CN103275151B - A kind of process for purification of Matachrom - Google Patents
A kind of process for purification of Matachrom Download PDFInfo
- Publication number
- CN103275151B CN103275151B CN201310165912.XA CN201310165912A CN103275151B CN 103275151 B CN103275151 B CN 103275151B CN 201310165912 A CN201310165912 A CN 201310165912A CN 103275151 B CN103275151 B CN 103275151B
- Authority
- CN
- China
- Prior art keywords
- erythromycin
- matachrom
- liquid
- purification
- extraction liquid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention provides a kind of process for purification of Matachrom.A process for purification for Matachrom, mainly comprises (1) and carries out preliminary decolouring impurity elimination to erythromycin diafiltration liquid flocculation agent, extract after being purified liquid with erythromycin special solvent, further to decolour impurity elimination to extraction liquid gac.(2) by process after erythromycin extraction liquid phase inversion to purifying aqueous phase, again the erythromycin in aqueous phase is extracted in N-BUTYL ACETATE, cyclohexane mixed solvent, utilize the method for two-step crystallization to obtain erythromycin crystal liquid, be dried after separation to Matachrom finished product.In finished product, Erythromycin A content reaches more than 83%.The present invention is directed to traditional processing technology utilizes special solvent to extract erythromycin from erythromycin diafiltration liquid, then the crystallization of extraction liquid is carried out, finally be dried after separation to the shortcoming that in Matachrom finished product, Erythromycin A content is low, decolouring impurity elimination is carried out to diafiltration liquid and extraction liquid, the method of two-step crystallization after phase inversion, improves the content of Erythromycin A in Matachrom finished product.
Description
Technical field
The invention belongs to biological and new medical technology field, be specifically related to a kind of process for purification of the method extracting crystallization Matachrom from erythromycin filtrate, particularly Matachrom.
Background technology
Matachrom is the thiocyanate-of erythromycin.It is that domestic erythromycin derivatives series product are as the basic material of Roxithromycin, erythromycin ethylsuccinate, Azythromycin, clarithromycin etc.Because erythromycin and derivative thereof and downstream series product are in clinical extensive application, become the third-largest medicine on microbiotic market, the world, therefore, the basic material medicine adapted with it also has the wide market space.Erythromycin main active ingredient is Erythromycin A, and impurity component mainly contains berythromycin, Erythromycin C, Erythromycin D, Erythromycin E, ErF etc.Erythromycin A content is higher, and impurity component content is fewer, and its product price is higher.Therefore, the related products of preparation containing high purity Erythromycin A, has a good application prospect.
In erythromycin fermentation liquid, the concentration of erythromycin is very low, accounts for 0.4 ~ 0.8%.As everyone knows, the starting point concentration of separate object is lower, and the cost of separating-purifying is higher; The character of erythromycin is unstable, and fermented liquid is easily contaminated, and this just causes strict restriction to the isolation technique means that can adopt; In erythromycin fermentation liquid, the relative concentration of impurity is higher, and the character of some of them impurity is very similar with erythromycin, they cannot be separated with the Matachrom product obtaining high-content by the isolation technique of some routines.
Current most domestic enterprise adopts solvent extraction technique to carry out Hydrolysis kinetics to Matachrom.This technology utilization special solvent extracts erythromycin from erythromycin diafiltration liquid, then carries out the crystallization of extraction liquid, is finally dried after separation to Matachrom finished product.This operational path is in actual production, owing to being mingled with the rear remaining great amount of soluble protein of fermentation and wet goods impurity in fermented liquid, extraction process does not carry out impurity and purification process to diafiltration liquid, extraction liquid, and just utilize special solvent to carry out single extraction to erythromycin, then extraction liquid is obtained Matachrom after dehydration, crystallization, centrifugation, drying, its Erythromycin A content is lower.Large about 77 ~ 80%, impurity (mainly Erythromycin C) content is 3 ~ 5%.
Patent application: CN201210134607.X, disclose a kind of preparation method of Matachrom, after erythromycin fermentation liquid removal of impurities, with base extraction, then extract with butylacetate, collect organic phase and add sodium thiocyanate solution wherein, control pH is 4.0-6.0, stirs, crystallization, drying, obtains Matachrom powder.This invention take erythromycin fermentation liquid as raw material, and by removal of impurities process, adopt extraction and the mode that combines of Sodium Thiocyanate 99 salify, obtain refining Matachrom, this method is simple to operate, cost is low, can meet mass-produced requirement, product yield and purity high.This invention is by resin column adsorbing contaminant, but the researchist in this field knows that this mode can only adsorb a part of impurity, and also have most of impurity can be retained in filtrate, final residue, in finished product, effectively can not reduce foreign matter content, improves finished product purity.
