CN102408462B - Preparation method of erythromycin thiocyanate - Google Patents
Preparation method of erythromycin thiocyanate Download PDFInfo
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- CN102408462B CN102408462B CN201110396176.XA CN201110396176A CN102408462B CN 102408462 B CN102408462 B CN 102408462B CN 201110396176 A CN201110396176 A CN 201110396176A CN 102408462 B CN102408462 B CN 102408462B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention relates to a preparation method of erythromycin thiocyanate, which comprises the following steps: adding sodium hydroxide into an erythromycin fermentation liquid to regulate the pH value, filtering, concentrating, and recrystallizing to obtain the erythromycin thiocyanate. The method provided by the invention greatly reduces the consumption of the organic solvent, lowers the production cost, reduces the generation of waste residues, and is beneficial to environmental protection and production safety.
Description
Technical field
The present invention relates to a kind of preparation method of Matachrom, particularly a kind of Matachrom aqueous crystallization and acetone recrystallization technique, belong to medical biotechnology field.
Background technology
Erythromycin is a kind of alkaline antibiotic of separating from streptomyces erythreus nutrient solution nineteen fifty-two, erythromycin has broad-spectrum antibacterial action, to gram positive organism, as staphylococcus, micrococcus scarlatinae, viridans streptococci, streptococcus pneumoniae, streptococcus faecium, clostridium, diphtheria corynebacterium etc. have stronger restraining effect.To gram-negative bacteria, as gonococcus, helicobacter, bordetella pertussis, Brucella, legionella and hemophilus influenzae, bacterioide also have suitable restraining effect.China is from the nineteen fifty-seven production of trial-produceing successfully and progressively have high input.
The extracting method of erythromycin is mainly solvent extration at present, and extraction solvent used is butylacetate, under alkaline condition, from ferment filtrate, uses n-butyl acetate extraction, then through other processing, obtains final crystalline product.This technique main drawback is: during n-butyl acetate extraction, solvent-oil ratio is large.Patent CN95105997.1 discloses " process for extracting macrolide antibiotics ", in this technique, extraction agent---eight carbon alcohol (n-Octanol, isooctyl alcohol or secondary octanol) and thinner (normal hexane, hexanaphthene, normal heptane, sulfonated kerosene or hydrogenation kerosene) extract, and extraction liquid is stripped with acetic acid and sodium-acetate buffer in ferment filtrate employing.There is complicated operation in the method, and directly extracts with ferment filtrate, and required organic solvent requirement is large, is unfavorable for environment protection and operational safety.
Summary of the invention
An object of the present invention is to provide a kind of method simple, be easy to aqueous crystallization and the acetone recrystallization technique of the Matachrom grasped.
The present invention seeks to be achieved through the following technical solutions:
The preparation method of Matachrom of the present invention comprises the steps:
(1) fermented liquid is concentrated: it is 7.5～9.0 that the sodium hydroxide solution that erythromycin fermentation liquid is 5～20% by concentration is adjusted pH, adopts the ceramic membrane filter in 50nm～100nm aperture, and filtered liquid concentrates by the nanofiltration membrane of 200 molecular weight, obtains erythromycin concentrated solution;
(2) crystallization: erythromycin concentrated solution is placed in to crystallizer, every BOU erythromycin adds 5～20% sodium thiocyanate solutions of 0.15～0.2kg, it is 5.5～7.0 that glacial acetic acid solution with 20～80% regulates pH, crystallization Matachrom, solidliquid mixture obtains Matachrom crude product through centrifugation, Matachrom crude product adds acetone according to 1: 1～1: 8 ratio, it is 9.5～10.5 that the sodium hydroxide solution that is 5%～20% by concentration regulates pH, Matachrom is changed into erythromycin, standing, get acetone soln, every BOU erythromycin adds 5～20% sodium thiocyanate solutions of 0.15～0.2kg, with 20～80% glacial acetic acid solutions, adjust pH to 5.5～7.5, by 1～3 times of lysate volume, add 45～60 ℃ of purified water, 20～35 ℃ of crystallization control temperature, adopt variable-frequency motor slowly to stir 10 minutes, standing cooling enters the separated Matachrom wet product that obtains of whizzer for 0.5～2 hour again, in Matachrom wet product whizzer, use respectively acetone, 45～60 ℃ of purified water drip washing, centrifugation is until mother liquor discharge, dry, obtain Matachrom finished product.
The preparation method of a kind of Matachrom of the present invention is preferably as follows step:
(1) fermented liquid is concentrated: it is 8.0～8.4 that the sodium hydroxide solution that erythromycin fermentation liquid is 10% by concentration is adjusted pH, adopts the ceramic membrane filter in 50nm～100nm aperture, and filtered liquid concentrates by the nanofiltration membrane of 200 molecular weight, obtains erythromycin concentrated solution.
