CN101643758A - Method for extracting monensin sodium by methanol extraction method - Google Patents
Method for extracting monensin sodium by methanol extraction method Download PDFInfo
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- CN101643758A CN101643758A CN200810138899A CN200810138899A CN101643758A CN 101643758 A CN101643758 A CN 101643758A CN 200810138899 A CN200810138899 A CN 200810138899A CN 200810138899 A CN200810138899 A CN 200810138899A CN 101643758 A CN101643758 A CN 101643758A
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Abstract
The invention provides a method for extracting monensin sodium by a methanol extraction method, belongs to the field of biopharmaceuticals and engineering, and is mainly used for producing a monensinpure substance (sodium salt mode) by a fermentation method. The method comprises the following steps: culturing strains in a sand soil tube; culturing strains on an inclined surface; preparing first order seed culture solution and second order seed culture solution; preparing fermentation liquor; making a filter cake; dissolving and releasing the filter cake; extracting the filter cake; and decoloring the filter cake. The method is characterized in that the process of extraction adopts mycelium with moisture content of between 20 and 30 percent, adds 5 to 8 times of methanol of which the concentration is between 60 and 90 percent to the mycelium according to weight ratio, adjusts the temperature at between 15 and 35 DEG C, and stirs the mixture for 30 to 40 minutes to ensure that the mixture is sufficiently dissolved; and a finished product is prepared through activated carbon decoloration, filtration, crystallization, separation, drying and package. The method has high product extraction rate, namely reaching over 90 percent, low cost, good product quality, namely the product is in accordance with the requirement of the monensin sodium pure substance of an American USP standard, and high economic benefit, and can be widely applied in the field of biopharmaceuticals and engineering.
Description
Technical field
With the method for extracting monensin sodium by methanol extraction method, belong to bio-pharmaceuticals and engineering field.Be mainly used in production with the pure product of monensin (sodium-salt form) of fermentative Production.
Background technology
Monensin belongs to the polyethers ion carrier antibiotic, also claim monensin, cinnamycin, it is the acid microbiotic that Chinese cassia tree ground streptomycete (Streptomyces cinnamonensis) produces with five rings polyether structure, found to have the anticoccidial effect in 1967, ratifying production in the U.S. as anticoccidiosis medicine in 1971 goes on the market, ratified again in 1984 as ox, the growth stimulant of sheep, obtain promotion and application more than 40 countries and regions, it has been the special-purpose microbiotic of class livestock and poultry with fastest developing speed since the seventies, nearly 30,000 tons of year usage quantity, preventing coccidium infection and improving on the ruminant feed turnover ratio and obtained remarkable economic efficiency that usage quantity rises year by year.Polyether antibiotics mainly has higher anti-microbial activity to gram-positive microorganism, and what have also has anti-microbial effect to some fungi, but very weak to the Gram-negative bacteria effect.The activity that the livestock and poultry coccidia is had wide spectrum.Not only 6 kinds of Eimeria diseases of chicken there are control and preventive effect, the coccidias of calf, lamb, piglet, sub-rabbit etc. is all had higher activity, and the resistance slower development.Mainly act on the coccidia life history early stage (sub-sporozoite is to first-generation schizont), polyether antibiotics has the effect of tangible improvement feed efficiency to ruminating animal.At present, the livestock breeding industry of China is to mass-producing, intensivization development, and especially the breed scale of beef cattle will further enlarge the consumption of monensin in continuous expansion.
The main manufacturer of monensin is the big pharmaceutical factory of Lilly, and its annual production is about 20,000 tons, and annual sales amount is 1.72 hundred million dollars.China began to introduce the production technology and the technology of monensin in recent years, had progressively formed scale, but on the market all with the form appearance of monensin pre-mixture, do not have monensin sodium products production and sale.Monensin is easy inactivation in acidic aqueous environment, and is very stable under the alkaline condition, and its drying crystalline can prolonged preservation be stablized, and the stability in feed might as well.
Domestic enterprise does not have the batch process of monensin sodium pure product at present, nearly all is monensin pre-mixture product on the market.Study that a kind of product percentage extraction height, cost are low, the monensin sodium pure product of good product quality is very necessary.
Summary of the invention
The technical problem to be solved in the present invention is: overcome the problem that prior art exists, provide that a kind of product percentage extraction height, cost are low, the method with extracting monensin sodium by methanol extraction method of good product quality.