Patent application: CN201110097249.5, disclose a kind of preparation method of Matachrom, this invention provides a kind of preparation technology of Matachrom, adopt the method for secondary crystal, process is simple, without the need to increasing equipment, partly can improve the quality of Matachrom finished product, overcoming the final product quality fluctuation that the fermented liquid variation of quality causes.This patent of invention is by the selection of crystallization method, and part improves the final product quality of Matachrom, has its limitation.
Patent application: CN201210434104.4, discloses the refining of a kind of Matachrom and preparation method, the invention provides a kind of process for purification of Matachrom and the preparation method of Matachrom.A process for purification for Matachrom, it comprises: (1) gets Matachrom crude product, and after dissolving in a solvent, alkaline purification, crosses and filter insolubles, after adding thiocyanate-, then add acid for adjusting pH to 5.5 ~ 8.3; (2) solid substance is separated out, washing, dry, obtain Matachrom finished product; Wherein, described in step (1), solvent is methyl alcohol, ethanol or Virahol; Or described solvent is mixed solvent two or more in methyl alcohol, ethanol, Virahol, water, acetone, methylene dichloride, ethyl acetate, butylacetate; In described mixed solvent, the content of methyl alcohol, ethanol or Virahol is at more than 30%w/w.This invention overcome traditional method think solvent of the present invention and water miscible, the technology prejudice of erythromycin impurity can not be reduced, not only not reduce purity and the yield of Matachrom finished product, also save considerably solvent cost and Simplified flowsheet step.This patent of invention has novelty, but its process for purification is from the crude product of Matachrom, does not provide the method for Hydrolysis kinetics Matachrom from erythromycin filtrate, has certain limitation.
Summary of the invention
For overcoming above the deficiencies in the prior art, the object of the present invention is to provide a kind of new Matachrom process for purification.The invention provides a kind of process for purification of Matachrom, it comprises following operation steps:
1, the erythromycin filtrate obtained after erythromycin fermentation liquid uses ultrafiltration membrance filter is got.
2, use flocculation agent to carry out decolouring impurity elimination to erythromycin filtrate, select the model of flocculation agent to be positively charged ion 600 flocculation agent, the usage quantity of flocculation agent is 0.4 ~ 2%.After process, the transmittance of diafiltration liquid is 15.7 ~ 16.7%, protein content 11.5 ~ 16.5mg/100ml.
3, by the extraction of special for the erythromycin diafiltration liquid erythromycin after removal of impurities organic solvent, the erythromycin extraction liquid gac obtained further decolours impurity elimination test.The usage quantity of gac is 0.4 ~ 2%.Process control PH:9.0 ~ 10.5, temperature: 30 ~ 45 DEG C, extraction liquid is tired: 15000 ~ 40000u/ml; Process mainly monitors the detection such as transmittance, albumen before and after the process of erythromycin extraction liquid, before process, the transmittance of extraction liquid is 37 ~ 40%, after process, the transmittance of extraction liquid is 77 ~ 81%, before process, the white content of extraction liquid eggs is 5 ~ 7mg/100ml, and after process, extraction liquid protein content is 0.5 ~ 1.2mg/100ml.
4, by process after erythromycin extraction liquid phase inversion to purifying aqueous phase, then the erythromycin in aqueous phase is extracted to carry out Matachrom in N-BUTYL ACETATE, cyclohexane solvent fractional crystallization, separation, drying.Process control PH:9.0 ~ 10.5, temperature: 30 ~ 45 DEG C, extraction liquid is tired: 15000 ~ 40000u/ml.The mixed solvent that the solvent that erythromycin crystal liquid uses is N-BUTYL ACETATE and hexanaphthene is not single N-BUTYL ACETATE or cyclohexane solvent.The blending ratio of N-BUTYL ACETATE and hexanaphthene is 1:0.1 ~ 1.Use mixed solvent can reduce solvent material consumption, improve crystallization yield, thus reduce production cost.
