CN1099039A - A kind of production technique of extracting erythromycin - Google Patents
A kind of production technique of extracting erythromycin Download PDFInfo
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- CN1099039A CN1099039A CN 94105208 CN94105208A CN1099039A CN 1099039 A CN1099039 A CN 1099039A CN 94105208 CN94105208 CN 94105208 CN 94105208 A CN94105208 A CN 94105208A CN 1099039 A CN1099039 A CN 1099039A
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- erythromycin
- thiocyanate
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Abstract
The present invention relates to a kind ofly from erythromycin fermentation liquid, to extract, the production technique of pure system erythromycin.Its technological process is: make extraction agent with the substituted aroma hydrocarbon, utilization is compared, and carries out single extraction and strip concentrating between water and organic phase, must contain the water-rich phase of extract, and then adopt thiocyanate-precipitator method precipitated crystal in water-rich phase, get Erythromycin Thiocyanate.Erythromycin Thiocyanate is dissolved in the solvent that acetone adds water changes alkaline purification, finally obtain the finished product erythromycin.The present invention has simplified operation owing to adopted new extractant, has improved yield, has reduced energy consumption, has saved raw material, has reduced production cost significantly.
Description
The present invention relates to a kind of production technique of from erythromycin fermentation liquid, extracting pure system erythromycin.
In prior art, extracting the common production technique that adopts of erythromycin is: use earlier the n-butyl acetate extraction method, utilization is compared, between water and organic phase, repeat solvent extraction and strip to concentrate, obtain containing the rich organic phase solution of erythromycin, in this richness organic phase solution, carry out freezing and crystallizing then, obtain the thick alkali of erythromycin, again will this thick alkali be dissolved in the solvent that acetone adds water and carry out purified crystals, obtain the thick alkali of erythromycin at last, again will this thick alkali be dissolved in the solvent that acetone adds water and carry out purified crystals, obtain the erythromycin of pure system at last.Above-mentioned technological process exists many shortcomings: 1. the extraction agent butylacetate has bigger water-soluble (water-soluble is 1%), and it in alkalescence and acidic solution decomposition can take place.Therefore, in extraction process, there is 1% extraction agent can be dissolved in the erythromycin fermentation liquid (being called for short feed liquid later on), makes the extraction agent loss bigger.Because decomposition, the extraction agent after single uses is impure more, can not reuse, and must reclaim through distillation.Therefore, except that the power consumption height, must establish aided process in addition.2. because must be in the technological process through organic phase freezing and crystallizing (Tc is-5 ℃), therefore the concentration requirement of organic phase solution is higher, the organic phase solution that single extraction obtains can not reach desired concentration, will make the numerous rope of technological process through twice extraction at least.Simultaneously, the freezing and crystallizing envrionment temperature requires harsh, and power consumption is high.Moreover behind the freezing and crystallizing, the residual quantity of erythromycin is higher in the crystalline mother solution, has reduced the rate of recovery.Find out that by above-mentioned analysis existing manufacturing technique not only exists the numerous rope of operation, aided process is many, the shortcoming that the rate of recovery is low, but also it is high to exist power consumption, significant loss is big.Up to now, yet there are no the novel method that the people proposes to improve above-mentioned technology in the prior art.
The objective of the invention is provides a kind of production technique of improved extraction erythromycin in order to overcome the shortcoming of above-mentioned technological process.It can conservation, simplify processing step, the cancellation aided process, cut down the consumption of energy, and improves the rate of recovery.
Solution of the present invention is as follows: this production technique comprises following several steps successively:
1. with organic solvent as extraction agent, utilization is compared, and carries out solvent extraction and strip to concentrate between water and organic phase solution, obtains containing the concentrated solution of extract;
2. will be 1. the concentrated solution that obtains of step carry out crystallization treatment, obtain crystallisate.