(2) recrystallization: erythromycin concentrated solution is placed in to crystallizer, every BOU erythromycin adds 10% the sodium thiocyanate solution of 0.18kg, it is 6.0～6.5 that glacial acetic acid solution with 50% regulates pH, crystallization Matachrom, solidliquid mixture obtains Matachrom crude product through centrifugation, Matachrom crude product adds acetone according to 1: 4 ratio, it is 9.8～10.0 that the sodium hydroxide solution that is 8% by concentration regulates pH, Matachrom is changed into erythromycin, standing separation, divide sub-cloud mother liquor to get acetone soln, every BOU erythromycin adds 10% the sodium thiocyanate solution of 0.18kg, with 50% glacial acetic acid solution, adjust pH to 6.5, by 1.5 times of lysate volume, add 50～55 ℃ of purified water, 25～30 ℃ of crystallization control temperature, adopt variable-frequency motor slowly to stir 10 minutes, , standing cooling enters the separated Matachrom wet product that obtains of whizzer for 1 hour, Matachrom wet product is used respectively acetone, 50～55 ℃ of purified water drip washing in whizzer, dry, obtain Matachrom finished product.
The preparation method of a kind of Matachrom of the present invention is preferably as follows step:
(1) fermented liquid is concentrated: it is 7.8～8.2 that the sodium hydroxide solution that erythromycin fermentation liquid is 15% by concentration is adjusted pH, adopts the ceramic membrane filter in 50nm～100nm aperture, and filtered liquid concentrates by the nanofiltration membrane of 200 molecular weight, obtains erythromycin concentrated solution.
(2) recrystallization: erythromycin concentrated solution is placed in to crystallizer, every BOU erythromycin adds 15% the sodium thiocyanate solution of 0.15kg, it is 6.0～6.5 that glacial acetic acid solution with 40% regulates pH, crystallization Matachrom, solidliquid mixture obtains Matachrom crude product through centrifugation, Matachrom crude product adds acetone according to 1: 3 ratio, it is 9.6～9.8 that the sodium hydroxide solution that is 10% by concentration regulates pH, Matachrom is changed into erythromycin, standing, get acetone soln, every BOU erythromycin adds 15% the sodium thiocyanate solution of 0.15kg, with 40% glacial acetic acid solution, adjust pH to 6.5, by 1.0 times of lysate volume, add 50～55 ℃ of purified water, 25～30 ℃ of crystallization control temperature, adopt variable-frequency motor slowly to stir 10 minutes, , standing cooling enters the separated Matachrom wet product that obtains of whizzer for 1 hour, Matachrom wet product is used respectively acetone, 50～55 ℃ of purified water drip washing in whizzer, dry, obtain Matachrom finished product.
Described erythromycin fermentation liquid is prepared as follows:
(1) erythromycin seed liquor is cultivated: 1. female slant pore preparation: by freezing streptomyces erythareus (the producing bacterium) spore (bacterial classification that the streptomyces erythareus that the present invention uses is Guangdong Province's commercial extensive sale in microbial strains preservation center being kept in sand pipe, GIM numbering: GIM4.14, other numberings: AS4.198), be inoculated on the slant medium of sterilizing, under 32～34 ℃ of conditions of temperature, cultivate 7～9 days; 2. sub-slant pore preparation: by female slant pore, be inoculated on the slant medium of sterilizing, under 32～34 ℃ of conditions of temperature, cultivate 7～9 days; 3. seed culture: by sub-slant pore, be inoculated in the seed culture medium through sterilizing, through three grades of seed enlarged culturing, obtain erythromycin seed liquor;
(2) fermentation: erythromycin seed liquor is inoculated in the substratum of sterilizing by 10～20% volume ratios, passes into sterile air and stir 15～30 hours, add nutritive substance, through cultivation in 7～10 days, obtain erythromycin fermentation liquid.
Above-mentioned female slant pore is prepared substratum and is comprised of following component: starch 0.1～1.0 weight part, corn steep liquor 0.05～0.2 weight part, agar 0.1～1.0 weight part, glucose 0.1～1.0 weight part, sodium-chlor 0.5～2.0 weight part, calcium chloride 0.1～1.0 weight part, use tap water constant volume are to 100 parts by volume.
Above-mentioned sub-slant pore is prepared slant medium and is comprised of following component: starch 0.1～1.0 weight part, corn steep liquor 0.05～0.2 weight part, agar 0.1～1.0 weight part, glucose 0.1～1.0 weight part, sodium-chlor 0.5～2.0 weight part, calcium chloride 0.1～1.0 weight part, use tap water constant volume are to 100 parts by volume.
