CN104262431A - Method and device for extracting erythromycin thiocyanate - Google Patents
Method and device for extracting erythromycin thiocyanate Download PDFInfo
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- CN104262431A CN104262431A CN201410488092.2A CN201410488092A CN104262431A CN 104262431 A CN104262431 A CN 104262431A CN 201410488092 A CN201410488092 A CN 201410488092A CN 104262431 A CN104262431 A CN 104262431A
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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
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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
Abstract
The invention provides a method and device for extracting erythromycin thiocyanate. The method comprises the following steps: filtering erythromycin fermentation liquor by using an ultrafiltration membrane so as to remove impurities and colors, carrying out further impurities and colors removal on filter liquor by using the ultrafiltration membrane, concentrating filter liquor by using a nanofiltration membrane, and finally, carrying out extraction on the obtained product by using a recrystallization process, so that the high-purity erythromycin thiocyanate is obtained. Compared with traditional erythromycin thiocyanate extraction processes, the method and device disclosed by the invention have the advantages that the yield of extracted erythromycin A is high; the purity of the extracted erythromycin A is high; an operation process is simplified; and the solvent cost is reduced, the industrial pollution is less, and the like.
Description
Technical field
The present invention relates to a kind of Matachrom extracting method and device, belong to technology of pharmaceutical engineering field.
Background technology
Matachrom (being called for short sulphur red) is the thiocyanate-of erythromycin, and it is that domestic erythromycin derivatives series product are as basic materials such as Roxithromycin, erythromycin ethylsuccinate, Azythromycin, clarithromycins.Due to erythromycin and the extensive application clinically of derivative product thereof, become the third-largest medicine on microbiotic market, the world, the Matachrom market requirement at home and abroad therefore as its synthesis material also has rising.Erythromycin is multi-component antibiotic, except active principle Erythromycin A, also comprises the isomeric by-products such as berythromycin, C, D, E, F.Erythromycin C and A are structurally extremely similar, reduce in extractive technique the content of Erythromycin C, reduce toxicity be key a bit.
The method that current most domestic medicine enterprise adopts is Plate Filtration method, namely uses zinc sulfate as flocculation agent, precipitates with proteins react, then uses plate-and-frame filter press to be separated.Although in this method comparative maturity stablize, the problem of environmental pollution of zine ion now realize by people and pay attention to, this pretreatment process is also eliminated gradually, and new membrane separation technique becomes a kind of and well selects.Domestic Matachrom production technique, also exists following shortcoming: 1, Matachrom yield is low; 2, operating automation degree is low; 3, labour intensity is large; 4, reagent cost is high; 5, environmental pollution is serious etc.
Chinese patent CN1500799A discloses the method utilizing membrane sepn to extract erythromycin, the method is that employing erythromycin fermentation liquid carries out basic micro-filtration, ultrafiltration adds the last solvent extraction of nanofiltration and obtains finished product, although this technique have employed membrane separation technique, but the effect simply taking micro-filtration to add ultrafiltration cannot to reach decolouring in Matachrom leaching process and remove toxin, and flux decline is very fast in membrane filtration processes, film recovers very difficult, and the Matachrom quality product finally obtained is not high.
Chinese patent CN20121013467.X discloses a kind of preparation method of Matachrom, after erythromycin fermentation liquid removal of impurities, with base extraction, then extract by ethyl acetate, collect organic phase and add sodium thiocyanate solution, control pH4.0-6.0, stir, crystallization, dry, obtain Matachrom powder.Although this invented technology obtains, Matachrom product yield is high, and purity is high, and operation sequence is complicated, and use reagent cost high, the environmental pollution caused is serious.
Summary of the invention
The technical problem that the present invention solves is: in existing Matachrom production technique, product purity is not high, product yield is low.The present invention improves its extraction process, proposes a kind of Matachrom extracting method and device.
Technical scheme:
A kind of Matachrom extracting method, comprises the steps:
1st step, erythromycin fermentation liquid ultrafiltration membrance filter, obtain ultrafiltration permeate; Ultrafiltration permeate nanofiltration is concentrated, obtains nanofiltration dope;
2nd step, by nanofiltration dope organic solvent extraction, obtain organic phase, then organic phase ceramic membrane is filtered, obtain ceramic membrane filtrate;
3rd step, in ceramic membrane filtrate, add Sodium Thiocyanate 99, then after carrying out crystallization, separation, drying, obtain Matachrom.
Further, ultra-filtration membrane molecular weight cut-off is the film of 5000 ~ 200000Da or its mean pore size scope is 0.02 ~ 50nm;
Further, transmembrane pressure 0.1 ~ 0.5MPa in ultra-filtration process; Crossflow velocity is 0.5 ~ 5m/s preferably;
Further, the material of ultra-filtration membrane is pottery;
Further, before ultrafiltration step, carry out pre-filtering by microfiltration membrane; The material of microfiltration membrane is pottery; The mean pore size of microfiltration membrane is 0.2 μm ~ 2 μm;
Further, the material of nanofiltration membrane is selected from rhodia based polymer, polymeric amide, SPSF, polyacrylonitrile, polyester, sulfonated polyether sulfone, polyimide and vinyl polymer; Be more preferably sulfonated polyether sulfone; The molecular weight cut-off of nanofiltration membrane is preferably 200 ~ 500Da; Nanofiltration working pressure at 1.0 ~ 3.0MPa, temperature 40 ~ 50 DEG C;
Further, organic solvent is selected from methyl alcohol, ethanol, acetone, ethyl acetate, butylacetate, chloroform;
Further, ceramic membrane refers to hydrophobic ceramic film.
According to another aspect of the present invention, a kind of Matachrom extraction element, include ultra-filtration membrane, nanofiltration membrane, extraction tower, the transport pipe of erythromycin fermentation liquid is connected to the entrance retaining side of ultra-filtration membrane, the per-meate side of ultra-filtration membrane is connected to the entrance of nanofiltration membrane, the outlet retaining side of nanofiltration membrane is connected to extraction tower, the bottom of extraction tower is connected to the entrance of ceramic membrane, the per-meate side of ceramic membrane is connected to tundish, tundish are provided with Sodium Thiocyanate 99 storage tank, tundish are connected with crystallization kettle, equipment for separating liquid from solid, drying installation successively.
Further, extraction tower is provided with organic solvent storage tank.
Further, the bottom of extraction tower is also provided with tapping valve.
Further, equipment for separating liquid from solid is whizzer.
Further, the input channel of erythromycin fermentation liquid is after the entrance being first connected to microfiltration membrane, the entrance retaining side of the ultra-filtration membrane that the per-meate side of microfiltration membrane is connected to again.
Beneficial effect
Matachrom method provided by the invention, the product purity obtained is high, yield is high.
Accompanying drawing explanation
Fig. 1 is Matachrom extraction element structural representation provided by the invention.
Wherein, 1, ultra-filtration membrane; 2, nanofiltration membrane; 3, extraction tower; 4, organic solvent storage tank; 5, ceramic membrane; 6, tundish; 7, Sodium Thiocyanate 99 storage tank; 8, crystallization kettle; 9, equipment for separating liquid from solid; 10, drying installation; 11, tapping valve; 12, microfiltration membrane.
Embodiment
Below by embodiment, the present invention is described in further detail.But it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted concrete technology or condition person in embodiment, according to the technology described by the document in this area or condition (" mineral membrane isolation technique and the application " of such as reference Xu Nan equality work, Chemical Industry Press, 2003) or carry out according to product description.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Approximate language used herein can be used for modifying the statement of any quantity in whole specification sheets and claims, and it can permit changing under the condition not causing its relevant basic function to change.Therefore, the value of being modified by the term of such as " about " is not limited to specified exact value.In at least some cases, approximate language can be corresponding with the precision of the instrument for measuring this value.Unless separately pointed out in context or statement, otherwise range limit can carry out combining and/or exchanging, and this scope is confirmed as and comprises included all subranges herein.Except in operation embodiment or except indicating in elsewhere, the numeral of the amount, reaction conditions etc. of all expression compositions used in specification sheets and claims or express the modification that all should be understood to be subject to word " about " in all cases.
The raw material that the present invention adopts is erythromycin (Erythromycin, EM) fermented liquid, the fermented bacterium adopted can be streptomyces erythareus well known in the art (Streptomyces erytheas), also can be the bacterial classification adopting other screening or artificial mutation to obtain, 6 kinds of molecular structures are mainly comprised: Erythromycin A, B, C, D, E, F, wherein main component is Erythromycin A in the erythromycin that fermentation produces.Chinese Pharmacopoeia regulation in 2010, tiring of the every 1mg of anhydrous erythromycin is not less than 920 erythromycin units, and the content of Erythromycin A is not less than 88%.
Namely erythromycin be synthesized by microbe fermentation method, the fermentation raw material used in the present invention can be the growth promoting the bacterial classification cultivated, the raw material of the good production as object fermentative production thing can be made, preferably can use the liquid nutrient medium such as suitably containing carbon source, nitrogenous source, inorganic salts and organic micro-nutrients such as the amino acid added as required and VITAMIN.As above-mentioned carbon source, the carbohydrates such as such as glucose, sucrose, fructose, semi-lactosi, lactose and maltose, the starch saccharificating liquid containing these carbohydrates, sweet potato molasses, beet sirup, senior molasses (High Test Molasses), sugarcane juice, cane juice extract or concentrated solution, alcohols and the glycerine etc. such as sugared, purifying or crystallization from sugarcane juice the purifying sugar of the raw material of purifying or crystallization and the organic acid such as acetic acid, fumaric acid, ethanol from sugarcane juice preferably can be used.Carbohydrate described here refers to the initial oxidation resultant of polyvalent alcohol, there is an aldehyde radical or ketone group, and the sugar with aldehyde radical is classified as aldose, has the carbohydrate that the sugar of ketone group is classified as ketose, be preferably glucose, sucrose, fructose, semi-lactosi, lactose or maltose.Above-mentioned carbon source, can add together when cultivating and starting, can also add in batches or continuously in cultivation.In addition, as above-mentioned nitrogenous source, peptide class, various fermentation thalli and the hydrolyzable things thereof etc. such as such as ammonia, ammoniacal liquor, ammonium salt class, urea, Nitrates, other auxiliary organic nitrogen source such as oil meal class, soybean hydrolyzable liquid, caseinolytic thing, other amino acid, vitamins, corn steep liquor, yeast or yeast extract, meat extract, peptone used can be used.In addition, as above-mentioned inorganic salts, such as phosphoric acid salt, magnesium salts, calcium salt, molysite and manganese salt etc. can suitably be added.And, use defoamer can also be added as required.For fermentation culture conditions, as long as can cultivate, be just not particularly limited, but be preferably 4 ~ 8 at pH, temperature is carried out in the scope of 20 ~ 40 DEG C.The pH mineral acid of fermentation culture or Organic Acid and Base material and urea, calcium carbonate and ammonia etc., adjust to the predetermined value in above-mentioned scope.
In fermented liquid, the content of erythromycin is very low, and the overwhelming majority is the impurity such as a large amount of mycelium, unspent solid medium, various pigment, protein, inorganic salt and microbial metabolites.First by ultra-filtration membrane, these impurity, colloid, particle etc. are filtered in technique of the present invention.0.02 ~ 50nm for the film of ultra-filtration membrane of the present invention to be molecular weight cut-off be 5000 ~ 200000Da or its mean pore size scope, referred to as ultra-filtration membrane, UF film etc.At this, when the aperture of ultra-filtration membrane is too small and be difficult to the aperture measuring film surface with electron microscope etc., with being called that the value of molecular weight cut-off replaces mean pore size to be used as the index of pore size.About molecular weight cut-off, as described in art technology document: " will take molecular weight solute as transverse axis, prevention rate is the longitudinal axis, and be called molecular weight cut-off curve to the curve that data are drawn.And by prevention rate be 90% molecular weight be called the molecular weight cut-off of film ", molecular weight cut-off, as the index of film properties representing ultra-filtration membrane, is well known to those skilled in the art.In the step of ultrafiltration, transmembrane pressure is preferably from 0.1 ~ 0.5MPa, and the filtration that ultra-filtration membrane of the present invention carries out also can be able to be dead-end filtration for cross flow filter.From the view point of the energy expenditure of pump, be preferably dead-end filtration.But for the liquid of filterableness difference, be preferably cross flow filter, crossflow velocity is 0.5 ~ 5m/s preferably.In this external filtration, preferably carry out the operation of backwash, aeration.This is because suppress the pollution of film.Before the filtration that this external employing ultra-filtration membrane carries out, in order to contaminant restraining matter, solid-liquid separation process can be carried out as pre-treatment.About solid-liquid separating method, be not particularly limited.As the method for concrete solid-liquid separation process, centrifugation mode, expression separation mode, filter type, floating separate mode, settlement separate mode can be enumerated.As centrifugation mode, horizontal continuous centrifuge can be illustrated, be separated board-like separating centrifuge, centrifugal filter, as filter type, band filter, belt press, flypress, precoat filter, pressure filter etc. can be illustrated.But be not particularly limited in above-mentioned any one, as long as the load to film when can reduce ultrafiltration membrane treatment by above-mentioned any one or its combination.After ultrafiltration, contain some erythromycin and some small molecular weight impurities by the permeate of gained, send in the isolation/concentration step of follow-up nanofiltration.As particularly preferred, micro-filtration can be adopted as the pre-treating technology of ultrafiltration, the micro-filtration described in the present invention is preferably the film that mean pore size is 0.2 μm ~ 2 μm.
As the material of these microfiltration membrane or ultra-filtration membrane, as long as can realize removing above-mentioned water-soluble polymer and the such the object of the invention of colloid composition, be not particularly limited, can enumerate: the organic materialss such as Mierocrystalline cellulose, cellulose ester, polysulfones, polyethersulfone, polyvinyl chloride, propenyl chloride, polyolefine, polyvinyl alcohol, polymethylmethacrylate, poly(vinylidene fluoride), tetrafluoroethylene, or the inorganic materials such as metal or pottery such as stainless steel.The material of microfiltration membrane or ultra-filtration membrane can consider that the proterties of hydrolyzate or running cost are suitably selected, and considers, preferably ceramic material, such as: Al from handling easiness
2o
3, TiO
2, ZrO
2deng.
The permeate of ultrafiltration, after nanofiltration, small molecular weight impurity wherein, pigment etc. can be made to enter per-meate side through nanofiltration membrane, and erythromycin is retained by nanofiltration membrane, play effect that is concentrated and purifying.Nanofiltration membrane is the film being defined as " prevention is less than the particle of 2nm and the macromolecular pressure drive membrane of dissolving " herein.Be applicable to the film that effective nanofiltration membrane of the present invention is preferably such: have electric charge on the surface at this film, be thus separated (particle size separation) by pore and have benefited from the electric charge on this film surface electrostatic separation combination and show the separation efficiency of raising.Therefore, such nanofiltration membrane must be adopted, this nanofiltration membrane can using as reclaim the erythromycin of target undertaken being separated by electric charge from other ions with different charge characteristic while, remove high score subclass material by particle size separation.As the material of the nanofiltration membrane used in the present invention, the macromolecular materials such as rhodia based polymer, polymeric amide, SPSF, polyacrylonitrile, polyester, sulfonated polyether sulfone, polyimide and vinyl polymer can be used.In a preferred embodiment of the present invention, the material of the nanofiltration membrane of employing is sulfonated polyether sulfone, finds that this film can solve the not high problem of purity of the erythromycin finally obtained, and can keep higher product yield.In addition, being not limited to the film be only made up of a kind of material, can be the film comprising multiple described material.About membrane structure, described film can be asymmetric membrane, and it has tight zone at least one side of film, and to have from tight zone to film inner or another side aperture and become large micropore gradually; Or composite membrane, it has the very thin functional layer formed by other material on the tight zone of asymmetric membrane.The molecular weight cut-off of nanofiltration membrane is preferably 200 ~ 500Da, if when molecular weight cut-off is excessive, can cause having too much erythromycin to cause the reduction of yield through nanofiltration membrane, if when molecular weight cut-off filters, nanofiltration membrane cannot play the effect of screening preferably, the foreign matter content in final finished product can be caused more, working pressure is at 1.0 ~ 3.0MPa, temperature 40 ~ 50 DEG C, when working pressure is too high, the transmitance of erythromycin can be caused higher, when working pressure is too low, cannot make nanofiltration membrane produce enough selectivity through, make the purity of product not high.
After obtaining nanofiltration concentrated solution, wherein containing erythromycin and other some macromolecular impurity, because erythromycin is easily molten in methyl alcohol, ethanol, acetone and some lipid, can these erythromycin can be transferred in the middle of organic phase by the mode of extraction, the organic solvent adopted is well known to those skilled in the art, can include without limitation: methyl alcohol, ethanol, acetone, ethyl acetate, butylacetate, chloroform etc., optimal selection ethyl acetate, the volumetric usage extracting organic solvent used is preferably 1/4 ~ 1/2 of nanofiltration liquid dope volume.
In technique of the present invention, again carry out filtering the purity that can improve product further to extracting the organic phase obtained by ceramic membrane, ceramic membrane described in this step refers to the separatory membrane of some metal oxide materials, mean pore size scope preferably 50 ~ 500nm, more excellent is 200nm, and its material is preferably Al
2o
3, TiO
2, ZrO
2deng.In a preferred embodiment of the present invention, hydrophobic ceramic membrane is preferably adopted to filter organic phase, the method making ceramic membrane produce hydrophobically modified is well known to those skilled in the art, such as method of modifying disclosed in patent documentation CN101280241A, hydrophobic ceramic membrane is generally characterized it by the method for water droplet contact angle, the water droplet contact angle preferably 90 ~ 160 ° of the hydrophobic ceramic film that the present invention adopts.
Containing a dimethylamino in erythromycin molecule, make it present weakly alkaline, pKa=8.6, salt can be formed with inorganic or organic acid.Erythromycin inorganic salt have erythromycin lactic acid salt, erythromycin oxalate, erythromycin salt hydrochlorate etc.; Organic salt comprises benzyl carbonate, stearate, Lactobionate etc.Matachrom (Erythromycin Thiocyanate) is the thiocyanate-of erythromycin, easily molten in methyl alcohol, ethanol, slightly soluble in water, chloroform, in the scope of pH=5 ~ 7, Nature comparison is stablized, when pH is about 10, erythromycin can be converted into.By adding thiocyanate-, making erythromycin transfer to crystallization in aqueous phase, the effect of separation, purification of target product can be played, and impurity being stayed in mother liquor; Especially, when adopting hydrophobic ceramic film to filter, the moisture in organic phase can be made to be removed, the impurity in these aqueous phases finally be there will not be in thiocyanate-crystallizing system, prevent water-soluble impurity from having influence on the quality of product.
Adopt sulfuric acid development process to tire to erythromycin in the present invention to analyze.Be utilize erythromycin and the colour developing of Matachrom hydrolysis reaction to have obtained the maximum absorption at a particular wavelength, and meet Law of Lambert-Beer, color is directly proportional to content.Under sour environment, erythromycin lactone ring C
6on hydroxyl and C
9carbonyl forms hemiketal hydroxyl, then with C
8on hydrogen cancellation one water molecules, formed dehydrate, C
12on hydroxyl further with C
8-C
9double bond addition obtains spiral ketal, after this acidolysis further, C
10on hydrogen and C
11on hydroxyl cancellation a part water, hydrolysis obtain erythromycin amine and red mould sugar, present yellow.Then adopt ultraviolet spectrophotometry to carry out mensuration absorbancy, contrast trial-product and standard substance calculate tires.
Erythromycin is multi-component antibiotic, and main ingredient is Erythromycin A, and separately also containing berythromycin, C, the mensuration of Erythromycin Components content adopts and also may contain other degradation products in addition, for investigating quality product, technogenic influence, need have clear and definite mensuration to its component.Concrete operations are according to Chinese Pharmacopoeia 2005, and the mensuration of Erythromycin Components content adopts high performance liquid chromatography.
Chromatographic condition
(1) chromatographic column: weighting agent is Yi Lite BDS C18 post (4.6 × 250mm × 5 μm) of octadecylsilane chemically bonded silica;
(2) moving phase: phosphate solution (getting dipotassium hydrogen phosphate 8.7g, in water-soluble 1000mL, is 8.2 with 20% phosphorus acid for adjusting pH)-acetonitrile (45:55);
(3) determined wavelength: 215nm;
(4) flow velocity: 1.0mL/min;
(5) sample size: 20.00 μ L;
(6) column temperature: 35 DEG C.
Because the response value of Erythromycin Components all kinds of in sample in high performance liquid chromatography is different, area normalization method should not be adopted to calculate, this paper with each component concentration of erythromycin in calculated by peak area trial-product, for the content of impurity, adopts the correction up factor to contrast with principal constituent according to external standard method.In trial-product, namely the content of berythromycin be multiplied by correction factor 0.7 by the calculated by peak area after correction, and the correction factor of Erythromycin C is 0.09.
Experiment erythromycin fermentation liquid, fermented liquid initially tire between 4000 ~ 6000u/ml, pH is about 7.
Based on above-mentioned method, the extraction element adopted in following examples as shown in Figure 1, the transport pipe of erythromycin fermentation liquid is connected to the entrance of ultra-filtration membrane 1 by pump, the per-meate side of ultra-filtration membrane 1 is connected to the entrance of nanofiltration membrane 2 by pump, the outlet retaining side of nanofiltration membrane 2 is connected to extraction tower 3, extraction tower 3 is provided with organic solvent storage tank 4, the bottom of extraction tower 3 is provided with tapping valve 11, the bottom of extraction tower 3 is also connected to the entrance of ceramic membrane 5 by pump, the per-meate side of ceramic membrane 5 is connected to tundish 6, tundish 6 are provided with Sodium Thiocyanate 99 storage tank 7, tundish 6 successively with crystallization kettle 8, equipment for separating liquid from solid 9 is connected with drying installation 10.In another one embodiment, be first the entrance by being connected to microfiltration membrane 12 at the transport pipe of erythromycin fermentation liquid, the per-meate side of microfiltration membrane 12 is connected to ultra-filtration membrane 1 by pump again.
This device when in use, first by erythromycin fermentation liquid is pumped into microfiltration membrane 12, after micro-filtrate membrane filtration, again its filtrate is filtered by pumping into ultra-filtration membrane 1, the filtrate of ultra-filtration membrane 1 pumps into nanofiltration membrane 2 and concentrates, the concentrated solution of nanofiltration membrane 2 is sent in extraction tower 3 and is extracted, organic solvent is put into extraction tower 3 from organic solvent storage tank 4, after extraction completes, open the tapping valve 11 bottom extraction tower 3, water layer is discharged, retain organic phase, organic phase in extraction tower 3 pumps in ceramic membrane 5 again and filters, the filtrate of ceramic membrane 5 is sent in tundish 6, in tundish 6, Sodium Thiocyanate 99 is added again by Sodium Thiocyanate 99 storage tank 7, after reaction, again the feed liquid in tundish 6 is sent into crystallization kettle 8 and carry out crystallization, feed liquid after crystallization is sent into equipment for separating liquid from solid 9 again and is separated, equipment for separating liquid from solid 9 can adopt whizzer etc., and then solids sent into after drying installation 10 carries out drying, Matachrom can be obtained.
Embodiment 1
Get erythromycin fermentation liquid 100L and be warming up to 65 DEG C, then through titanium oxide ceramics ultrafiltration membrance filter, the mean pore size of ultra-filtration membrane is 20nm, transmembrane pressure 0.2MPa, crossflow velocity 2m/s, after concentrated 8 times, the permeate of ultrafiltration is sent into nanofiltration membrane concentrate, the material of nanofiltration membrane is SPSF, molecular weight cut-off 200Da, nanofiltration temperature 50 C, pressure 1.4MPa, concentrate, concentrated 8 times, obtain concentrated solution, add the acetone of concentrated solution volume 1/4 more wherein, extract, separate organic phase, in organic phase, stream adds the sodium thiocyanate solution (adding 0.4 molar sulphur Zassol in the erythromycin of every 1 mole) of 20wt.%, pH about 7.5 is adjusted to again with 50% glacial acetic acid solvent, purified water is added by 1 times of organic phase volume, crystallization control temperature 25 ~ 30 DEG C, slow stirring 10 minutes, leave standstill 4h again, filtration obtains Matachrom wet product, with methyl alcohol, purified water drip washing, dry, obtain finished product.Erythromycin total recovery 77.4%; Detect according to HPLC method, the content 81.5% of Erythromycin A, the content 1.6% of berythromycin, the content of Erythromycin C is 2.1%.
Embodiment 2
Get erythromycin fermentation liquid 100L and be warming up to 65 DEG C, filter with Alumina Membrane for Microfiltration, the mean pore size of microfiltration membrane is 200nm, by MF permeate liquid through titanium oxide ceramics ultrafiltration membrance filter, the mean pore size of ultra-filtration membrane is 20nm, transmembrane pressure 0.2MPa, crossflow velocity 2m/s, after concentrated 8 times, the permeate of ultrafiltration is sent into nanofiltration membrane concentrate, the material of nanofiltration membrane is SPSF, molecular weight cut-off 200Da, nanofiltration temperature 50 C, pressure 1.4MPa, concentrate, concentrated 8 times, obtain concentrated solution, add the acetone of concentrated solution volume 1/4 more wherein, extract, separate organic phase, in organic phase, stream adds the sodium thiocyanate solution (adding 0.4 molar sulphur Zassol in the erythromycin of every 1 mole) of 20wt.%, pH about 7.5 is adjusted to again with 50% glacial acetic acid solvent, purified water is added by 1 times of organic phase volume, crystallization control temperature 25 ~ 30 DEG C, slow stirring 10 minutes, leave standstill 4h again, filtration obtains Matachrom wet product, with methyl alcohol, purified water drip washing, dry, obtain finished product.Erythromycin total recovery 79.2%; Detect according to HPLC method, the content 83.2% of Erythromycin A, the content 1.6% of berythromycin, the content of Erythromycin C is 2.1%.Can be found out by embodiment 1 and embodiment 2, before ultrafiltration, carry out micro-filtration pre-filtering, the purity of finished product can be improved.
Embodiment 3
Get erythromycin fermentation liquid 100L and be warming up to 55 DEG C, through titanium oxide ceramics ultrafiltration membrance filter, the mean pore size of ultra-filtration membrane is 20nm, transmembrane pressure 0.3MPa, crossflow velocity 4m/s, after concentrated 10 times, the permeate of ultrafiltration is sent into nanofiltration membrane concentrate, the material of nanofiltration membrane adopts polymeric amide respectively, SPSF, polyacrylonitrile, sulfonated polyether sulfone and polyimide, molecular weight cut-off 200Da, nanofiltration temperature 40 DEG C, pressure 2.0MPa, concentrate, concentrated 8 times, obtain concentrated solution, add the acetone of concentrated solution volume 1/4 more wherein, extract, separate organic phase, in organic phase, stream adds the sodium thiocyanate solution (adding 0.4 molar sulphur Zassol in the erythromycin of every 1 mole) of 20wt.%, pH about 7.5 is adjusted to again with 50% glacial acetic acid solvent, purified water is added by 1 times of organic phase volume, crystallization control temperature 25 ~ 30 DEG C, slow stirring 10 minutes, leave standstill 4h again, filtration obtains Matachrom wet product, with methyl alcohol, purified water drip washing, dry, obtain finished product.Yield under different condition and content, as following table, as can be seen from the table, when adopting sulfonated polyether sulfone filtering film, effectively can retain erythromycin and separating impurity, can solve the problem improving yield.
| Nanofiltration membrane material | Yield % | Erythromycin A % | Berythromycin % | Erythromycin C % |
| Polymeric amide | 73.5 | 82.1 | 1.4 | 1.9 |
| SPSF | 77.1 | 81.5 | 1.5 | 1.5 |
| Polyacrylonitrile | 74.7 | 79.5 | 1.4 | 1.6 |
| Sulfonated polyether sulfone | 84.3 | 84.3 | 1.3 | 1.4 |
| Polyimide | 81.9 | 80.9 | 1.5 | 1.6 |
Embodiment 4
Get erythromycin fermentation liquid 100L and be warming up to 50 DEG C, through titanium oxide ceramics ultrafiltration membrance filter, the mean pore size of ultra-filtration membrane is 20nm, transmembrane pressure 0.4MPa, crossflow velocity 5m/s, after concentrated 10 times, the permeate of ultrafiltration is sent into nanofiltration membrane concentrate, the material of nanofiltration membrane adopts sulfonated polyether sulfone, molecular weight cut-off adopts 200Da respectively, 300Da, 400Da, 500Da, 800Da, nanofiltration temperature 46 DEG C, pressure 2.5MPa, concentrate, concentrated 9 times, obtain concentrated solution, add the acetone of concentrated solution volume 1/3 more wherein, extract, separate organic phase, in organic phase, stream adds the sodium thiocyanate solution (adding 0.4 molar sulphur Zassol in the erythromycin of every 1 mole) of 20wt.%, pH about 7.5 is adjusted to again with 50% glacial acetic acid solvent, purified water is added by 1 times of organic phase volume, crystallization control temperature 25 ~ 30 DEG C, slow stirring 10 minutes, leave standstill 4h again, filtration obtains Matachrom wet product, with methyl alcohol, purified water drip washing, dry, obtain finished product.Yield under different condition and content, as following table, as can be seen from the table, when adopting molecular weight cut-off to be the nanofiltration membrane of 300Da, effectively can retain erythromycin and separating impurity, can solve the problem improving yield.
| Molecular weight cut-off Da | Yield % | Erythromycin A % | Berythromycin % | Erythromycin C % |
| 200 | 83.5 | 83.8 | 1.5 | 1.6 |
| 300 | 85.7 | 89.1 | 1.0 | 1.0 |
| 400 | 82.4 | 83.4 | 1.4 | 1.4 |
| 500 | 77.7 | 82.4 | 1.5 | 1.5 |
| 800 | 72.4 | 83.4 | 1.6 | 1.5 |
Embodiment 5
Get erythromycin fermentation liquid 100L and be warming up to 50 DEG C, through titanium oxide ceramics ultrafiltration membrance filter, the mean pore size of ultra-filtration membrane is 20nm, transmembrane pressure 0.4MPa, crossflow velocity 5m/s, after concentrated 10 times, the permeate of ultrafiltration is sent into nanofiltration membrane concentrate, the material of nanofiltration membrane adopts sulfonated polyether sulfone, molecular weight cut-off adopts 300Da, nanofiltration temperature 46 DEG C, pressure 2.5MPa, concentrate, concentrated 9 times, obtain concentrated solution, add the acetone of concentrated solution volume 1/3 more wherein, extract, separate organic phase, the alumina ceramic membrane that organic phase is 200nm by mean pore size filters, in the organic phase penetrated, stream adds the sodium thiocyanate solution (adding 0.4 molar sulphur Zassol in the erythromycin of every 1 mole) of 20wt.%, pH about 7.5 is adjusted to again with 50% glacial acetic acid solvent, purified water is added by 1 times of organic phase volume, crystallization control temperature 25 ~ 30 DEG C, slow stirring 10 minutes, leave standstill 4h again, filtration obtains Matachrom wet product, with methyl alcohol, purified water drip washing, dry, obtain finished product.Erythromycin total recovery 85.1%; Detect according to HPLC method, the content 91.1% of Erythromycin A, the content 1.0% of berythromycin, the content of Erythromycin C is 1.0%.Can be found out by embodiment 4 and embodiment 5, after ceramic membrane filter is carried out to organic phase, the purity of Erythromycin A in product can be improved.
Embodiment 6
Get erythromycin fermentation liquid 100L and be warming up to 50 DEG C, through titanium oxide ceramics ultrafiltration membrance filter, the mean pore size of ultra-filtration membrane is 20nm, transmembrane pressure 0.4MPa, crossflow velocity 5m/s, after concentrated 10 times, the permeate of ultrafiltration is sent into nanofiltration membrane concentrate, the material of nanofiltration membrane adopts sulfonated polyether sulfone, molecular weight cut-off adopts 200Da respectively, 300Da, 400Da, 500Da, 800Da, nanofiltration temperature 46 DEG C, pressure 2.5MPa, concentrate, concentrated 9 times, obtain concentrated solution, add the acetone of concentrated solution volume 1/3 more wherein, extract, separate organic phase, organic phase is undertaken filtering that (lyophobic alumina ceramic membrane prepares by the following method: the supporting layer of the ceramic membrane of employing is Alpha-alumina by the lyophobic alumina ceramic membrane that mean pore size is 200nm, separating layer is zirconium white, mean pore size is 0.2 μm, method of modifying is: after ceramic membrane is soaked 5 hours in the toluene being dissolved with trimethylchlorosilane, 5 times are repeatedly cleaned with ethanol, last at 120 DEG C dry 3 hours in an oven, stand-by, trimethylchlorosilane consumption is 20mmol/g, contact angle is about 130 °), in the organic phase penetrated, stream adds the sodium thiocyanate solution (adding 0.4 molar sulphur Zassol in the erythromycin of every 1 mole) of 20wt.%, pH about 7.5 is adjusted to again with 50% glacial acetic acid solvent, purified water is added by 1 times of organic phase volume, crystallization control temperature 25 ~ 30 DEG C, slow stirring 10 minutes, leave standstill 4h again, filtration obtains Matachrom wet product, with methyl alcohol, purified water drip washing, dry, obtain finished product.Erythromycin total recovery 87.4%; Detect according to HPLC method, the content 92.3% of Erythromycin A, the content 1.0% of berythromycin, the content of Erythromycin C is 1.1%.Can being found out by embodiment 5 and embodiment 6, can product purity be improved to adopting the ceramic membrane of hydrophobically modified.
Embodiment 7
Get erythromycin fermentation liquid 100L and be warming up to 65 DEG C, filter with Alumina Membrane for Microfiltration, the mean pore size of microfiltration membrane is 200nm, by MF permeate liquid through titanium oxide ceramics ultrafiltration membrance filter, the mean pore size of ultra-filtration membrane is 20nm, transmembrane pressure 0.2MPa, crossflow velocity 2m/s, after concentrated 8 times, the sodium polyacrylate of 0.05g/L will be added in the permeate of ultrafiltration, send into nanofiltration membrane again to concentrate, the material of nanofiltration membrane is SPSF, molecular weight cut-off 200Da, nanofiltration temperature 50 C, pressure 1.4MPa, concentrate, concentrated 8 times, obtain concentrated solution, add the acetone of concentrated solution volume 1/4 more wherein, extract, separate organic phase, in organic phase, stream adds the sodium thiocyanate solution (adding 0.4 molar sulphur Zassol in the erythromycin of every 1 mole) of 20wt.%, pH about 7.5 is adjusted to again with 50% glacial acetic acid solvent, purified water is added by 1 times of organic phase volume, crystallization control temperature 25 ~ 30 DEG C, slow stirring 10 minutes, leave standstill 4h again, filtration obtains Matachrom wet product, with methyl alcohol, purified water drip washing, dry, obtain finished product.Erythromycin total recovery 79.2%; Detect according to HPLC method, the content 87.4% of Erythromycin A, the content 1.3% of berythromycin, the content of Erythromycin C is 1.7%.Can be found out by embodiment 2 and embodiment 7, in nanofiltration process, add sodium polyacrylate a part of small molecular weight impurity can be made through nanofiltration membrane, prevent these impurity can not be separated in extraction process, and then have influence on the quality of finished product.
Claims (10)
1. a Matachrom extracting method, is characterized in that, comprises the steps:
1st step, erythromycin fermentation liquid ultrafiltration membrance filter, obtain ultrafiltration permeate; Ultrafiltration permeate nanofiltration is concentrated, obtains nanofiltration dope;
2nd step, by nanofiltration dope organic solvent extraction, obtain organic phase, then organic phase ceramic membrane is filtered, obtain ceramic membrane filtrate;
3rd step, in ceramic membrane filtrate, add Sodium Thiocyanate 99, then after carrying out crystallization, separation, drying, obtain Matachrom.
2. Matachrom extracting method according to claim 1, is characterized in that: ultra-filtration membrane molecular weight cut-off is the film of 5000 ~ 200000Da or its mean pore size scope is 0.02 ~ 50 nm; The material of ultra-filtration membrane is pottery.
3. Matachrom extracting method according to claim 1, is characterized in that: transmembrane pressure 0.1 ~ 0.5 MPa in ultra-filtration process; Crossflow velocity is 0.5 ~ 5 m/s preferably.
4. Matachrom extracting method according to claim 1, is characterized in that: before ultrafiltration step, carries out pre-filtering by microfiltration membrane; The material of microfiltration membrane is pottery; The mean pore size of microfiltration membrane is 0.2 μm ~ 2 μm.
5. Matachrom extracting method according to claim 1, is characterized in that: the material of nanofiltration membrane is selected from rhodia based polymer, polymeric amide, SPSF, polyacrylonitrile, polyester, sulfonated polyether sulfone, polyimide and vinyl polymer; Be more preferably sulfonated polyether sulfone; The molecular weight cut-off of nanofiltration membrane is preferably 200 ~ 500Da; Nanofiltration working pressure at 1.0 ~ 3.0MPa, temperature 40 ~ 50 DEG C.
6. Matachrom extracting method according to claim 1, is characterized in that: organic solvent is selected from methyl alcohol, ethanol, acetone, ethyl acetate, butylacetate, chloroform.
7. Matachrom extracting method according to claim 1, is characterized in that: the ceramic membrane in the 2nd step refers to hydrophobic ceramic film.
8. a Matachrom extraction element, include ultra-filtration membrane (1), nanofiltration membrane (2), extraction tower (3), it is characterized in that: the transport pipe of erythromycin fermentation liquid is connected to the entrance retaining side of ultra-filtration membrane (1), the per-meate side of ultra-filtration membrane (1) is connected to the entrance of nanofiltration membrane (2), the outlet retaining side of nanofiltration membrane (2) is connected to extraction tower (3), the bottom of extraction tower (3) is connected to the entrance of ceramic membrane (5), the per-meate side of ceramic membrane (5) is connected to tundish (6), tundish (6) are provided with Sodium Thiocyanate 99 storage tank (7), tundish (6) successively with crystallization kettle (8), equipment for separating liquid from solid (9), drying installation (10) connects.
9. Matachrom extraction element according to claim 8, is characterized in that: extraction tower (3) is provided with organic solvent storage tank (4); The bottom of extraction tower (3) is also provided with tapping valve (11); Equipment for separating liquid from solid (9) is whizzer; The input channel of erythromycin fermentation liquid is after the entrance being first connected to microfiltration membrane (12), the entrance retaining side of the ultra-filtration membrane (1) that the per-meate side of microfiltration membrane (12) is connected to again.
10. Matachrom extraction element according to claim 9, is characterized in that: the molecular weight cut-off of described ultra-filtration membrane (1) is the film of 5000 ~ 200000Da or its mean pore size scope is 0.02 ~ 50 nm; The material of ultra-filtration membrane (1) is pottery; The material of microfiltration membrane (12) is pottery; The mean pore size of microfiltration membrane (12) is 0.2 μm ~ 2 μm; The material of nanofiltration membrane (2) is selected from rhodia based polymer, polymeric amide, SPSF, polyacrylonitrile, polyester, sulfonated polyether sulfone, polyimide or vinyl polymer; The molecular weight cut-off of nanofiltration membrane (2) is preferably 200 ~ 500Da.
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| CN106589025A (en) * | 2016-12-20 | 2017-04-26 | 宁夏启元药业有限公司 | Extraction method of erythromycin |
| CN108373490A (en) * | 2017-11-24 | 2018-08-07 | 宁夏启元药业有限公司 | A kind of separation method of erythromycin impurity B |
| CN109553650A (en) * | 2017-09-25 | 2019-04-02 | 联邦制药(内蒙古)有限公司 | The aqueous extraction method of erythromycin fermentation liquid |
| CN111377574A (en) * | 2020-04-15 | 2020-07-07 | 浙江迪萧环保科技有限公司 | High-efficiency separation and extraction method of high-concentration ciprofloxacin synthetic liquid |
| CN111848701A (en) * | 2019-04-29 | 2020-10-30 | 伊犁川宁生物技术有限公司 | Continuous crystallization method of crude erythromycin thiocyanate |
| CN112047816A (en) * | 2020-09-23 | 2020-12-08 | 扬州大学 | Method for synthesizing ether by catalyzing alcohol with trimethylhalosilane |
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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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| CN106589025A (en) * | 2016-12-20 | 2017-04-26 | 宁夏启元药业有限公司 | Extraction method of erythromycin |
| CN109553650A (en) * | 2017-09-25 | 2019-04-02 | 联邦制药(内蒙古)有限公司 | The aqueous extraction method of erythromycin fermentation liquid |
| CN109553650B (en) * | 2017-09-25 | 2020-11-20 | 联邦制药(内蒙古)有限公司 | Water phase extraction method of erythromycin fermentation liquor |
| CN108373490A (en) * | 2017-11-24 | 2018-08-07 | 宁夏启元药业有限公司 | A kind of separation method of erythromycin impurity B |
| CN111848701A (en) * | 2019-04-29 | 2020-10-30 | 伊犁川宁生物技术有限公司 | Continuous crystallization method of crude erythromycin thiocyanate |
| CN111377574A (en) * | 2020-04-15 | 2020-07-07 | 浙江迪萧环保科技有限公司 | High-efficiency separation and extraction method of high-concentration ciprofloxacin synthetic liquid |
| CN112047816A (en) * | 2020-09-23 | 2020-12-08 | 扬州大学 | Method for synthesizing ether by catalyzing alcohol with trimethylhalosilane |
| CN112047816B (en) * | 2020-09-23 | 2023-05-16 | 扬州大学 | Method for synthesizing ether by catalyzing alcohol with trimethyl halosilane |
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