The technical solution adopted for the present invention to solve the technical problems is: the method for this usefulness extracting monensin sodium by methanol extraction method, comprise that sand bacterial classification, slant strains, first order seed nutrient solution, secondary seed nutrient solution, fermented liquid, filter cake, dissolving discharge, extract, decolour, it is characterized in that: it is 20% that the mycelium water capacity is adopted in extraction, add the methyl alcohol of 5-8 concentration doubly by weight at 60-90%, controlled temperature 15-35 ℃, stirring makes abundant dissolving, again through activated carbon decolorizing, filtration, crystallization, separation, drying, pack, make finished product.
The preferred version of above-mentioned method with extracting monensin sodium by methanol extraction method is: it is the mycelium of 20%-25% that water capacity is adopted in extraction, adding 5-8 concentration doubly by weight is the methyl alcohol of 60-90%, controlled temperature 20-30 ℃, stir and made abundant dissolving in 30 minutes, again through activated carbon decolorizing, filtration, crystallization, separation, drying, pack, make finished product.
The key technical problem that the present invention need solve is to select suitable solvent/extraction agent and working control parameter, and this solvent should be guaranteed: the monensin after (1) will ferment in the mycelium dissolves as much as possible and discharges, to improve yield; (2) employed solvent/extraction agent should have cost low, be convenient to characteristics such as recycling, to reduce production costs.
The present invention at first carries out dissolution extraction with methyl alcohol to the monensin in the back mycelium that ferments in leaching process, obtain meeting the monensin sodium pure product of U.S. USP standard then by processes such as decolouring impurity elimination, Crystallization Separation, dryings.
Compared with prior art, the beneficial effect that method had with extracting monensin sodium by methanol extraction method of the present invention is: adopt methyl alcohol as solvent/extraction agent, methanol prices is moderate, also is convenient to distill recovery, and the Methanol Recovery rate can reach 90% in the mother liquor; And methyl alcohol belongs to three kind solvents, is lower toxicity, and environmental pollution is little, personnel injured low, can better improve Working environment.The dissolution extraction process is operated at normal temperatures, and is easy to control, has improved operating environment.Product percentage extraction height: more than 90%; Low, the good product quality of cost: product meets the monensin sodium pure product requirement of U.S. USP standard.The economic benefit height, can be widely used in bio-pharmaceuticals and engineering industrial circle.
Embodiment
Be soluble in lower alcohol according to monensin sodium, rudimentary ether, acetone, organic solvent and water-fast characteristics such as benzene, select methyl alcohol and ethanol to carry out controlled trial, finally determined with methyl alcohol as solvent/extraction agent, the main technique step and the controlled variable of operation are: after fermentative production finishes, monensin is present in the mycelium, fermented liquid carried out the mycelium that obtains wetting after the solid-liquid separation with sheet frame, water capacity is about 20%, add 5-8 methyl alcohol doubly by weight, (need not heat generally speaking for controlled temperature 15-35 ℃, can suitably heat winter), stir and made abundant dissolving in 30 minutes, reach the purpose that thorough extraction discharges, solid-liquid separation obtains the methanol solution of monensin then, again through activated carbon decolorizing, filter, crystallization, separate, dry packing obtains the monensin sodium pure product.
Definite process of concrete processing method and parameter request is as follows:
Embodiment 1
1. slant strains is cultivated: a small amount of sand tube spore of picking is inoculated on the slant medium after the sterilization, cultivates 240 hours, and preserves in 1-6 ℃ of refrigerator then for 32 ℃.
2. first order seed and secondary seed are cultivated: 2 of cultured slant strains are inoculated under aseptic conservation in the 500L first order seed substratum of sterilization; cultivated 26 hours for 35 ℃; by in the 2000L secondary seed medium after the aseptic pipeline immigration sterilization of steam sterilizing, cultivated 24 hours for 35 ℃ then.
3. fermentation culture: the aseptic pipeline of secondary seed nutrient solution by steam sterilizing moved in the 25000L fermention medium after the sterilization, and temperature is controlled at 35 ℃, PH and is controlled at 6.4-6.8, cultivates 325 hours.Add glucose, soya-bean oil of sterilization etc. in the culturing process according to the metabolism situation, with normal growth and the metabolism of keeping thalline.Fermentation culture finishes, and the monensin content in the fermented liquid is at 36500u/ml.
4. filtering fermentation liquor separates: fermented liquid is regulated PH to 9.2 with solid sodium hydroxide, carry out solid-liquid separation, blowing with sheet frame then, obtain the mycelium filter cake of moisture content 20-30%.
5. dissolving: take by weighing 200 kilograms of moisture contents and be 25% filter cake, under agitation slowly add and put into the dissolving vessel that 1200L concentration is 80% methyl alcohol, methanol temperature is controlled at 25 ℃, stirs 30 minutes, allows the monensin in the filter cake fully be discharged in the methyl alcohol.Stop stirring, left standstill 15 minutes.Then methanol solution is filled in the bleacher, obtains methanol solution 1170L.
6. decolouring: add 6 kilograms of needle-use activated carbons in bleacher, adsorption bleaching 30 minutes filters then, obtains destainer 1160L, and destainer is collected in the stainless steel crystallizer.
7. crystallization, separation: open crystallizer and stir, slowly add purified water 2500L, monensin can slowly be separated out with crystal habit.Purified water adds the back and continues to stir 60 minutes, observes the crystallization situation with the beaker sampling, confirms that crystallization is complete.Then crystal solution is separated with whizzer, centrifugal 30 minutes, obtain 6 kilograms of the wet crystal 6s of monensin.
8. dry, packing: the wet crystal of monensin is sucked in the double-cone dryer, and vacuum degree control temperature 85-95 ℃, dry 4.5 hours, obtains 62.1 kilograms of finished products-0.07 to-0.09MPa.Finished product detects through the sampling of check portion of company quality, and quality product meets existing USP standard.
As calculated, the yield from the wet cake to the finished product is 92%.
Embodiment 2
Dissolving: take by weighing 200 kilograms of moisture contents and be 20% filter cake, under agitation slowly add and put into the dissolving vessel that 1000L concentration is 70% methyl alcohol, methanol temperature is controlled at 20 ℃, stirs 35 minutes, allows the monensin in the filter cake fully be discharged in the methyl alcohol.Stop stirring, left standstill 15 minutes.Then methanol solution is filled in the bleacher, obtains methanol solution 970L.
All the other technological processs obtain 65.5 kilograms of finished products with embodiment 1.Finished product detects through the sampling of check portion of company quality, and quality product meets existing USP standard.As calculated, the yield from the wet cake to the finished product is 91%.
Embodiment 3
Dissolving: take by weighing 200 kilograms of moisture contents and be 30% filter cake, under agitation slowly add and put into the dissolving vessel that 1400L concentration is 90% methyl alcohol, methanol temperature is controlled at 20 ℃, stirs 35 minutes, allows the monensin in the filter cake fully be discharged in the methyl alcohol.Stop stirring, left standstill 15 minutes.Then methanol solution is filled in the bleacher, obtains methanol solution 1360L.
All the other technological processs obtain 57.4 kilograms of finished products with embodiment 1.Finished product detects through the sampling of check portion of company quality, and quality product meets existing USP standard.As calculated, the yield from the wet cake to the finished product is 91%.
Claims (3)
1, uses the method for extracting monensin sodium by methanol extraction method, comprise that sand pipe bacterial classification, slant strains, first order seed nutrient solution, secondary seed nutrient solution, fermented liquid, filter cake, dissolving discharge, extract, decolour, it is characterized in that: it is the mycelium of 20%-30% that water capacity is adopted in extraction, adding 5-8 concentration doubly by weight is the methyl alcohol of 60-90%, controlled temperature 15-35 ℃, stir and made abundant dissolving in 30-40 minute, again through activated carbon decolorizing, filtration, crystallization, separation, drying, pack, make finished product.
2, the method with extracting monensin sodium by methanol extraction method according to claim 1, it is characterized in that: it is the mycelium of 20%-25% that water capacity is adopted in extraction, adding 5-8 concentration doubly by weight is the methyl alcohol of 60-90%, controlled temperature 20-30 ℃, stir and made abundant dissolving in 30 minutes, again through activated carbon decolorizing, filtration, crystallization, separation, drying, pack, make finished product.
3, the method with extracting monensin sodium by methanol extraction method according to claim 1 and 2 is characterized in that: concrete processing method is as follows:
(1) slant strains is cultivated: a small amount of sand tube spore of picking is inoculated on the slant medium after the sterilization, cultivates 240 hours, and preserves in 1-6 ℃ of refrigerator then for 32 ℃;
(2) first order seed and secondary seed are cultivated: 2 of cultured slant strains are inoculated under aseptic conservation in the 500L first order seed substratum of sterilization, cultivated 26 hours for 35 ℃, by in the 2000L secondary seed medium after the aseptic pipeline immigration sterilization of steam sterilizing, cultivated 24 hours for 35 ℃ then;
(3) fermentation culture: the aseptic pipeline of secondary seed nutrient solution by steam sterilizing moved in the 25000L fermention medium after the sterilization, and temperature is controlled at 35 ℃, PH and is controlled at 6.4-6.8, cultivates 325 hours;
(4) filtering fermentation liquor separates: fermented liquid is regulated PH to 9.2 with solid sodium hydroxide, carry out solid-liquid separation, blowing with sheet frame then, obtain the mycelium filter cake of moisture content 20-30%;
(5) dissolving: take by weighing 200 kilograms of moisture contents and be 25% filter cake, under agitation slowly add and put into the dissolving vessel that 1200L concentration is 80% methyl alcohol, methanol temperature is controlled at 25 ℃, stirred 30 minutes, allow the monensin in the filter cake fully be discharged in the methyl alcohol, stop stirring, left standstill 15 minutes;
(6) decolouring: add 6 kilograms of needle-use activated carbons in bleacher, adsorption bleaching 30 minutes filters then, obtains destainer 1160L, and destainer is collected in the stainless steel crystallizer;
(7) crystallization, separation: open crystallizer and stir, slowly add purified water 2500L, monensin can slowly be separated out with crystal habit, purified water adds the back and continues to stir 60 minutes, observe the crystallization situation with the beaker sampling, confirm that crystallization is complete, then crystal solution is separated with whizzer, centrifugal 30 minutes, obtain 6 kilograms of the wet crystal 6s of monensin.
(8) dry, packing: the wet crystal of monensin is sucked in the double-cone dryer, and vacuum degree control temperature 85-95 ℃, dry 4.5 hours, obtains 62.1 kilograms of finished products-0.07 to-0.09MPa.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363588A (en) * | 2011-05-30 | 2012-02-29 | 濮阳泓天威药业有限公司 | Decolouring method applied in antibiotic solvent extraction technology |
| CN102973516A (en) * | 2012-12-05 | 2013-03-20 | 山东齐发药业有限公司 | Method for preparing monensin premix |
| CN103923099A (en) * | 2014-04-14 | 2014-07-16 | 宁夏泰瑞制药股份有限公司 | Preparation method of monensin crystal or sodium salt thereof |
| CN104557964A (en) * | 2014-12-15 | 2015-04-29 | 山东齐发药业有限公司 | Preparation method of high-purity refined monensin sodium |
| CN108929331A (en) * | 2018-08-21 | 2018-12-04 | 山东齐发药业有限公司 | The preparation method of rumensin, rumensin and products thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3501568A (en) * | 1964-09-28 | 1970-03-17 | Lilly Co Eli | Novel antibiotic a3823 complex and process for production thereof |
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- 2008-08-06 CN CN2008101388998A patent/CN101643758B/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363588A (en) * | 2011-05-30 | 2012-02-29 | 濮阳泓天威药业有限公司 | Decolouring method applied in antibiotic solvent extraction technology |
| CN102363588B (en) * | 2011-05-30 | 2014-12-31 | 濮阳泓天威药业有限公司 | Decolouring method applied in antibiotic solvent extraction technology |
| CN102973516A (en) * | 2012-12-05 | 2013-03-20 | 山东齐发药业有限公司 | Method for preparing monensin premix |
| CN102973516B (en) * | 2012-12-05 | 2013-10-16 | 山东齐发药业有限公司 | Method for preparing monensin premix |
| CN103923099A (en) * | 2014-04-14 | 2014-07-16 | 宁夏泰瑞制药股份有限公司 | Preparation method of monensin crystal or sodium salt thereof |
| CN104557964A (en) * | 2014-12-15 | 2015-04-29 | 山东齐发药业有限公司 | Preparation method of high-purity refined monensin sodium |
| CN108929331A (en) * | 2018-08-21 | 2018-12-04 | 山东齐发药业有限公司 | The preparation method of rumensin, rumensin and products thereof |
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Address after: No.1, Jinyang Road, economic development zone, Gaoqing County, Zibo City, Shandong Province, 256300 Patentee after: SHANDONG JINYANG PHARMACEUTICAL Co.,Ltd. Address before: 255100 No. 469, main street, Zichuan District, Shandong, Zibo Patentee before: SHANDONG JINYANG PHARMACEUTICAL Co.,Ltd. |
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Denomination of invention: Method for extracting monemycin sodium by methanol extraction Effective date of registration: 20211228 Granted publication date: 20120125 Pledgee: Gaoqing County sub branch of China Postal Savings Bank Co.,Ltd. Pledgor: SHANDONG JINYANG PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016743 |