Above-mentioned first order seed enlarged culturing condition is: (1) substratum forms: analysis for soybean powder 2～4 weight parts, starch 1～2 weight part, CaCO
30.6～0.8. weight part, dextrin 1～2 weight part, sulphur ammonium 0.2～0.4 weight part, corn steep liquor 1～4 weight part, vegetables oil 0.5～1 weight part, use tap water constant volume are to 100 parts by volume; (2) temperature is 32～34 ℃; (3) incubation time is 48～96 hours;
Above-mentioned two, three grades of seed enlarged culturing conditions are: (1) substratum forms: analysis for soybean powder 2.0～4.5 weight parts, starch 2.5～4.0 weight parts, CaCO
30.5～0.7 weight part, sodium-chlor 0.4～0.6 weight part, dextrin 2.5～4.0 weight parts, sulphur ammonium 0.1～0.3 weight part, corn steep liquor 1～2 weight part, vegetables oil 0.8～1.5 weight part, foam killer 0～0.02 weight part, use tap water constant volume are to 100 parts by volume; (2) temperature is 32～34 ℃; (3) incubation time is 24～48 hours.
Above-mentioned fermention medium consists of: analysis for soybean powder 3.5～5.5 weight parts, starch 2.0～4.0 weight parts, sulphur ammonium 0.08～0.15 weight part, CaCO
30.6～1.0 weight part, vegetables oil 0.5～1.0 weight part, foam killer 0.005～0.02 weight part, use tap water constant volume are to 100 parts by volume.
Above-mentioned interpolation composition of nutritive substance is: liquid sugar 10～50 weight parts, vegetables oil 1～10 weight part, n-propyl alcohol solution 0.5～5 weight part.
Above-mentioned vegetables oil is: any in peanut oil, rapeseed oil, soybean oil, Oleum Gossypii semen, sesame oil, sunflower seed oil, sweet oil, zedoary turmeric oil, Oleum Bulbus Allii, Oleum Hippophae, Radix Angelicae Sinensis oil, Oils, Zingiber officinale, Fructus Forsythiae oil, perilla oil, Oleum Citri Reticulatae, Viscotrol C, spearmint oil, ucuhuba oil.
Described vegetables oil is preferably any in soybean oil, rapeseed oil.
Described liquid sugar is 20～70% glucose solutions.
Described n-propyl alcohol solution is 20～70% n-propyl alcohol solution.
Described foam killer is polyethers foam killer.
Described polyethers foam killer is any one or two kinds of composition in polyoxypropylene glycerine and polyoxyethylene oxypropylene glycerine.
The inventive method is as follows with the progressive that existing Matachrom preparation method compares:
1, ceramic membrane filter does not add the throw outs such as zinc sulfate, polymerize aluminum chloride, and microorganism growth breeding can not be subject to metal ion and suppress, and the biochemical of gained filter residue greatly improves, and is easy to be developed to compoiste fertilizer and biogas, reduces waste residue and produces; Make production cost greatly reduce simultaneously.
2, do not use sheet frame, production scene is without rinsing sheet frame and cleaning filter cloth, and place is anhydrous without slag, realizes cleaner production.
3, adopt after nanofiltration membrane concentration technology, the concentrated solvents such as butylacetate that do not re-use of extraction of erythromycin extract concentrated to erythromycin, use and the volume of the circular flow of organic solvent greatly reduce, the safety in production of enterprise is more guaranteed, need not carry out Distillation recovery butylacetate to the factory effluent after extracting.
4, after adopting nanofiltration concentrated, nanofiltration membrane infiltration water, apart from outside micro-inorganic salt, without other organism, can be made cover water and the unit bath water of ceramic membrane unit, economizes on resources.
5, adopt after primary crystallization, with a small amount of acetone recrystallization, purify, Erythromycin A component can be up to 90%, and the quality of Matachrom greatly improves, and organic solvent usage quantity greatly reduces, and is conducive to environmental protection and production safety.
Following embodiment will contribute to those of ordinary skill in the art further to understand the present invention, but not limit in any form the present invention.
Experimental example 1 simultaneous test
Existing Matachrom preparation method:
It is 8.0～8.4 that the sodium hydroxide solution that it is 10% by concentration that fermented liquid is put after tank is adjusted pH, add afterwards the flocculation of 4% zinc sulfate, after flocculation, with Plate Filtration, remove solid substance, filtrate is adjusted to pH6.0～6.5 with glacial acetic acid solution, with double solvent extractions such as butylacetates, solvent is added to Sodium Thiocyanate 99 and Glacial acetic acid, and Matachrom is crystallized out again, crystal, through washing, oven dry, obtains Matachrom.