3. will be 2. the crystallisate that obtains of step be dissolved in the solvent that acetone adds water, change the alkali crystallization, the crystallisate that obtains is again through after washing, the drying, finished product.
Wherein said extraction and reextraction concentration technology are: carry out a solvent extraction with substituted aroma hydrocarbon one-component as extraction agent, obtain containing the rich organic phase solution of extract, the rich organic phase solution that obtains is stripped, obtain containing the rich organic phase solution of extract, making a gesture of measuring of its extraction agent and feed liquid is 1: 3～7, rich organic phase and making a gesture of measuring of reverse-extraction agent are 3～6: 1, reverse-extraction agent can be added that phosphoric acid or SODIUM PHOSPHATE, MONOBASIC add phosphoric acid or sodium-acetate adds the damping fluid that acid acid is formed by sodium hydrogen phosphate, and the pH value of reverse-extraction agent is 3.5～5.5.
Described crystallization treatment technology is: adopt the thiocyanate-precipitator method to carry out precipitated crystal, promptly in the water-rich phase solution that obtains, add the thiocyanate-precipitation agent, leave standstill then, suction filtration, obtain crystallisate, crystallisate after washing, dehydration, drying, obtains the Erythromycin Thiocyanate of white powder again.The add-on of its precipitation agent is to precipitate 1.0～1.5 times of erythromycin molar weight.
By above-mentioned solution as can be seen, the present invention has carried out 2 important improvement, and the one, extraction agent has been carried out selecting again, the 2nd, selected the aqueous phase precipitation crystallization process for use.It is that so stable chemical performance is its no water-soluble loss and chemical loss in extraction process because it is water insoluble as extraction agent that the present invention adopts the substituted aroma hydrocarbon.Therefore, the extraction agent after the use is impure hardly, does not need distillation to reclaim, and is reusable.Thereby saved raw material, cancelled aided process, reduced energy consumption, production cost is reduced significantly.Owing to the extraction agent stable performance, the organic phase that extracts through single just can reach higher concentration again, adds the aqueous phase precipitation crystallization process that the present invention adopts, therefore, only need just can carry out precipitated crystal, thereby cancel the operation of re-extract through single extraction and reextraction.Simultaneously, because the aqueous phase precipitation crystallization process can reach precipitation fully, thereby the residual quantity of crystalline mother solution erythromycin is greatly reduced, and crystallization is carried out at normal temperatures.Not only improve yield, also saved energy consumption.In sum, superiority of the present invention is that operation is simple, yield is high, and production cost is low.
Below in conjunction with embodiment the present invention is described in further detail.
(1) solvent extraction: making a gesture of measuring of organic phase and water is 1: 3.5(V/V), organic phase is pure substituted aroma hydrocarbon one-component, the feed liquid water is for containing erythromycin 2000～2500 μ g/ml(biological values) solution (filtering fermentation liquor liquid), pH value is about 7.1, and the mode of contacting is that rotating paddle stirs.Step is: feed liquid is stirred be heated to 35～40 ℃, transfer pH value to 10.2～10.4 with sodium hydroxide solution, add organic phase, open and stirred 10 minutes, stop to stir, add emulsion splitter, about 1 minute of standing demix, after phase interface was clear, rich organic phase was filtered, and extracted surplus liquid and discarded.Rich organic phase filtrate content is 10000～12500 μ g/ml, single extraction rate 98%, and described emulsion splitter is a cetrimonium bromide, add-on is 0.008% of a feed concentration.Adding emulsion splitter can make the foam turbidity screen of two-phase boundary become a phase boundary surface layer clearly.
(2) strip: reverse-extraction agent adopts and adds the damping fluid that acetic acid is formed by sodium-acetate, and its pH value is 3.8, and the back extraction temperature is no more than 15 ℃, and the way of contact is that blade stirs.Carry out twice following current respectively and strip, rich organic phase of twice reextraction and making a gesture of measuring of damping fluid are 3: 1 and 6: 1.The final pH value of back extraction is no more than 6.The water-rich phase that obtains after the back extraction contains erythromycin 20000～25000 μ g/ml, back extraction ratio＞98%.
