor, obtain nimoctin concentrated solution with macroporous adsorbing resin for purification vat liquor.
The following specifically describes according to the method extracting nimoctin from fermented liquid of the present invention.
Step a), uses ceramic membrane concentrated broth.
Described fermented liquid be any art methods obtain wherein containing the fermented liquid of nimoctin, its chromatographic purity such as can reach 50 ~ 80%, preferably 55 ~ 70%, such as its chromatographic purity is 60% or 61%; This fermented liquid has necessarily tires, such as 1000 ~ 3000 μ g/ml, preferably 1500 ~ 2500 μ g/ml, more preferably 1800 ~ 2200 μ g/ml, and such as it is tired is 1972 μ g/ml, 2050 μ g/ml or 2180 μ g/ml.
The ceramic membrane that the present invention adopts is the one in microfiltration membrane, mainly refers to by aluminum oxide (Al
2o
3), zirconium white (ZrO
2), titanium dioxide (TiO
2) and/or silicon-dioxide (SiO
2) etc. the porous-film prepared of inorganic materials, and have the forms such as multi-pore channel formula, flat or duct type, membrane pore size is generally 1-200nm, preferred 3-100nm, more preferably 5-50nm, such as 50nm.
In non-limiting manner, the specification of the ceramic membrane that the present invention can adopt such as: Pall1960 type film core, 19 passages, passage aperture d=6mm, membrane pore size D=50nm, the long L=1 ~ 1.2m of film core, filtration area S=0.358 ~ 0.42m
2.
The present invention adopt ceramic membrane be in use placed in treatment tank, treatment tank can be equipped with trier impeller pump, its specification such as: H=36m, Q=10T/h, P=3kW.
Ceramic membrane also can be equipped with multiple film cylinder placing ceramic film core, such as 2 ~ 10 film cylinders, preferably 3 ~ 8 film cylinders, more preferably 4 ~ 6 film cylinders.Such as single filtration area S=0.42m
2time, 6 film cylinders can be provided with, have 36 film cores in each film cylinder, total area S=90.72m
2, charging pump: H=30m, Q=150T/h, P=30kW, force (forcing) pump: H=30m, Q=1580m
3/ h, P=220kW.
Why the present invention adopts ceramic membrane, be because ceramic membrane to have chemical stability good, can acidproof, alkaline-resisting, organic solvent-resistant; Physical strength is large, can counterflush; Anti-microbe ability is strong, and high temperature resistant, pore size distribution is narrow, separation efficiency high.And ceramic membrane is automatic operation, and the cycle of operation is short, and labor cost is low.Under certain solvent strength condition, ceramic membrane can realize appearing of fermented liquid effective constituent, and the effluent liquid of peritoneal effluent after macroporous adsorbing resin for purification can overlap and be back to ceramic membrane lixiviate, greatly save the usage quantity of solvent, also greatly simplify existing technique simultaneously, eliminate a large amount of flocculating aidss, also can not introduce secondary pollution, realize cleaner production, thus alleviate environmental protection pressure! In addition, ceramic membrane has more tiny aperture, and filtrate quality improves greatly, not only can remove thalline, except impurity such as Deproteinizations, can also alleviate the pressure of follow-up workshop section.If ceramic membrane is combined resin column can make the abnormal raising of nimoctin yield.
Step a) in, can add in fermented liquid in ceramic membrane concentration process water, tensio-active agent, acid, alkali, organic solvent or change broth temperature.
According to the present invention, after step a) is concentrated, usually fermentating liquid volume can be narrowed down to about 1/2 ~ 1/5, preferably 1/3 ~ 1/4.Such as, the treatment tank of nemadectin fermentation broth through being equipped with ceramic membrane of 55L concentrates, ceramic membrane appears after end appears 39L water and obtains fermented liquid concentrated solution 16L, or it is more extensive, the treatment tank of nemadectin fermentation broth through being equipped with ceramic membrane of such as 180L concentrates, ceramic membrane appears after end appears 126L water and obtains fermented liquid concentrated solution 54L, or more extensive, such as 21m
3the treatment tank of nemadectin fermentation broth through being equipped with ceramic membrane concentrate, ceramic membrane appears end and appears 15m
3fermented liquid concentrated solution 6m is obtained after water
3.Thus greatly reduce post-processing difficulty.