Matachrom preparation method of the present invention:
(1) fermented liquid is concentrated: after erythromycin fermentation liquid slagging-off, it is 8.0～8.4 that the sodium hydroxide solution that is 10% by concentration is adjusted pH, the ceramic membrane filter that adopts 50nm～100nm aperture, filtered liquid concentrates by the nanofiltration membrane of 200 molecular weight, obtains erythromycin concentrated solution.
(2) recrystallization: erythromycin concentrated solution is placed in to crystallizer, add 10% sodium thiocyanate solution (every BOU erythromycin adds 10% sodium thiocyanate solution of 0.18kg), it is 6.0～6.5 that glacial acetic acid solution with 50% regulates pH, crystallization Matachrom, solidliquid mixture obtains Matachrom crude product through centrifugation, Matachrom crude product adds acetone according to 1: 4 ratio, it is 9.8～10.0 that the sodium hydroxide solution that is 10% by concentration regulates pH, Matachrom is changed into erythromycin, standing, get acetone soln, add 10% sodium thiocyanate solution (every BOU erythromycin adds 10% sodium thiocyanate solution of 0.18kg), with 50% glacial acetic acid solution, adjust pH to 6.5, by 1.5 times of lysate volume, add 50～55 ℃ of purified water, 25～30 ℃ of crystallization control temperature, stop stirring, within standing 1 hour, enter the separated Matachrom wet product that obtains of whizzer, Matachrom wet product is used respectively acetone, 50～55 ℃ of purified water drip washing, dry, obtain Matachrom finished product.
Table one Matachrom preparation method's comparison
Known by table one: the present invention's ceramic membrane filter used does not add the throw outs such as zinc sulfate, polymerize aluminum chloride, has reduced organic consumption, makes production cost greatly reduce simultaneously; Do not use sheet frame, production scene is without rinsing sheet frame and cleaning filter cloth, and place is anhydrous without slag, realizes cleaner production; Adopt after nanofiltration membrane concentration technology, the concentrated solvents such as N-BUTYL ACETATE that do not re-use of the extraction of erythromycin extract and concentrate erythromycin, and use and the volume of the circular flow of organic solvent greatly reduce; After adopting nanofiltration concentrated, nanofiltration membrane infiltration water, apart from outside micro-inorganic salt, without other organism, can be made cover water and the unit bath water of ceramic membrane unit, economizes on resources; Adopt after primary crystallization, with a small amount of acetone recrystallization, purify, Erythromycin A component can be up to 90%, and the quality of Matachrom greatly improves.
Following embodiment is used for further illustrating but is not limited to the present invention.
Embodiment 1: the preparation of erythromycin fermentation liquid
(1) fermented liquid is concentrated: after erythromycin fermentation liquid slagging-off, it is 8.0～8.4 that the sodium hydroxide solution that is 10% by concentration is adjusted pH, the ceramic membrane filter that adopts 50nm～100nm aperture, filtered liquid concentrates by the nanofiltration membrane of 200 molecular weight, obtains erythromycin concentrated solution.
(2) recrystallization: erythromycin concentrated solution is placed in to crystallizer, add 10% sodium thiocyanate solution (every BOU erythromycin adds 10% sodium thiocyanate solution of 0.18kg), it is 6.0～6.5 that glacial acetic acid solution with 50% regulates pH, crystallization Matachrom, solidliquid mixture obtains Matachrom crude product through centrifugation, Matachrom crude product adds acetone according to 1: 4 ratio, it is 9.8～10.0 that the sodium hydroxide solution that is 10% by concentration regulates pH, Matachrom is changed into erythromycin, standing, get acetone soln, add 10% sodium thiocyanate solution (every BOU erythromycin adds 10% sodium thiocyanate solution of 0.18kg), with 50% glacial acetic acid solution, adjust pH to 6.5, by 1.5 times of lysate volume, add 50～55 ℃ of purified water, 25～30 ℃ of crystallization control temperature, stop stirring, within standing 1 hour, enter the separated Matachrom wet product that obtains of whizzer, Matachrom wet product is used respectively acetone, 50～55 ℃ of purified water drip washing, dry, obtain Matachrom finished product.