(3) precipitated crystal: the pH value to 7.0 of transferring strip aqueous with sodium hydroxide solution, add precipitation agent, precipitation agent is selected following a kind of potassium sulfocyanate, Sodium Thiocyanate 99, ammonium thiocyanate for use, being stirred to precipitation then separates out, left standstill 2～4 hours, suction filtration, distilled water wash, centrifuge dehydration, drying, the Erythromycin Thiocyanate of white powder.The add-on of precipitation agent is for precipitating 1.3 times of erythromycin molar weight.Mother liquor behind the precipitated crystal reaches and precipitates calibration value completely, yield＞90% through chemical analysis.The biological value of Erythromycin Thiocyanate＞800 μ g/ml.
(4) change the alkali crystallization: the exsiccant Erythromycin Thiocyanate is dissolved in the solvent that acetone adds water, and making a gesture of measuring of solution composition is: salt: acetone: water=1: 6: 12(W: V: V).Add sodium hydroxide solution again to solution pH value＞9.5.Solution normal temperature was placed 12 hours down, and suction filtration gets the erythromycin crystallisate.Use 55 ℃ of distilled water wash crystallisates again, the dry finished product that gets.Change alkali crystalline filtrate and transfer to pH value=10.2～10.4, be heated to 40 ℃ with sodium hydroxide, extraction once more, the organic phase after the extraction is returned and is incorporated in the master routine the rich organic phase of single extraction into and strip, and down carries out by the precipitated crystal step.Commentaries on classics alkali crystalline washing water return in the stock liquid and down carry out by the extraction step in the master routine.The biological value of the finished product erythromycin that this step obtains＞920 μ g/ml, index are higher than the " index of Chinese pharmacopoeia (90 years versions) defined.
Use this technology, for Erythromycin Thiocyanate, one-pass finished yield＞75%.For erythromycin, one-pass finished yield＞70% has improved 5～10% than prior art.
In small test, can get following result:
Feed liquid 3000ml content 2500 μ g/ml
Salt 7.3 gram biological value＞800 μ g/ml are moisture＜and 7%
Alkali 5.6 gram biological value＞920 μ g/ml are moisture＜and 7%
Can find out further that by the foregoing description the present invention has not only avoided the shortcoming of prior art, has improved yield, has reduced production cost.Simultaneously, final product quality is higher than " Chinese pharmacopoeia (90 years versions) defined index, i.e. biological value＞920 μ g/ml.In addition, but utilize this technology output Erythromycin Thiocyanate and two kinds of finished products of erythromycin, they all can be used as the raw material of macrocyclic lipoid antibiotics medicine commonly used.And existing technology can only a kind of finished product of output.
Claims (3)
1, a kind of production technique of extracting erythromycin comprises following several steps successively:
1. with organic solvent as extraction agent, utilization is compared, and carries out solvent extraction and strip to concentrate between water and organic phase solution, obtains containing the concentrated solution of extract;
2. will be 1. the concentrated solution that obtains of step carry out crystallization treatment, obtain crystallisate;
3. will be 2. the crystallisate that obtains of step be dissolved in the solvent that acetone adds water, change the alkali crystallization, the crystallisate that obtains is again through after washing, the drying, finished product;
It is characterized in that:
A, described extraction and reextraction concentration technology are: carry out a solvent extraction with substituted aroma hydrocarbon one-component as extraction agent, obtain containing the rich organic phase solution of extract, the rich organic phase solution that obtains is stripped, obtain containing the water-rich phase solution of extract, making a gesture of measuring of its extraction agent and feed liquid is 1: 3～7, rich organic phase and making a gesture of measuring of reverse-extraction agent are 3～6: 1, reverse-extraction agent can be added that phosphoric acid or SODIUM PHOSPHATE, MONOBASIC add phosphoric acid or sodium-acetate adds the damping fluid that acid acid is formed by sodium hydrogen phosphate, and the pH value of reverse-extraction agent is 3.5～5.5;
B, described crystallization treatment technology are: adopt the thiocyanate-precipitator method to carry out precipitated crystal, promptly in the water-rich phase solution that obtains, add the thiocyanate-precipitation agent, leave standstill then, suction filtration, obtain crystallisate, crystallisate is again after washing, dehydration, drying, obtain the Erythromycin Thiocyanate of white powder, the add-on of its precipitation agent is to precipitate 1.0～1.5 times of erythromycin molar weight.