5, in crystallisation process, adopt two-step crystallization technique, crystallisation process controls Sodium Thiocyanate 99 dosage, and it is 50 ~ 60% of the total dosage of Sodium Thiocyanate 99 that the first step controls Sodium Thiocyanate 99 dosage, drips acetum PH:6.5 ~ 7.5, acid addition time 60 ~ 70 minutes; Second step stream adds Sodium Thiocyanate 99 residual content, and drips on acetum control PH:5.0 ~ 5.5, acid addition time 80 ~ 90 minutes.Size due to degree of supersaturation directly affects the speed of nucleating process and crystal growth processes, therefore we adopt the mode of two step crystallizations in crystallisation process, under differing temps, PH condition, controlled the degree of supersaturation of solution by the concentration changing salt forming agent, to reach refining object.
6, crystal solution obtains Matachrom after being separated drying, and in Matachrom finished product, the content of Erythromycin A is more than 82%, and the content of major impurity Erythromycin C is below 3%.
Embodiment
The present invention will be described by the following examples.But be to be understood that the present invention is not limited to specific embodiments described here.All technology realized based on content of the present invention all belong to scope of the present invention.
Embodiment 1
Get 50L erythromycin filtrate, use positively charged ion 600 flocculation agent to carry out decolouring impurity elimination to erythromycin filtrate, the usage quantity of flocculation agent is 0.4%.Before process, transmittance is 3.1%, and after process, the transmittance of diafiltration liquid is 15.7%, protein content 34.6mg/100ml before process, protein content 11.5mg/100ml after process.By the erythromycin filtrate after removal of impurities with the extraction of erythromycin special organic solvent, the erythromycin extraction liquid gac obtained further decolours impurity elimination.The usage quantity of gac is 0.4%.Process control PH:9.0, temperature: 35 DEG C, extraction liquid is tired: 15000u/ml; Before the process of erythromycin extraction liquid, transmittance is 39.8%, and the transmittance after process is 77.4%, and before process, protein content is 6.4mg/100ml, and after process, protein content is 0.9mg/100ml.By process after erythromycin extraction liquid phase inversion to purifying aqueous phase, then the erythromycin in aqueous phase is extracted to carry out Matachrom in N-BUTYL ACETATE, cyclohexane solvent fractional crystallization, separation, drying.Process control PH:9.0, temperature: 35 DEG C, extraction liquid is tired: 15000u/ml.The mixed solvent that the solvent that erythromycin crystal liquid uses is N-BUTYL ACETATE and hexanaphthene.The blending ratio of N-BUTYL ACETATE and hexanaphthene is 1:0.3.Crystallisation process controls Sodium Thiocyanate 99 dosage, and it is 55% of the total dosage of Sodium Thiocyanate 99 that the first step controls Sodium Thiocyanate 99 dosage, drips acetum PH:6.5, acid addition time 60 minutes; Second step stream adds Sodium Thiocyanate 99 residual content, and drips acetum control PH:5.0, acid addition time 90 minutes.Through being separated Erythromycin A content 83.1% in dried Matachrom finished product, the content 0.54% of major impurity Erythromycin C.
Embodiment 2
Get 50L erythromycin filtrate, use positively charged ion 600 flocculation agent to carry out decolouring impurity elimination to erythromycin filtrate, the usage quantity of flocculation agent is 1%.Before process, transmittance is 2.4%, and the transmittance of Filtrate is 13.6%, protein content 28.7mg/100ml, protein content 14.5mg/100ml before process.By the erythromycin filtrate after removal of impurities with the extraction of erythromycin special organic solvent, the erythromycin extraction liquid gac obtained further decolours impurity elimination.The usage quantity of gac is 1%.Process control PH:9.5, temperature: 30 DEG C, extraction liquid is tired: 30000u/ml; Before the process of erythromycin extraction liquid, transmittance is 37.6%, and the transmittance after process is 80.2%, and before process, protein content is 5.7mg/100ml, and after process, protein content is 1.6mg/100ml.By process after erythromycin extraction liquid phase inversion to purifying aqueous phase, then the erythromycin in aqueous phase is extracted to carry out Matachrom in N-BUTYL ACETATE, cyclohexane solvent fractional crystallization, separation, drying.Process control PH:9.0, temperature: 30 DEG C, extraction liquid is tired: 30000u/ml.The mixed solvent that the solvent that erythromycin crystal liquid uses is N-BUTYL ACETATE and hexanaphthene.The blending ratio of N-BUTYL ACETATE and hexanaphthene is 1:0.5.Crystallisation process controls Sodium Thiocyanate 99 dosage, and it is 50% of the total dosage of Sodium Thiocyanate 99 that the first step controls Sodium Thiocyanate 99 dosage, drips acetum PH:6.5, acid addition time 60 minutes; Second step stream adds Sodium Thiocyanate 99 residual content, and drips acetum control PH:5.0, acid addition time 80 minutes.Through being separated Erythromycin A content 84.2% in dried Matachrom finished product, the content 0.43% of major impurity Erythromycin C.