The preparation of erythromycin fermentation liquid
(1) erythromycin seed liquor is cultivated: 1. female slant pore preparation: by freezing streptomyces erythareus (the producing bacterium) spore being kept in sand pipe, be inoculated on the slant medium of sterilizing, substratum forms: starch 0.2g, corn steep liquor 0.1g, agar 0.2g, glucose 0.8g, sodium-chlor 1.5g, calcium chloride 0.8g, uses tap water constant volume to 100ml; Under 34 ℃ of conditions of temperature, cultivate 8 days; 2. sub-slant pore preparation: by female slant pore, be inoculated on the slant medium of sterilizing, substratum consists of: starch 0.2g, corn steep liquor 0.15g, agar 0.6g, glucose 0.2g, sodium-chlor 0.8g, calcium chloride 0.8g, uses tap water constant volume to 100ml; Under 34 ℃ of conditions of temperature, cultivate 8 days; 3. seed culture: by sub-slant pore, be inoculated in the seed culture medium through sterilizing, through three grades of seed enlarged culturing, obtain erythromycin seed liquor;
(2) fermentation: erythromycin seed liquor is inoculated in the substratum of sterilizing in 20% ratio, and substratum consists of: analysis for soybean powder 5.0g, starch 2.5g, sulphur ammonium 0.15g, CaCO
30.7g, rapeseed oil 0.9g, polyoxyethylene oxypropylene glycerine 0.005g, uses tap water constant volume to 100ml; Pass into sterile air and stir, at 15 hours, adding 60% glucose solution 40g, rapeseed oil 5g, 30% n-propyl alcohol 1g, through cultivation in 7 days, obtains erythromycin fermentation liquid.
First order seed enlarged culturing base composition is preferably: analysis for soybean powder 2g, starch 2g, CaCO
30.75g, dextrin 1g, sulphur ammonium 0.4g, corn steep liquor 3g, rapeseed oil 0.8g, uses tap water constant volume to 100ml.
Two, three grades of seed enlarged culturing bases form: (1) substratum forms: analysis for soybean powder 4g, starch 3g, CaCO
30.5g, sodium-chlor 0.4g, dextrin 4g, sulphur ammonium 0.3g, corn steep liquor 1g, rapeseed oil 0.8g, polyoxyethylene oxypropylene glycerine 0.01g, uses tap water constant volume to 100ml.
Embodiment 2: a kind of preparation method of Matachrom
(1) fermented liquid is concentrated: after erythromycin fermentation liquid slagging-off, it is 7.8～8.2 that the sodium hydroxide solution that is 15% by concentration is adjusted pH, the ceramic membrane filter that adopts 50nm～100nm aperture, filtered liquid concentrates by the nanofiltration membrane of 200 molecular weight, obtains erythromycin concentrated solution.
(2) recrystallization: erythromycin concentrated solution is placed in to crystallizer, add 15% sodium thiocyanate solution (every BOU erythromycin adds 15% sodium thiocyanate solution of 0.15kg), it is 6.0～6.5 that glacial acetic acid solution with 40% regulates pH, crystallization Matachrom, solidliquid mixture obtains Matachrom crude product through centrifugation, Matachrom crude product adds acetone according to 1: 3 ratio, it is 9.6～9.8 that the sodium hydroxide solution that is 15% by concentration regulates pH, Matachrom is changed into erythromycin, standing, get acetone soln, add 15% sodium thiocyanate solution (every BOU erythromycin adds 15% sodium thiocyanate solution of 0.15kg), with 40% glacial acetic acid solution, adjust pH to 6.5, by 1.0 times of lysate volume, add 50～55 ℃ of purified water, 25～30 ℃ of crystallization control temperature, stop stirring, within standing 2 hours, enter the separated Matachrom wet product that obtains of whizzer, Matachrom wet product is used respectively acetone, 50～55 ℃ of purified water drip washing, dry, obtain Matachrom finished product.
The preparation of erythromycin fermentation liquid
(1) erythromycin seed liquor is cultivated: 1. female slant pore preparation: by freezing streptomyces erythareus (the producing bacterium) spore being kept in sand pipe, be inoculated on the slant medium of sterilizing, substratum consists of: starch 0.5g, corn steep liquor 0.1g, agar 0.5g.Glucose 0.5g, sodium-chlor 1g, calcium chloride 0.5g, uses tap water constant volume to 100ml; Under 34 ℃ of conditions of temperature, cultivate 9 days; 2. sub-slant pore preparation: by female slant pore, be inoculated on the slant medium of sterilizing, substratum consists of: starch 0.4g, corn steep liquor 0.2g, agar 0.4g, glucose 0.4g, sodium-chlor 1.5g, calcium chloride 1.0g, uses tap water constant volume to 100ml; Under 34 ℃ of conditions of temperature, cultivate 9 days; 3. seed culture: by sub-slant pore, be inoculated in the seed culture medium through sterilizing, through three grades of seed enlarged culturing, obtain erythromycin seed liquor;
(2) fermentation: erythromycin seed liquor is inoculated in the substratum of sterilizing in 10% ratio, and substratum consists of: analysis for soybean powder 4.5g, starch 3.0g, sulphur ammonium 0.12g, CaCO
30.gg, soybean oil 0.7g, polyoxypropylene glycerine 0.01g, uses tap water constant volume to 100ml; Pass into sterile air and stir 20 hours, adding 40% glucose solution 20g, soybean oil 4g, 60% n-propyl alcohol solution 2g, through cultivation in 8 days, obtains erythromycin fermentation liquid.