In the step b) of invention, continue to add in fermented liquid concentrated solution or interval adds the mixture that one or several are selected from alcohol, glycol, ketone, ester class, carboxylic-acid organic solvent or above-mentioned solvent and water, and use ceramic membrane to carry out lixiviate, thus obtain nimoctin vat liquor.
Step b can carry out in step a) ceramic membrane concentration process, also can carry out after step a) ceramic membrane concentration process terminates.
According to the present invention, the mixture of water, tensio-active agent, acid, alkali, organic solvent and water can be added in above-mentioned fermented liquid or fermented liquid concentrated solution, or change broth temperature, thus change fermented liquid character.
Extraction solvent can be selected from alcohol, such as: methyl alcohol, ethanol, Virahol; Glycol, such as: 1,3-PD; Ketone, such as: acetone; Ester class, such as: ethyl acetate, butylacetate; Carboxylic-acid, such as: acetic acid.
The solvent of lixiviate directly can apply that one or several are used in combination, and also can be that one or several and water are used in combination, wherein the ratio of water be 1% to 60% (V:V).
In a preferred embodiment, the organic solvent that lixiviate uses is methyl alcohol, ethanol, acetone, ethyl acetate, acetic acid.
In a preferred embodiment, the organic solvent that lixiviate uses is methyl alcohol, ethanol, and lixiviate with an organic solvent feature is the water containing 1% ~ 60% (V:V) that have an appointment.
According to the present invention, step b) can repeat repeatedly, preferably repeats 2 ~ 10 times, more preferably repeats 3 ~ 5 times.Such as when adding 48L methyl alcohol to 16L fermented liquid concentrated solution, through ceramic membrane filter, appearing after side obtains nimoctin methanol extract at ceramic membrane, when material liquid volume is less than 30L in tank, continues in ceramic membrane treatment tank, add 75% methyl alcohol and carry out lixiviate.Class of operation in other scale situations seemingly.
In step c) of the present invention, with macroporous adsorbing resin for purification nimoctin vat liquor, thus obtain nimoctin concentrated solution.
The vat liquor that step b) obtains first can be transferred to upper prop liquid temporary storage tank, then adds in macroporous adsorptive resins by the vat liquor in upper prop liquid temporary storage tank, also can directly add in macroporous adsorptive resins by vat liquor, add preferably by pumping mode.
According to the present invention, the any conventional macroporous adsorptive resins of spendable prior art, described macroporous adsorbent resin is a kind of not containing the cancellated high molecular polymer sorbent material of ionic group, preferred HB60, XAD-1600, D101, more preferably HB60 resin column, its specification is such as: size range 0.3-1.25mm, volume density 0.670kg/L, specific surface area: 500-700m
2/ g, aperture: 10-12nm, pore volume: 1.2-1.4cm
3/ g; .
The effluent liquid of macroporous adsorptive resins can be any conventional solvent, preferred steps b) in operable extraction solvent, such as effluent liquid solvent can be selected from alcohol, such as: methyl alcohol, ethanol, Virahol; Glycol, such as: 1,3-PD; Ketone, such as: acetone; Ester class, such as: ethyl acetate, butylacetate; Carboxylic-acid, such as: acetic acid.Directly can apply one or several used in combination, also can be that one or several and water are used in combination, wherein the ratio of water be 1% to 60%.In preferred embodiments, effluent liquid solvent is methyl alcohol, ethanol, acetone, ethyl acetate, acetic acid, and in a more preferred embodiment, effluent liquid solvent is methyl alcohol, ethanol, especially containing have an appointment 1% ~ 60% the organic solvent of water.
According to the present invention, the effluent liquid solvent used in step c) is identical with the extraction solvent used in step b), such as, if the extraction solvent used in step b) is 75% methyl alcohol, the effluent liquid solvent then used in step c) is also 75% methyl alcohol, if the extraction solvent used in step b) is 85% methyl alcohol, the effluent liquid solvent then used in step c) is also 85% methyl alcohol, if the extraction solvent used in step b) is 60% ethanol, then the effluent liquid solvent used in step c) is also 60% ethanol.
According to preferred embodiment, the effluent liquid solvent used in step c) can overlap and be back in step b), carries out ceramic membrane lixiviate as extraction solvent.Thus reduce costs, and there is the effect of environmental protection.
According to the present invention, leaching process can be followed the tracks of with high performance liquid phase, when nimoctin in vat liquor is tired lower than 200 μ g/ml, stop adding extraction solvent, and by ceramic membrane, feed liquid is concentrated, after reaching certain volume, then stop ceramic membrane filter.And all vat liquors are finally sent into macroporous adsorptive resins, carry out last enrichment.
By the inventive method, the tiring of final concentrated solution of acquisition can reach 3000 more than μ g/ml, and chromatographic purity is not less than the chromatographic purity of nemadectin fermentation broth.The present invention can reach more than 93% by implementation procedure nimoctin extract yield, and preferably more than 94%.
specific implementation method
The present invention is further illustrated below by embodiment.It should be understood that embodiments of the invention are for illustration of the present invention instead of limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
HPLC systems axiol-ogy condition
Chromatographic column: Yi Lite HypersilODS, 5mm, 250mm × 4.6mm, or quite
Column temperature: room temperature
Flow velocity: 1.0ml/min
Determined wavelength: 240nm
Sample size: 20 μ l
Working time: more than three times of main peak retention time
Moving phase is prepared: methyl alcohol: water=85:15
Standardized solution is prepared: precision takes about 20mg Working Control product in 100ml volumetric flask, adds chromatogram dissolve with methanol and is diluted to scale, shaking up.Be stored in 2-8 DEG C.
Chromatography Program:
Get standardized solution continuous sample introduction three times, the relative standard deviation of its main peak area must not be greater than 2.0%, extracting sample solution sample introduction, and record collection of illustrative plates, the retention time of main peak is about 10min.
Calculate:
According to the peak area of standardized solution and sample solution, calculate as follows and tire.
R
f=standardized solution main peak average area/concentration of standard solution (μ g/ml)
Sample is tired=(sample solution peak area/R
f) × extension rate
Embodiment 1
:
Nemadectin fermentation broth 55L, tire 1972 μ g/ml, chromatographic purity 60%.Containing nimoctin 108.5g.(ceramic membrane specification is as follows: Pall1960 type film core, 19 passages, passage aperture d=6mm, membrane pore size D=50nm, the long L=1m of film core, filtration area S=0.358m fermented liquid to be put into ceramic membrane treatment tank
2, trier impeller pump: H=36m, Q=10T/h, P=3kW), start is filtered, and ceramic membrane appears after end appears 39L water and obtains fermented liquid concentrated solution 16L.In fermented liquid concentrated solution, add 48L methyl alcohol be mixed with the feed liquid that methanol content is 75%, after stirring, open ceramic membrane filter, appear side at ceramic membrane and obtain nimoctin methanol extract.When the material liquid volume prepared in tank is less than 30L, continues in ceramic membrane treatment tank, add 75% methyl alcohol prepared and carry out lixiviate.Vat liquor is transferred to upper prop liquid temporary storage tank, to HB60 resin column, (HB60 resin specification is as follows: size range 0.3-1.25mm, volume density 0.670kg/L, specific surface area: 500-700m by the lixiviate liquid pump in upper prop liquid temporary storage tank for turn on pump
2/ g, aperture: 10-12nm, pore volume: 1.2-1.4cm
3/ g) enrichment.HB60 resin column upper prop effluent liquid is 75% methyl alcohol, and cover is back to ceramic membrane lixiviate.Follow the tracks of leaching process with high performance liquid phase, when nimoctin in vat liquor tire lower than during 200 μ g/ml stop add 75% methyl alcohol, feed liquid is concentrated into 15L, stops ceramic membrane filter, residue feed liquid be that waste residue processes further.By all lixiviate liquid pumps to HB60 resin column, last pregnant solution volume is 32L.Detect through HPLC, it is 3200 μ g/ml that concentrated solution is tired, chromatographic purity 61%, and containing nimoctin 102.4g, whole process nimoctin extract yield is 94.4%.