Embodiment 3
Get 50L erythromycin filtrate, use positively charged ion 600 flocculation agent to carry out decolouring impurity elimination to erythromycin filtrate, the usage quantity of flocculation agent is 1.5%.Before process, transmittance is 3.7%, and the transmittance of Filtrate is 16.7%, protein content 27.5mg/100ml, protein content 15.7mg/100ml before process.By the extraction of special for the erythromycin diafiltration liquid erythromycin after removal of impurities organic solvent, the erythromycin extraction liquid gac obtained further decolours impurity elimination.The usage quantity of gac is 1.5%.Process control PH:10.5, temperature: 45 DEG C, extraction liquid is tired: 40000u/ml; Before the process of erythromycin extraction liquid, transmittance is 37.4%, and the transmittance after process is 78.7%, and before process, protein content is 6.2mg/100ml, and after process, protein content is 1.1mg/100ml.By process after erythromycin extraction liquid phase inversion to purifying aqueous phase, then the erythromycin in aqueous phase is extracted to carry out Matachrom in N-BUTYL ACETATE, cyclohexane solvent fractional crystallization, separation, drying.Process control PH:10.5, temperature: 45 DEG C, extraction liquid is tired: 40000u/ml.The mixed solvent that the solvent that erythromycin crystal liquid uses is N-BUTYL ACETATE and hexanaphthene.The blending ratio of N-BUTYL ACETATE and hexanaphthene is 1:0.8.Crystallisation process controls Sodium Thiocyanate 99 dosage, and it is 60% of the total dosage of Sodium Thiocyanate 99 that the first step controls Sodium Thiocyanate 99 dosage, drips acetum PH:7.5, acid addition time 70 minutes; Second step stream adds Sodium Thiocyanate 99 residual content, and drips acetum control PH:5.5, acid addition time 90 minutes.Through being separated Erythromycin A content 86.4% in dried Matachrom finished product, the content 0.54% of major impurity Erythromycin C.
Claims (4)
1. the process for purification of a Matachrom, it is characterized in that: erythromycin fermentation liquid obtains filtrate after using ultrafiltration membrance filter, filtrate to be decoloured impurity elimination by flocculation agent, and the filtrate after impurity elimination is extracted liquid with after the special organic solvent extraction of erythromycin, and extraction liquid gac carries out decolouring impurity elimination; By process after erythromycin extraction liquid phase inversion to purifying aqueous phase, then the erythromycin in aqueous phase is extracted in N-BUTYL ACETATE, cyclohexane mixed solvent carry out Matachrom two step crystallizations, separation, drying, obtain Matachrom;
Described N-BUTYL ACETATE extraction process, control pH:9.0 ~ 10.5, temperature: 30 ~ 45 DEG C, extraction liquid is tired: 15000 ~ 40000u/ml;
Described two step crystallisation processs, it is 50 ~ 60% of the total dosage of Sodium Thiocyanate 99 that the first step controls Sodium Thiocyanate 99 dosage, drips acetum pH:6.5 ~ 7.5, acid addition time 60 ~ 70 minutes; Second step stream adds Sodium Thiocyanate 99 residual content, and drips acetum control pH:5.0 ~ 5.5, acid addition time 80 ~ 90 minutes.
2. the process for purification of a kind of Matachrom according to claim 1, is characterized in that, filtrate to be decoloured impurity elimination with flocculation agent, and flocculation agent model used is positively charged ion 600, and the usage quantity of flocculation agent is 0.4 ~ 2%.
3. the process for purification of a kind of Matachrom according to claim 1, is characterized in that the usage quantity of gac is 0.4 ~ 2%, and gac comprises particulate state and Powdered.