First order seed enlarged culturing condition is: (1) analysis for soybean powder 3g, starch 1.5g, CaCO
30.7g, dextrin 1.5g, sulphur ammonium 0.3g, corn steep liquor 2g, soybean oil 0.7g, uses tap water constant volume to 100ml; (2) temperature is 33 ℃; (3) incubation time is 70 hours;
Two, three grades of seed enlarged culturing conditions are: (1) substratum forms: analysis for soybean powder 3.5g, starch 3.2g, CaCO
30.6g, sodium-chlor 0.5g, dextrin 3.2g, sulphur ammonium 0.2g, corn steep liquor 1.5g, soybean oil 1.1g, polyoxypropylene glycerine 0.005g, uses tap water constant volume to 100ml; (2) temperature is 32～34 ℃; (3) incubation time is 24～48 hours.
Claims (8)
1. a preparation method for Matachrom, is characterized in that the method comprises the steps:
(1) fermented liquid is concentrated: it is 7.5 ~ 9.0 that the sodium hydroxide solution that erythromycin fermentation liquid concentration is 5 ~ 20% is adjusted pH, adopts the ceramic membrane filter in nm aperture, 50nm ~ 100, and filtered liquid concentrates by the nanofiltration membrane of 200 molecular weight, obtains erythromycin concentrated solution;
(2) crystallization: erythromycin concentrated solution is placed in to crystallizer, every BOU erythromycin adds 5 ~ 20% sodium thiocyanate solutions of 0.15 ~ 0.2kg, it is 5.5 ~ 7.0 that glacial acetic acid solution with 20 ~ 80% regulates pH, crystallization Matachrom, solidliquid mixture obtains Matachrom crude product through centrifugation, Matachrom crude product adds acetone according to 1:1 ~ 1:8 ratio, it is 9.5 ~ 10.5 that the sodium hydroxide solution that is 5% ~ 20% by concentration regulates pH, Matachrom is changed into erythromycin, standing, get acetone soln, every BOU erythromycin adds 5 ~ 20% sodium thiocyanate solutions of 0.15 ~ 0.2kg, with 20 ~ 80% glacial acetic acid solutions, adjust pH to 5.5 ~ 7.5, by 1 ~ 3 times of lysate volume, add 45 ~ 60 ℃ of purified water, 20 ~ 35 ℃ of crystallization control temperature, adopt variable-frequency motor slowly to stir 10 minutes, standing cooling enters the separated Matachrom wet product that obtains of whizzer for 0.5 ~ 2 hour again, in Matachrom wet product whizzer, use respectively acetone, 45 ~ 60 ℃ of purified water drip washing, centrifugation is until mother liquor discharge, dry, obtain Matachrom finished product,
Erythromycin fermentation liquid is prepared in accordance with the following steps:
(1) erythromycin seed liquor is cultivated: 1. female slant pore preparation: by freezing, be kept at streptomyces erythareus (producing bacterium) spore inoculating in sand pipe on the slant medium through sterilizing, under 32 ~ 34 ℃ of conditions of temperature, cultivate 7 ~ 9 days, the female slant pore of described erythromycin is prepared substratum and is comprised of following component: starch 0.1 ~ 1.0 weight part, corn steep liquor 0.05 ~ 0.2 weight part, agar 0.1 ~ 1.0 weight part, glucose 0.1 ~ 1.0 weight part, sodium-chlor 0.5 ~ 2.0 weight part, calcium chloride 0.1 ~ 1.0 weight part, tap water preparation; 2. sub-slant pore preparation: by female slant pore, be inoculated on the slant medium of sterilizing, under 32 ~ 34 ℃ of conditions of temperature, cultivate 7 ~ 9 days, the sub-slant pore of described erythromycin is prepared substratum and is comprised of following component: starch 0.1 ~ 1.0 weight part, corn steep liquor 0.05 ~ 0.2 weight part, agar 0.1 ~ 1.0 weight part, glucose 0.1 ~ 1.0 weight part, sodium-chlor 0.5 ~ 2.0 weight part, calcium chloride 0.1 ~ 1.0 weight part, use tap water constant volume are to 100 parts by volume; 3. seed culture: by sub-slant pore, be inoculated in the seed culture medium through sterilizing, through three grades of seed enlarged culturing, obtain erythromycin seed liquor, described first order seed enlarged culturing substratum is: analysis for soybean powder 2 ~ 4 weight parts, starch 1 ~ 2 weight part, CaCO
30.6 ~ 0.8 weight part, dextrin 1 ~ 2 weight part, sulphur ammonium 0.2 ~ 0.4 weight part, corn steep liquor 1 ~ 4 weight part, vegetables oil 0.5 ~ 1 weight part, use tap water constant volume are to 100 parts by volume, and two, three grades of seed enlarged culturing bases of described erythromycin consist of: analysis for soybean powder 2.0 ~ 4.5 weight parts, starch 2.5 ~ 4.0 weight parts, CaCO
30.5 ~ 0.7 weight part, sodium-chlor 0.4 ~ 0.6 weight part, dextrin 2.5 ~ 4.0 weight parts, sulphur ammonium 0.1 ~ 0.3 weight part, corn steep liquor 1 ~ 2 weight part, vegetables oil 0.8 ~ 1.5 weight part, foam killer 0 ~ 0.02 weight part, use tap water constant volume are to 100 parts by volume;
(2) fermentation: erythromycin seed liquor is inoculated in the substratum of sterilizing by 10 ~ 20% volume ratios, pass into sterile air and open and stir, add nutritive substance, through 7 ~ 10 days, cultivate, obtain erythromycin fermentation liquid, described abomacetin fermentation substratum consists of: analysis for soybean powder 3.5 ~ 5.5 weight parts, starch 2.0 ~ 4.0 weight parts, sulphur ammonium 0.08 ~ 0.15 weight part, CaCO
30.6 ~ 1.0 weight part, vegetables oil 0.5 ~ 1.0 weight part, foam killer 0.005 ~ 0.02 weight part, use tap water constant volume are to 100 parts by volume; Described composition of nutritive substance is: liquid sugar 10 ~ 50 weight parts, vegetables oil 1 ~ 10 weight part, n-propyl alcohol solution 0.5 ~ 5 weight part.
2. the preparation method of Matachrom as claimed in claim 1, is characterized in that the method comprises the steps:
(1) fermented liquid is concentrated: it is 8.0 ~ 8.4 that the sodium hydroxide solution that erythromycin fermentation liquid is 10% by concentration is adjusted pH, adopts the ceramic membrane filter in nm aperture, 50nm ~ 100, and filtered liquid concentrates by the nanofiltration membrane of 200 molecular weight, obtains erythromycin concentrated solution;
(2) recrystallization: erythromycin concentrated solution is placed in to crystallizer, every BOU erythromycin adds 10% the sodium thiocyanate solution of 0.18kg, it is 6.0 ~ 6.5 that glacial acetic acid solution with 50% regulates pH, crystallization Matachrom, solidliquid mixture obtains Matachrom crude product through centrifugation, Matachrom crude product adds acetone according to 1:4 ratio, it is 9.8 ~ 10.0 that the sodium hydroxide solution that is 8% by concentration regulates pH, Matachrom is changed into erythromycin, standing separation, divide sub-cloud mother liquor to get acetone soln, every BOU erythromycin adds 10% the sodium thiocyanate solution of 0.18kg, with 50% glacial acetic acid solution, adjust pH to 6.5, by 1.5 times of lysate volume, add 50 ~ 55 ℃ of purified water, 25 ~ 30 ℃ of crystallization control temperature, adopt variable-frequency motor slowly to stir 10 minutes, standing cooling enters the separated Matachrom wet product that obtains of whizzer for 1 hour, Matachrom wet product is used respectively acetone, 50 ~ 55 ℃ of purified water drip washing in whizzer, dry, obtain Matachrom finished product.
3. the preparation method of Matachrom as claimed in claim 1, is characterized in that the method comprises the steps:
(1) fermented liquid is concentrated: it is 7.8 ~ 8.2 that the sodium hydroxide solution that erythromycin fermentation liquid is 15% by concentration is adjusted pH, adopts the ceramic membrane filter in nm aperture, 50nm ~ 100, and filtered liquid concentrates by the nanofiltration membrane of 200 molecular weight, obtains erythromycin concentrated solution;
(2) recrystallization: erythromycin concentrated solution is placed in to crystallizer, every BOU erythromycin adds 15% the sodium thiocyanate solution of 0.15kg, it is 6.0 ~ 6.5 that glacial acetic acid solution with 40% regulates pH, crystallization Matachrom, solidliquid mixture obtains Matachrom crude product through centrifugation, Matachrom crude product adds acetone according to 1:3 ratio, it is 9.6 ~ 9.8 that the sodium hydroxide solution that is 10% by concentration regulates pH, Matachrom is changed into erythromycin, standing, get acetone soln, every BOU erythromycin adds 15% the sodium thiocyanate solution of 0.15kg, with 40% glacial acetic acid solution, adjust pH to 6.5, by 1.0 times of lysate volume, add 50 ~ 55 ℃ of purified water, 25 ~ 30 ℃ of crystallization control temperature, adopt variable-frequency motor slowly to stir 10 minutes, , standing cooling enters the separated Matachrom wet product that obtains of whizzer for 1 hour, Matachrom wet product is used respectively acetone, 50 ~ 55 ℃ of purified water drip washing in whizzer, dry, obtain Matachrom finished product.
4. the preparation method of the Matachrom as described in as arbitrary in claim 1-3, is characterized in that erythromycin first order seed enlarged culturing temperature is 32 ~ 34 ℃, and incubation time is 48 ~ 96 hours.
5. the preparation method of the Matachrom as described in as arbitrary in claim 1-3, is characterized in that two, three grades of seed enlarged culturing temperature of erythromycin are 32 ~ 34 ℃, and incubation time is 24 ~ 48 hours.
6. the preparation method of Matachrom as claimed in claim 1, is characterized in that described liquid sugar is 20 ~ 70% glucose solutions.
7. the preparation method of Matachrom as claimed in claim 1, is characterized in that described n-propyl alcohol solution is 20 ~ 70% n-propyl alcohol solution.
8. the preparation method of Matachrom as claimed in claim 1, is characterized in that described foam killer is any one or two kinds of composition in polyoxypropylene glycerine and polyoxyethylene oxypropylene glycerine.
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| CN102659881B (en) * | 2012-04-28 | 2014-12-17 | 安徽丰原发酵技术工程研究有限公司 | Method for preparing erythromycin thiocyanate |
| CN102876766B (en) * | 2012-10-31 | 2014-10-15 | 国药集团威奇达药业有限公司 | Fermentation process of cephalosporin C |
| CN102911228A (en) * | 2012-11-02 | 2013-02-06 | 伊犁川宁生物技术有限公司 | Refining method and preparation method of erythromycin thiocyanate |
| CN103044508B (en) * | 2013-01-09 | 2013-11-27 | 宁夏启元药业有限公司 | Method for extracting crystallized erythromycin thiocyanate from fermentation liquid |
| CN103113440B (en) * | 2013-01-30 | 2015-05-20 | 伊犁川宁生物技术有限公司 | Preparation method of erythromycin thiocyanate |
| CN103304612B (en) * | 2013-06-25 | 2016-01-20 | 伊犁川宁生物技术有限公司 | A kind of concentration method of erythromycin fermentation liquid |
| CN103483407B (en) * | 2013-10-10 | 2015-11-18 | 宁夏启元药业有限公司 | A kind of Matachrom extractive crystallization double solvent and extractive crystallization method |
| CN104262431A (en) * | 2014-09-22 | 2015-01-07 | 江苏久吾高科技股份有限公司 | Method and device for extracting erythromycin thiocyanate |
| CN105777827A (en) * | 2014-12-15 | 2016-07-20 | 宁夏启元药业有限公司 | Extraction method of high-purity erythromycin E |
| CN105237600A (en) * | 2015-10-23 | 2016-01-13 | 伊犁川宁生物技术有限公司 | Method for recovering erythromycin from erythromycin-containing wastewater |
| CN105348340A (en) * | 2015-11-27 | 2016-02-24 | 宁夏启元药业有限公司 | Preparation method of erythromycin thiocyanate |
| CN105601687B (en) * | 2016-03-28 | 2019-05-24 | 四川新迪医药化工有限公司 | A kind of refining methd of erythromycin thiocyanate |
| CN110066743B (en) * | 2018-01-22 | 2022-06-24 | 伊犁川宁生物技术有限公司 | Erythromycin production strain with improved fermentation foul smell and application thereof |
| 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 |
| CN110003295B (en) * | 2019-04-29 | 2020-05-12 | 宜昌东阳光药业股份有限公司 | Preparation method of erythromycin thiocyanate |
| CN109942655B (en) * | 2019-04-29 | 2020-05-12 | 宜昌东阳光药业股份有限公司 | Continuous crystallization method of erythromycin thiocyanate crude product |
| CN112978993B (en) * | 2021-02-25 | 2022-03-18 | 宜昌东阳光生化制药有限公司 | Method for recovering thiocyanate ions from rectification waste liquid of erythromycin thiocyanate crystallization mother liquor and application |
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