Embodiment 2:
Nemadectin fermentation broth 180L, tire 2050 μ g/ml, and chromatographic purity 60%, containing nimoctin 369.0g.(ceramic membrane specification is as follows: Pall1960 type film core, 19 passages, passage aperture d=6mm, membrane pore size D=50nm, the long L=1m of film core, filtration area S=0.358m fermented liquid to be put into ceramic membrane treatment tank
2, trier impeller pump: H=36m, Q=10T/h, P=3kW), start is filtered, and ceramic membrane appears after end appears 126L water and obtains fermented liquid concentrated solution 54L.In fermented liquid concentrated solution, add the feed liquid that 306L methyl alcohol is mixed with 85% methanol content, after stirring, open ceramic membrane filter, appear side at ceramic membrane and obtain nimoctin methanol extract.When the material liquid volume prepared in tank is less than 50L, continues in ceramic membrane treatment tank, add 85% methyl alcohol prepared and carry out lixiviate.Vat liquor is transferred to upper prop liquid temporary storage tank, to HB60 resin column, (HB60 resin specification is as follows: size range 0.3-1.25mm, volume density 0.670kg/L, specific surface area: 500-700m by the lixiviate liquid pump in upper prop liquid temporary storage tank for turn on pump
2/ g, aperture: 10-12nm, pore volume: 1.2-1.4cm
3/ g) enrichment.HB60 resin column upper prop effluent liquid is 85% methyl alcohol, and cover is back to ceramic membrane lixiviate.Follow the tracks of leaching process with high performance liquid phase, when nimoctin in vat liquor tire lower than during 200 μ g/ml stop add 85% methyl alcohol, feed liquid is concentrated into 30L, stops ceramic membrane filter, residue feed liquid be that waste residue processes further.By all lixiviate liquid pumps to HB60 resin column, last pregnant solution volume is 115L.Detect through HPLC, it is 3008 μ g/ml that concentrated solution is tired, chromatographic purity 61%, and containing nimoctin 345.9g, whole process nimoctin extract yield is 93.7%.
Embodiment 3:
Nemadectin fermentation broth 21m
3, tire 2180 μ g/ml, and chromatographic purity 61%, containing nimoctin 45.8kg.(ceramic membrane specification is as follows: Pall1960 type film core, 19 passages, passage aperture d=6mm, membrane pore size D=50nm, the long L=1.2m of film core, single filtration area S=0.42m fermented liquid to be put into ceramic membrane treatment tank
2, have 6 film cylinders, have 36 film cores in each film cylinder, total area S=90.72m
2, charging pump: H=30m, Q=150T/h, P=30kW, force (forcing) pump: H=30m, Q=1580m
3/ h, P=220kW), start is filtered, and ceramic membrane appears end and appears 15m
3fermented liquid concentrated solution 6m is obtained after water
3.9m is added in fermented liquid concentrated solution
3ethanol, after stirring, records ethanol degree about 60%, opens ceramic membrane filter, appears side obtain nimoctin alcohol extract at ceramic membrane.When the material liquid volume prepared in tank is less than 4m
3time, continue to add 60% alcohol steep in ceramic membrane treatment tank.Vat liquor is transferred to upper prop liquid temporary storage tank, to HB60 resin column, (HB60 resin specification is as follows: size range 0.3-1.25mm, volume density 0.670kg/L, specific surface area: 500-700m by the lixiviate liquid pump in upper prop liquid temporary storage tank for turn on pump
2/ g, aperture: 10-12nm, pore volume: 1.2-1.4cm
3/ g) enrichment.HB60 resin column upper prop effluent liquid 60% ethanol, cover is back to ceramic membrane lixiviate.Follow the tracks of leaching process with high performance liquid phase, when nimoctin in vat liquor tire lower than during 200 μ g/ml stop add 60% ethanol, feed liquid is concentrated into 4m
3, stop ceramic membrane filter, residue feed liquid is that waste residue processes further.By all lixiviate liquid pumps to HB60 resin column, last pregnant solution volume is 12m
3.Detect through HPLC, it is 3620 μ g/ml that concentrated solution is tired, chromatographic purity 62%, and containing nimoctin 43.4kg, whole process nimoctin extract yield is 94.8%.
More than in conjunction with embodiment and exemplary example to invention has been detailed description, but these explanations can not be interpreted as limitation of the present invention.It will be appreciated by those skilled in the art that when not departing from spirit and scope of the invention, can carry out multiple equivalencing, modification or improvement to technical solution of the present invention and embodiment thereof, these all fall within the scope of the present invention.Protection scope of the present invention is as the criterion with claims.
Claims (10)
1. from fermented liquid, extract a method for nimoctin, the method comprises:
A) ceramic membrane concentrated broth is used, optionally, then
B) continue to add in fermented liquid concentrated solution or interval adds the mixture that one or several are selected from alcohol, glycol, ketone, ester class, carboxylic-acid organic solvent or above-mentioned solvent and water, and use ceramic membrane lixiviate, acquisition nimoctin vat liquor.
2. method according to claim 1, the method also comprises:
C) with macroporous adsorbing resin for purification nimoctin vat liquor, nimoctin concentrated solution is obtained.
3., according to the method for claim 1 or 2, in step a), described ceramic membrane is by aluminum oxide (Al
2o
3), zirconium white (ZrO
2), titanium dioxide (TiO
2) and/or silicon-dioxide (SiO
2) porous-film prepared, and having multi-pore channel formula, flat or duct type form, membrane pore size is 1-200nm, preferred 3-100nm, more preferably 5-50nm, such as 50nm.
4. the method according to any one of claims 1 to 3, in step a), described ceramic membrane is placed in treatment tank, single film cylinder or multiple film cylinder placing ceramic film is housed, such as 2 ~ 10 in described treatment tank, preferably 3 ~ 8, more preferably 4 ~ 6 film cylinders.
5. the method according to any one of Claims 1-4, in the ceramic membrane concentration process of step a), or in the leaching process of step b), in fermented liquid or concentrated solution, add water, tensio-active agent, acid, alkali, organic solvent, or change broth temperature.
6. the method according to any one of claim 1 to 5, step b) in, described organic solvent is that one or several are selected from the mixture of alcohol, glycol, ketone, ester class, carboxylic-acid organic solvent or above-mentioned solvent and water, wherein the ratio of water is 1% to 60% (V:V), preferred extraction solvent is methyl alcohol, ethanol, acetone, ethyl acetate, acetic acid, more preferably extraction solvent is methyl alcohol, ethanol, containing the organic solvent of 1% ~ 60% water.
7. the method according to any one of claim 2 to 6, step c) in, described macroporous adsorbent resin is a kind of not containing the cancellated high molecular polymer sorbent material of ionic group, preferred HB60, XAD-1600, D101, more preferably HB60.
8. the method according to any one of claim 2 to 7, step c) in, the effluent liquid solvent of macroporous adsorptive resins is selected from alcohol, such as: methyl alcohol, ethanol, Virahol; Glycol, such as: 1,3-PD; Ketone, such as: acetone; Ester class, such as: ethyl acetate, butylacetate; Carboxylic-acid, such as: acetic acid.
9. method according to claim 8, wherein, the effluent liquid solvent used in step c) is identical with the extraction solvent used in step b).
10. the method according to any one of claim 2 to 9, wherein, step c) in resin column upper prop effluent liquid apply mechanically back step b) in.
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