2, the production technique of erythromycin as claimed in claim 1 is characterized in that: add the emulsion splitter cetrimonium bromide in solvent extraction, add-on is 0.002%～0.01% of a feed concentration.
3, as claim 1, the production technique of 2 described erythromycins is characterized in that: described thiocyanate-is selected for use following a kind of: potassium sulfocyanate, Sodium Thiocyanate 99, ammonium thiocyanate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94105208 CN1099039A (en) | 1994-05-17 | 1994-05-17 | A kind of production technique of extracting erythromycin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94105208 CN1099039A (en) | 1994-05-17 | 1994-05-17 | A kind of production technique of extracting erythromycin |
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| CN1099039A true CN1099039A (en) | 1995-02-22 |
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| CN 94105208 Pending CN1099039A (en) | 1994-05-17 | 1994-05-17 | A kind of production technique of extracting erythromycin |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0853087A1 (en) * | 1997-01-10 | 1998-07-15 | Biochemie S.A. | A process for the purification of erythromycin |
| CN1054131C (en) * | 1998-04-08 | 2000-07-05 | 浙江大学 | Process for extracting ilotycin by two aqueous phase extracting process |
| CN1064057C (en) * | 1998-04-08 | 2001-04-04 | 浙江大学 | Purifying method for epoxy ethane-epoxy propane random copolymer |
| CN102408462A (en) * | 2011-12-02 | 2012-04-11 | 伊犁川宁生物技术有限公司 | Preparation method of erythromycin thiocyanate |
| CN102659881A (en) * | 2012-04-28 | 2012-09-12 | 安徽丰原发酵技术工程研究有限公司 | Method for preparing erythromycin thiocyanate |
| US20140228555A1 (en) * | 2011-08-26 | 2014-08-14 | Hec Pharm Co., Ltd | Preparation process of erythromycin thiocyanate |
-
1994
- 1994-05-17 CN CN 94105208 patent/CN1099039A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0853087A1 (en) * | 1997-01-10 | 1998-07-15 | Biochemie S.A. | A process for the purification of erythromycin |
| CN1054131C (en) * | 1998-04-08 | 2000-07-05 | 浙江大学 | Process for extracting ilotycin by two aqueous phase extracting process |
| CN1064057C (en) * | 1998-04-08 | 2001-04-04 | 浙江大学 | Purifying method for epoxy ethane-epoxy propane random copolymer |
| US20140228555A1 (en) * | 2011-08-26 | 2014-08-14 | Hec Pharm Co., Ltd | Preparation process of erythromycin thiocyanate |
| US9409940B2 (en) * | 2011-08-26 | 2016-08-09 | Hec Pharm Co., Ltd. | Preparation process of erythromycin thiocyanate |
| CN102408462A (en) * | 2011-12-02 | 2012-04-11 | 伊犁川宁生物技术有限公司 | Preparation method of erythromycin thiocyanate |
| CN102408462B (en) * | 2011-12-02 | 2014-10-22 | 伊犁川宁生物技术有限公司 | Preparation method of erythromycin thiocyanate |
| CN102659881A (en) * | 2012-04-28 | 2012-09-12 | 安徽丰原发酵技术工程研究有限公司 | Method for preparing erythromycin thiocyanate |
| 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 |
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