4. the process for purification of a kind of Matachrom according to claim 1, is characterized in that, the blending ratio of N-BUTYL ACETATE and hexanaphthene is 1:0.1 ~ 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310165912.XA CN103275151B (en) | 2013-05-08 | 2013-05-08 | A kind of process for purification of Matachrom |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310165912.XA CN103275151B (en) | 2013-05-08 | 2013-05-08 | A kind of process for purification of Matachrom |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103275151A CN103275151A (en) | 2013-09-04 |
| CN103275151B true CN103275151B (en) | 2015-08-19 |
Family
ID=49057793
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310165912.XA Active CN103275151B (en) | 2013-05-08 | 2013-05-08 | A kind of process for purification of Matachrom |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103275151B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566417A (en) * | 2016-02-03 | 2016-05-11 | 昆山东大智汇技术咨询有限公司 | Erythromycin thiocyanate fermentation broth membrane-process impurity-removing purification process |
| CN106279320A (en) * | 2016-08-22 | 2017-01-04 | 宁夏启元药业有限公司 | A kind of extracting method of erythromycin lactate |
| 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 |
| CN113150044B (en) * | 2021-04-28 | 2022-03-18 | 宜昌东阳光生化制药有限公司 | Purification method of erythromycin thiocyanate |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020038020A1 (en) * | 2000-09-25 | 2002-03-28 | I-Horng Pan | Process for extracting glycoside using an aqueous two-phase system |
| WO2003027049A1 (en) * | 2001-09-20 | 2003-04-03 | Ezaki Glico Co., Ltd. | Method of extracting and method of purifying an effective substance |
| CN1554773A (en) * | 2003-12-26 | 2004-12-15 | 三达膜科技（厦门）有限公司 | Method for extracting fermentikve macrolide antibiotics using membrane |
| 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 |
| CN102731599A (en) * | 2011-04-15 | 2012-10-17 | 河南天方药业股份有限公司 | Method for preparing erythromycin thiocyanate |
| 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 |
-
2013
- 2013-05-08 CN CN201310165912.XA patent/CN103275151B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020038020A1 (en) * | 2000-09-25 | 2002-03-28 | I-Horng Pan | Process for extracting glycoside using an aqueous two-phase system |
| WO2003027049A1 (en) * | 2001-09-20 | 2003-04-03 | Ezaki Glico Co., Ltd. | Method of extracting and method of purifying an effective substance |
| CN1554773A (en) * | 2003-12-26 | 2004-12-15 | 三达膜科技（厦门）有限公司 | Method for extracting fermentikve macrolide antibiotics using membrane |
| CN102731599A (en) * | 2011-04-15 | 2012-10-17 | 河南天方药业股份有限公司 | Method for preparing 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 |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 汪敦佳,等.硫氰酸红霉素的制备.《精细石油化工》.1999,(第6期), * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103275151A (en) | 2013-09-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109651480A (en) | A method of separation momordica glycoside V | |
| CN103275151B (en) | A kind of process for purification of Matachrom | |
| CN101503433B (en) | Preparation of plant source glucosamine hydrochloride | |
| CN109438532B (en) | Method for extracting D-glucosamine | |
| CN102040638A (en) | Method for preparing nonsolvent of high-purity natamycin | |
| CN106831894B (en) | A kind of method of deacetylation Coupling Adsorption separation D-Glucosamine Hydrochloride | |
| CN102180935A (en) | Method for preparing high-purity sasanquasaponins | |
| CN103709235B (en) | A kind of method reducing the extraction high-purity enramycin that solvent uses | |
| CN105274179B (en) | A kind of technique of extraction l-Isoleucine | |
| CN103570663A (en) | Preparation method of high-purity quercetin | |
| CN1670037A (en) | Complex utilization of Gardenia | |
| CN103275150A (en) | Method for refining and preparing erythromycin thiocyanate | |
| CN105985315A (en) | Method for extracting nicotine from tobacco waste | |
| CN103402956B (en) | Method for preparing lutein crystal | |
| CN102925508A (en) | Method for preparing iridoid aglycone | |
| CN102603597B (en) | Preparation method of (S)-oxiracetam | |
| CN102417452B (en) | Preparation method of citrate | |
| CN104311616A (en) | Method for extracting high-purity esculine and fraxin from Cortex Fraxini | |
| CN111018939A (en) | Rapid refining method of tea saponin | |
| CN1687239A (en) | Method for preparing crystal of lycopene and concentrate | |
| CN104710492A (en) | Method for extracting androstenedione in bi-liquid phases system | |
| CN104292283A (en) | Nemadectin purification method | |
| CN103641886B (en) | A kind of process for purification of glutamine dipeptide | |
| CN103012506A (en) | Energy-saving process for extracting crystallized xylose and arabinose from xylose mother liquor | |
| CN110540570A (en) | method for separating and purifying fusidic acid through ion exchange resin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |