CN107619421A - The continuous chromatography isolation and purification method of lincomycin - Google Patents
The continuous chromatography isolation and purification method of lincomycin Download PDFInfo
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- CN107619421A CN107619421A CN201710852564.1A CN201710852564A CN107619421A CN 107619421 A CN107619421 A CN 107619421A CN 201710852564 A CN201710852564 A CN 201710852564A CN 107619421 A CN107619421 A CN 107619421A
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- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 title claims abstract description 55
- 229960005287 lincomycin Drugs 0.000 title claims abstract description 51
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000004587 chromatography analysis Methods 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000000746 purification Methods 0.000 title claims abstract description 17
- 238000002955 isolation Methods 0.000 title claims abstract description 6
- 239000000047 product Substances 0.000 claims abstract description 81
- 239000003480 eluent Substances 0.000 claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 239000000706 filtrate Substances 0.000 claims abstract description 13
- 229960001595 lincomycin hydrochloride Drugs 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 6
- LFZGYTBWUHCAKF-DCNJEFSFSA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride;hydrate Chemical compound O.Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 LFZGYTBWUHCAKF-DCNJEFSFSA-N 0.000 claims abstract 4
- 239000011347 resin Substances 0.000 claims description 98
- 229920005989 resin Polymers 0.000 claims description 98
- 239000007788 liquid Substances 0.000 claims description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 63
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 46
- 239000000463 material Substances 0.000 claims description 41
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 claims description 29
- 238000001179 sorption measurement Methods 0.000 claims description 29
- 238000004140 cleaning Methods 0.000 claims description 21
- 238000010521 absorption reaction Methods 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 239000012141 concentrate Substances 0.000 claims description 12
- 238000001514 detection method Methods 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 9
- 238000013461 design Methods 0.000 claims description 7
- 238000011010 flushing procedure Methods 0.000 claims description 7
- 230000004907 flux Effects 0.000 claims description 7
- 238000004088 simulation Methods 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 230000002745 absorbent Effects 0.000 claims description 6
- 239000002250 absorbent Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims 1
- 238000005516 engineering process Methods 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000010828 elution Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 230000008929 regeneration Effects 0.000 abstract 1
- 238000011069 regeneration method Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- POUMFISTNHIPTI-BOMBIWCESA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 POUMFISTNHIPTI-BOMBIWCESA-N 0.000 description 4
- 239000011344 liquid material Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- DZSDDKNXMARQMJ-AVXYAQEDSA-N (2S,4R)-4-ethyl-N-[(1R,2R)-2-hydroxy-1-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methylpyrrolidine-2-carboxamide Chemical compound CN1C[C@H](CC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 DZSDDKNXMARQMJ-AVXYAQEDSA-N 0.000 description 2
- 241001662103 Cryptocarya corrugata Species 0.000 description 2
- CWPMAVJRTHPUNS-UHFFFAOYSA-N Lincomycin B Natural products CCC1CC(NC(=O)C(C(C)O)C2OC(SC)C(O)C(O)C2O)N(C)C1 CWPMAVJRTHPUNS-UHFFFAOYSA-N 0.000 description 2
- DZSDDKNXMARQMJ-UHFFFAOYSA-N N-Desmethyllincomycin Natural products CN1CC(CC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 DZSDDKNXMARQMJ-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
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- 238000012545 processing Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940126680 traditional chinese medicines Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241001655322 Streptomycetales Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
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- 210000000936 intestine Anatomy 0.000 description 1
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- 230000003907 kidney function Effects 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Abstract
The present invention relates to a kind of continuous chromatography isolation and purification method of lincomycin, the present invention realizes efficiently separating for LCM component using continuous chromatography chromatography technique.The present invention is by the fermented filtrate of lincomycin obtained by biofermentation, into continuous chromatography system through adsorbing, washing miscellaneous, elution lincomycin, collect eluent and chromatogram column regeneration, the eluent concentration of collection, then through the Lincomycin Hydrochloride that decolourized to obtain into salt.Lincomycin yield using this law separation is high, and purity is high, and cost is low, environmental protection, is adapted to industrialized production.The present invention has that the production technology time is short, product yield is high, the content of Lincomycin Hydrochloride (giving money as a gift) reaches more than 99% in the final products of preparation, it is not high to solve the content of lincomycin hydrochloride of prior art production, and the shortcomings that the production technology time is long.
Description
Technical field
The invention belongs to pharmaceutical field, is related to a kind of isolation and purification method of antibacterials lincomycin.
Background technology
Lincomycin (C18H34N2O6S cillimycin, lincomycinum) are also known as, is a kind of effective suppression to gram-positive bacteria
Agent, its action principle are to act on the ribosomal 50S subunits of sensitive bacteria, prevent the extension of peptide chain, suppress the albumen of bacterial cell
Matter synthesizes.In higher concentrations, also there is bactericidal action to extremely sensitive bacterium.Lincomycin have resistance development slowly, group
Knit good penetrability, have the effect of preferable to infection in respiratory system etc., therefore lincomycin is widely used in clinical treatment.In mould
The drug-fast bacteria of other antibiotic such as element is gradually found, and in the case of causing these antibiotic usages restricted, lincomycin needs
The amount of asking gradually is increasing.
It is divided into six kinds of components (being shown in Table 1) of A, B, C, D, K, S because of substituted radical R difference in lincomycin molecule, is sending out
There is different degrees of expression during ferment, wherein component A accounts for more than 90%, and B component accounts for 5~10%, and its clinical efficacy is only A groups
The 20% of part, and toxicity is larger, the total amount of remaining 4 kinds of component is no more than 1%, and curative effect is similar to component A.The derivative of B component
Clinical practice have very big side effect, particularly intestines, Liver and kidney function are had a great influence.Therefore, Lincomycin B component is at it
Occupy critical role in quality control.In directly as medicinal lincomycin product, it is desirable to B component content be less than 5%, and
When making raw material production derivative using lincomycin, it is generally desirable to B component content to be less than 3%.U.S. FDA export-oriented is even more to require
B component content is less than 1%.
The lincomycin each component substituent of table 1
By research it was found that the production technology of lincomycin is more traditional at present, the hydrochloric acid woods for producing to obtain can be mould
Cellulose content is not high, and impurity content is also more, and the production technology time is grown, and can not meet the market demand.
The production technology of existing lincomycin：Lincomycin is typically entered under certain condition using lincomycin streptomycete
Row three grade fermemtation, is filtered to remove mycelium after the acidified processing of zymotic fluid, filtrate adjusts pH to 11 with NaOH, adds butanol thereto
Extraction refinement is carried out, adds the back extraction of HCL solution, after being concentrated under reduced pressure, charcoal absorption, crystallization, drying, obtains Lincomycin Hydrochloride original
Expect medicine.
Therefore, the present invention is improved on purification process, by continuous chromatography post on fermented filtrate of lincomycin, utilize
Adsorption rate of the lincomycin difference component on resin is different, reaches the purpose isolated and purified, obtains a kind of woods of high-purity
Can mycin prepare method.
The content of the invention
It is an object of the invention to provide a kind of continuous chromatography isolation and purification method of lincomycin.
Purification process of the present invention, step are as follows：
Step 1, continuous chromatography post on fermented filtrate of lincomycin, obtains eluent；
Step 2, eluent obtains lincomycin sterling by concentration, crystallizing and drying.
Wherein, upper continuous chromatography post, resin are selected from described in step 1：Macroporous absorbent resin HZ-802, R-802, Lan Xin -30,
The resin of AB-8, YPR- II, resin particle diameter is in 50~100 mesh, the uniformity more than 95%.
Wherein, eluent described in step 2 is as follows by concentration, the process dried：Using being concentrated under reduced pressure, vacuum is for concentration
0.02~0.15Mpa, operation temperature are 35~90 DEG C, and it is 25%~70% to be concentrated into lincomycin mass concentration, is concentrated
Liquid；The method that concentrate is crystallized with acetone obtains solid.
Wherein, continuous chromatography is selected from：Disk conveying type continuous chromatography piece-rate system or Simulation moving bed formula continuous chromatography
Piece-rate system.
Wherein, upper continuous chromatography post described in step 1, by paragraphs below district's groups into：
A, feed zone (14-17#)：
Charging is divided into two groups of parallel feeds in the region.By flow control, raw material initially enters 14# mouths and 15# mouths,
Series connection 17# mouths and 16# mouths, material liquid pass through resin column, and product is attracted on resin, detect 14# column outlets feed liquid and raw material
Liquid is consistent, then is determined as supersaturated absorption.The feed liquid that 17# mouths come out with 16# mouths is middle material, carries out applying mechanically charging.
B, water wash zone (10-13#) after feeding：
4 valve ports in the region connect in a series arrangement, after adsorption zone, after resin column adsorption saturation, turn to
Xi Liao areas, there is excessive material liquid in resin column, eluted remaining feed liquid in pillar and impurity B, C with water.Elute
Feed liquid carries out applying mechanically charging into middle material.
C, secondary feeds area (18-20#)
The valve port in the region is to be connected in series.Because adsorption zone supersaturation is adsorbed, part material liquid, institute are also contained in Xi Liao areas
It to set secondary feeds area, can so ensure the complete absorption of product, increase product yield.Simultaneously because impurity B can A with woods
Adsorption rate on resin is different, is adjusted by flow velocity, can be eluted out impurity B, but also can take part woods out of can
A。
D, product parsing area (7-9#)
In the region, using being connected in series mode.Behind Xi Liao areas, the impurity B, C in resin column are seldom, make
Product completion parsing is got off with n-butanol.The region soon rotates previous minute, it is necessary to detect 7# outlets, really in pillar
Protect 7# outlets and do not contain the product A or A of product containing very small amount, then representative products parse completely.Another detection production life cycle sample, confirms solution
The product design and purity analysed.
E, Xi Chun areas (2-6#)
In the region, using being connected in series mode.Because n-butanol density ratio water is small, so cleaned using anti-water inlet,
So cleaning performance can be relatively good, reduce cleaning water consumption, the region before rotation 1 minute, it is necessary to detect 2# outlet wash water,
Detect whether containing butanol, to judge whether Xi Chun areas clean up.
F, nip (1#) under resin
Because Xi Chun areas are using anti-water inlet cleaning way, so resin can be got on by top, in 1# posts using water by under resin
Push back, it is ensured that the using effect of next cycle charging.Use high flux flushing, because resin column cleans up, the area
Domain water can be with Reusability.
Preferably, purification process of the invention, comprises the following steps：
Step 1, continuous chromatography post on fermented filtrate of lincomycin, obtains eluent；
Step 2, eluent obtains lincomycin sterling by concentration, crystallizing and drying；
Wherein, upper continuous chromatography post, resin are selected from described in step 1：Macroporous absorbent resin HZ-802, R-802, Lan Xin -30,
The resin of AB-8, YPR- II, resin particle diameter is in 50~100 mesh, the uniformity more than 95%.Wherein, concentrated described in step 2 dry
Dry, method is as follows：Using being concentrated under reduced pressure, vacuum is 0.02~0.15Mpa for concentration, and operation temperature is 35~90 DEG C, is concentrated into
Lincomycin mass concentration is 25%~70%, obtains concentrate；The method that concentrate is crystallized with acetone obtains solid；
It is as follows using the separation of disk conveying type continuous chromatography or the separation of Simulation moving bed formula continuous chromatography, step：
A, feed zone (14-17#)：
Charging is divided into two groups of parallel feeds in the region.By flow control, raw material initially enters 14# mouths and 15# mouths,
Series connection 17# mouths and 16# mouths, material liquid pass through resin column, and product is attracted on resin, detect 14# column outlets feed liquid and raw material
Liquid is consistent, then is determined as supersaturated absorption.The feed liquid that 17# mouths come out with 16# mouths is middle material, carries out applying mechanically charging.
B, water wash zone (10-13#) after feeding：
4 valve ports in the region connect in a series arrangement, after adsorption zone, after resin column adsorption saturation, turn to
Xi Liao areas, there is excessive material liquid in resin column, eluted remaining feed liquid in pillar and impurity B, C with water.Elute
Feed liquid carries out applying mechanically charging into middle material.
C, secondary feeds area (18-20#)
The valve port in the region is to be connected in series.Because adsorption zone supersaturation is adsorbed, part material liquid, institute are also contained in Xi Liao areas
It to set secondary feeds area, can so ensure the complete absorption of product, increase product yield.Simultaneously because impurity B can with woods
Adsorption rate of the mycin A on resin is different, is adjusted by flow velocity, can be eluted out impurity B；
D, product parsing area (7-9#)
In the region, using being connected in series mode.Behind Xi Liao areas, the impurity B, C in resin column are seldom, make
Product completion parsing is got off with n-butanol.The region soon rotates previous minute, it is necessary to detect 7# outlets, really in pillar
Protect 7# outlets and do not contain the product A or A of product containing very small amount, then representative products parse completely.Another detection production life cycle sample, confirms solution
The product design and purity analysed.
E, Xi Chun areas (2-6#)
In the region, using being connected in series mode.Because n-butanol density ratio water is small, so cleaned using anti-water inlet,
So cleaning performance can be relatively good, reduce cleaning water consumption, the region before rotation 1 minute, it is necessary to detect 2# outlet wash water,
Detect whether containing butanol, to judge whether Xi Chun areas clean up.
F, nip (1#) under resin
Because Xi Chun areas are using anti-water inlet cleaning way, so resin can be got on by top, in 1# posts using water by under resin
Push back, it is ensured that the using effect of next cycle charging.Using high flux flushing, resin column is cleaned up, the region
Water can be with Reusability.
Wherein, the impurity B, C are respectively Lincomycin B component；Other poly-doped impurities (C containing lincomycin, D, K, S and
Other).
Wherein, fermented filtrate of lincomycin is provided by Jiangxi Guoyao Co., Ltd.
On fermented filtrate of lincomycin before continuous chromatography post, LCM constituent content：20-25g/L, impurity woods can be mould
Plain B component content：4-4.5%, pH：10-10.5 optically-active detects：4.0-4.3.
Related impurities effectively can be removed or reduce with the purification process of the present invention, resulting result is：Impurity woods
Can mycin B component≤0.3%, with high performance liquid chromatography (HPLC) determine Lincomycin Hydrochloride (LCM) purity >=
99.5%, moisture≤5%.
The continuous chromatography of the present invention is isolated and purified for existing method, has advantages below：
1) shorten purification time, 40min is shorten to by original 8h；
2) cost is reduced, slows down operating process；
3) purity of lincomycin is improved, reduces the generation of impurity；
4) due to continuous operation, product composition and concentration after absorption or ion exchange keep stable.
5) bed system is relatively fixed, resin demand can reduce 50-90%.
Brief description of the drawings
Fig. 1 continuous chromatographies isolate and purify the flow chart of lincomycin
Fig. 2 embodiments 1：9-11 day product purities
Fig. 3 embodiments 2：22-26 day product purities
Fig. 4 embodiments 2：26-28 day product purities
Embodiment
Embodiment 1
Step 1, continuous chromatography post on fermented filtrate of lincomycin, obtains eluent；
Step 2, eluent obtains lincomycin sterling by concentration, crystallizing and drying.
Wherein, upper continuous chromatography post, resin are selected from described in step 1：Macroporous absorbent resin HZ-802, resin particle diameter exist
50~100 mesh, the uniformity more than 95%.
Wherein, eluent described in step 2 is as follows by concentration, the process dried：Using being concentrated under reduced pressure, vacuum is for concentration
0.02~0.15Mpa, operation temperature are 35~90 DEG C, and it is 25%~70% to be concentrated into lincomycin mass concentration, is concentrated
Liquid；The method that concentrate is crystallized with acetone obtains solid.
Wherein, continuous chromatography is selected from：Disk conveying type continuous chromatography piece-rate system or Simulation moving bed formula continuous chromatography
Piece-rate system.
Wherein, upper continuous chromatography post described in step 1, by paragraphs below district's groups into：
A, feed zone (14-17#)：
Charging is divided into two groups of parallel feeds in the region.By flow control, raw material initially enters 14# mouths and 15# mouths,
Series connection 17# mouths and 16# mouths, material liquid pass through resin column, and product is attracted on resin, detect 14# column outlets feed liquid and raw material
Liquid is consistent, then is determined as supersaturated absorption.The feed liquid that 17# mouths come out with 16# mouths is middle material, carries out applying mechanically charging.
B, water wash zone (10-13#) after feeding：
4 valve ports in the region connect in a series arrangement, after adsorption zone, after resin column adsorption saturation, turn to
Xi Liao areas, there is excessive material liquid in resin column, eluted remaining feed liquid in pillar and impurity B, C with water.Elute
Feed liquid carries out applying mechanically charging into middle material.
C, secondary feeds area (18-20#)
The valve port in the region is to be connected in series.Because adsorption zone supersaturation is adsorbed, part material liquid, institute are also contained in Xi Liao areas
It to set secondary feeds area, can so ensure the complete absorption of product, increase product yield.Simultaneously because impurity B can A with woods
Adsorption rate on resin is different, is adjusted by flow velocity, can be eluted out impurity B, but also can take part woods out of can
A。
D, product parsing area (7-9#)
In the region, using being connected in series mode.Behind Xi Liao areas, the impurity B, C in resin column are seldom, make
Product completion parsing is got off with n-butanol.The region soon rotates previous minute, it is necessary to detect 7# outlets, really in pillar
Protect 7# outlets and do not contain the product A or A of product containing very small amount, then representative products parse completely.Another detection production life cycle sample, confirms solution
The product design and purity analysed.
E, Xi Chun areas (2-6#)
In the region, using being connected in series mode.Because n-butanol density ratio water is small, so cleaned using anti-water inlet,
So cleaning performance can be relatively good, reduce cleaning water consumption, the region before rotation 1 minute, it is necessary to detect 2# outlet wash water,
Detect whether containing butanol, to judge whether Xi Chun areas clean up.
F, nip (1#) is because Xi Chun areas are using anti-water inlet cleaning way under resin, so resin can be got on by top, in 1#
Resin is pushed falling by post using water, it is ensured that the using effect of next cycle charging.Using high flux flushing, due to resin
Post cleans up, and the regional water can be with Reusability.
It is described in detail with reference to Fig. 1, Fig. 2 and embodiment
Feeding liquid is the crude product that Jiangxi traditional Chinese medicines enter before fixed bed at present：
Daily switch on condition and testing result：
| Date | Feed liquid purity (%) | Primary crystallization (%) | Secondary crystallization (%) |
| No. 9 | 99.12 | 99.52 | 99.54 |
| No. 10-11 | 99.26 | 99.57 | 99.63 |
Device parameter is as follows：
Analyzed by data above, product purity can be stablized more than 99%.By the September 10 days-September product of 11 days
Sampling is crystallized, and it is 99.57% to draw the product purity after primary crystallization, and the product after secondary crystallization is 99.63%.It can sentence
Surely the product purity of target can be reached using the technique.And carry out secondary experiment and judge product yield.
Embodiment 2
Step is as follows：
Step 1, continuous chromatography post on fermented filtrate of lincomycin, obtains eluent；
Step 2, eluent obtains lincomycin sterling by concentration, crystallizing and drying.
Wherein, upper continuous chromatography post, resin are selected from described in step 1：Macroporous absorbent resin HZ-802, resin particle diameter exist
50~100 mesh, the uniformity more than 95%.
Wherein, eluent described in step 2 is as follows by concentration, the process dried：Using being concentrated under reduced pressure, vacuum is for concentration
0.02~0.15Mpa, operation temperature are 35~90 DEG C, and it is 25%~70% to be concentrated into lincomycin mass concentration, is concentrated
Liquid；The method that concentrate is crystallized with acetone obtains solid.
Wherein, continuous chromatography is selected from：Disk conveying type continuous chromatography piece-rate system or Simulation moving bed formula continuous chromatography
Piece-rate system.
Wherein, upper continuous chromatography post described in step 1, by paragraphs below district's groups into：
A, feed zone (14-17#)：
Charging is divided into two groups of parallel feeds in the region.By flow control, raw material initially enters 14# mouths and 15# mouths,
Series connection 17# mouths and 16# mouths, material liquid pass through resin column, and product is attracted on resin, detect 14# column outlets feed liquid and raw material
Liquid is consistent, then is determined as supersaturated absorption.The feed liquid that 17# mouths come out with 16# mouths is middle material, carries out applying mechanically charging.
B, water wash zone (10-13#) after feeding：
4 valve ports in the region connect in a series arrangement, after adsorption zone, after resin column adsorption saturation, turn to
Xi Liao areas, there is excessive material liquid in resin column, eluted remaining feed liquid in pillar and impurity B, C with water.Elute
Feed liquid carries out applying mechanically charging into middle material.
C, secondary feeds area (18-20#)
The valve port in the region is to be connected in series.Because adsorption zone supersaturation is adsorbed, part material liquid, institute are also contained in Xi Liao areas
It to set secondary feeds area, can so ensure the complete absorption of product, increase product yield.Simultaneously because impurity B can A with woods
Adsorption rate on resin is different, is adjusted by flow velocity, can be eluted out impurity B, but also can take part woods out of can
A。
D, product parsing area (7-9#)
In the region, using being connected in series mode.Behind Xi Liao areas, the impurity B, C in resin column are seldom, make
Product completion parsing is got off with n-butanol.The region soon rotates previous minute, it is necessary to detect 7# outlets, really in pillar
Protect 7# outlets and do not contain the product A or A of product containing very small amount, then representative products parse completely.Another detection production life cycle sample, confirms solution
The product design and purity analysed.
E, Xi Chun areas (2-6#)
In the region, using being connected in series mode.Because n-butanol density ratio water is small, so cleaned using anti-water inlet,
So cleaning performance can be relatively good, reduce cleaning water consumption, the region before rotation 1 minute, it is necessary to detect 2# outlet wash water,
Detect whether containing butanol, to judge whether Xi Chun areas clean up.
F, nip (1#) under resin
Because Xi Chun areas are using anti-water inlet cleaning way, so resin can be got on by top, in 1# posts using water by under resin
Push back, it is ensured that the using effect of next cycle charging.Use high flux flushing, because resin column cleans up, the area
Domain water can be with Reusability.
It is described in detail with reference to Fig. 1, Fig. 3, Fig. 4 and embodiment
Feeding liquid is the crude product that Jiangxi traditional Chinese medicines enter before fixed bed at present：
Daily switch on condition and testing result：
Secondary experiment September proceeds by the 22nd, purity data change when following table is run for adjustment.
As can be seen from the above table：Previous experiments work-in-process purity is not high, and waste port has many products to come out, may
Being due to that secondary feeds region is long causes feed liquid to be accumulated, and the later stage reduces secondary feeds region pillar quantity, and product purity is gradual
Rise.After data stabilization, No. 26 start continuous feeds, judgment experiment stability and yield.Specific data are as follows：
Per batch, charging is fixed, and does conservation of matter and calculated yield, specific data such as following table：
Yield is alcohol phase and aqueous phase percentage sum.
Specific device parameter is as follows：
Its secondary feed zone pillar number is 2.
Sampling crystallization, experimental result are as follows：
| Date | Feed liquid purity (%) | Primary crystallization (%) | Secondary crystallization (%) |
| No. 27 | 99.53 | 99.68 | 99.74 |
| No. 28 first | 99.58 | 99.74 | 99.79 |
| No. 28 second batchs | 99.6 | 99.71 | 99.77 |
On the basis of the technique of embodiment 1, by adjusting different zones pillar quantity distribution ratio, seek to improve product purity
Optimal allocation ratio, and carry out product yield judgement.
The comparison of embodiment 3, the purification process of the present invention and existing purification process
In order to investigate the optimal preparation method of lincomycin, the preparation method of the present invention is contrasted with existing process
Experiment, wherein：Scheme 1：Mycelium is filtered to remove after the acidified processing of zymotic fluid, filtrate adjusts pH to 11 with NaOH, adds thereto
Enter butanol and carry out extraction refinement, add the back extraction of HCL solution, after being concentrated under reduced pressure, charcoal absorption, crystallization, drying, obtaining hydrochloric acid woods can
Mycin bulk drug.Scheme 2：The purification process (embodiment 2) of the present invention.As a result show, the woods of purification process of the invention purifying
Can mycin purity index be substantially better than existing purification process.
Embodiment 4,
By purification process of the present invention, by feed liquid by load different model, particle diameter, the uniformity resin company
Continuous chromatographic column elution, later crystallization condition is identical, and gained lincomycin finished product purity data is as follows：
| Resin model | Particle diameter | The uniformity (%) | Feed liquid purity (%) | Primary crystallization (%) | Secondary crystallization (%) |
| HZ-802 | 50~100 | ≥95 | 99.53 | 99.68 | 99.74 |
| HZ-802 | ＞ 100 | ≥95 | 99.53 | 85.94 | 98.12 |
| HZ-802 | ＞ 100 | ＜ 95 | 99.53 | 84.72 | 96.65 |
| AB-8 | 50~100 | ≥95 | 99.53 | 99.52 | 99.69 |
| AB-8 | ＞ 100 | ≥95 | 99.53 | 86.15 | 97.95 |
| AB-8 | ＞ 100 | ＜ 95 | 99.53 | 83.18 | 96.35 |
| Lan Xin -30 | 50~100 | ≥95 | 99.53 | 99.45 | 99.66 |
| Lan Xin -30 | 50~100 | ＜ 95 | 99.53 | 86.35 | 98.37 |
| Lan Xin -30 | ＞ 100 | ＜ 95 | 99.53 | 84.17 | 96.28 |
| D-101 | 50~100 | ≥95 | 99.53 | 61.84 | 65.58 |
| D-101 | 50~100 | ＜ 95 | 99.53 | 59.75 | 62.38 |
| D-101 | ＞ 100 | ＜ 95 | 99.53 | 55.13 | 58.95 |
| BS-75 | 50~100 | ≥95 | 99.53 | 46.38 | 66.29 |
| BS-75 | 50~100 | ＜ 95 | 99.53 | 44.68 | 60.37 |
| BS-75 | ＞ 100 | ＜ 95 | 99.53 | 34.98 | 54.76 |
Claims (8)
1. the continuous chromatography isolation and purification method of a kind of lincomycin, it is characterised in that methods described step is as follows：
Step 1, continuous chromatography post on fermented filtrate of lincomycin, obtains eluent；
Step 2, eluent obtains lincomycin sterling by concentration, crystallizing and drying.
2. method according to claim 1, it is characterised in that upper continuous chromatography post, resin are selected from described in step 1：Macroporous absorption
The resin of resin HZ-802, R-802, Lan Xin -30, AB-8, YPR- II, resin particle diameter in 50~100 mesh, the uniformity 95% with
On.
3. method according to claim 1, it is characterised in that concentrate drying, method are as follows described in step 2：Concentration is using decompression
Concentration, vacuum be 0.02~0.15Mpa, and operation temperature is 35~90 DEG C, be concentrated into lincomycin mass concentration be 25%~
70%, obtain concentrate；The method that concentrate is crystallized with acetone obtains solid.
4. method according to claim 1, it is characterised in that continuous chromatography is selected from：Disk conveying type continuous chromatography piece-rate system
Or Simulation moving bed formula continuous chromatography piece-rate system.
5. method according to claim 1, it is characterised in that upper continuous chromatography post described in step 1, by paragraphs below district's groups into：
A, feed zone (14-17#)：
Charging is divided into two groups of parallel feeds in the region.By flow control, raw material initially enters 14# mouths and 15# mouths, is connecting
17# mouths and 16# mouths, material liquid pass through resin column, and product is attracted on resin, detection 14# column outlets feed liquid and material liquid one
Cause, be then determined as supersaturated absorption.The feed liquid that 17# mouths come out with 16# mouths is middle material, carries out applying mechanically charging.
B, water wash zone (10-13#) after feeding：
4 valve ports in the region connect in a series arrangement, after adsorption zone, after resin column adsorption saturation, turn to and wash material
Area, there is excessive material liquid in resin column, eluted remaining feed liquid in pillar and impurity B, C with water.The feed liquid eluted
Carry out applying mechanically charging into middle material.
C, secondary feeds area (18-20#)
The valve port in the region is to be connected in series.Because adsorption zone supersaturation is adsorbed, part material liquid is also contained in Xi Liao areas, so setting
Secondary feeds area is put, can so ensure the complete absorption of product, increases product yield.Simultaneously because impurity B and LCM
Adsorption rate on resin is different, is adjusted by flow velocity, can be eluted out impurity B；
D, product parsing area (7-9#)
In the region, using being connected in series mode.Behind Xi Liao areas, the impurity B, C in resin column are seldom, using just
Butanol gets off product completion parsing.The region soon rotates previous minute, it is necessary to detect 7# outlets in pillar, it is ensured that 7#
Outlet does not contain the product A or A of product containing very small amount, then representative products parse completely.Another detection production life cycle sample, confirms under parsing
The product design and purity come.
E, Xi Chun areas (2-6#)
In the region, using being connected in series mode.Because n-butanol density ratio water is small, so being cleaned using anti-water inlet, so
Cleaning performance can be relatively good, reduce cleaning water consumption, the region before rotation 1 minute, it is necessary to detect 2# outlet wash water, detection
Whether butanol is contained, to judge whether Xi Chun areas clean up.
F, nip (1#) under resin
Because Xi Chun areas are using anti-water inlet cleaning way, so resin can be got on by top, will be pushed back in 1# posts using water under resin
Fall, it is ensured that the using effect of next cycle charging.Using high flux flushing, resin column is cleaned up, the regional water can
With Reusability.
6. method according to claim 1, it is characterised in that comprise the following steps：
Step 1, continuous chromatography post on fermented filtrate of lincomycin, obtains eluent；
Step 2, eluent obtains lincomycin sterling by concentration, crystallizing and drying；
Wherein, upper continuous chromatography post, resin are selected from described in step 1：Macroporous absorbent resin HZ-802, R-802, Lan Xin -30, AB-
8th, the resins of YPR- II, resin particle diameter is in 50~100 mesh, the uniformity more than 95%.Wherein, concentrate drying described in step 2, side
Method is as follows：Using being concentrated under reduced pressure, vacuum is 0.02~0.15Mpa for concentration, and operation temperature is 35~90 DEG C, and being concentrated into woods can be mould
Plain mass concentration is 25%~70%, obtains concentrate；The method that concentrate is crystallized with acetone obtains solid；
It is as follows using the separation of disk conveying type continuous chromatography or the separation of Simulation moving bed formula continuous chromatography, step：
A, feed zone (14-17#)：
Charging is divided into two groups of parallel feeds in the region.By flow control, raw material initially enters 14# mouths and 15# mouths, is connecting
17# mouths and 16# mouths, material liquid pass through resin column, and product is attracted on resin, detection 14# column outlets feed liquid and material liquid one
Cause, be then determined as supersaturated absorption.The feed liquid that 17# mouths come out with 16# mouths is middle material, carries out applying mechanically charging.
B, water wash zone (10-13#) after feeding：
4 valve ports in the region connect in a series arrangement, after adsorption zone, after resin column adsorption saturation, turn to and wash material
Area, there is excessive material liquid in resin column, eluted remaining feed liquid in pillar and impurity B, C with water.The feed liquid eluted
Carry out applying mechanically charging into middle material.
C, secondary feeds area (18-20#)
The valve port in the region is to be connected in series.Because adsorption zone supersaturation is adsorbed, part material liquid is also contained in Xi Liao areas, so setting
Secondary feeds area is put, can so ensure the complete absorption of product, increases product yield.Simultaneously because impurity B and LCM
Adsorption rate on resin is different, is adjusted by flow velocity, can be eluted out impurity B；
D, product parsing area (7-9#)
In the region, using being connected in series mode.Behind Xi Liao areas, the impurity B, C in resin column are seldom, using just
Butanol gets off product completion parsing.The region soon rotates previous minute, it is necessary to detect 7# outlets in pillar, it is ensured that 7#
Outlet does not contain the product A or A of product containing very small amount, then representative products parse completely.Another detection production life cycle sample, confirms under parsing
The product design and purity come.
E, Xi Chun areas (2-6#)
In the region, using being connected in series mode.Because n-butanol density ratio water is small, so being cleaned using anti-water inlet, so
Cleaning performance can be relatively good, reduce cleaning water consumption, the region before rotation 1 minute, it is necessary to detect 2# outlet wash water, detection
Whether butanol is contained, to judge whether Xi Chun areas clean up.
F, nip (1#) under resin
Because Xi Chun areas are using anti-water inlet cleaning way, so resin can be got on by top, will be pushed back in 1# posts using water under resin
Fall, it is ensured that the using effect of next cycle charging.Using high flux flushing, resin column is cleaned up, the regional water can
With Reusability.
7. method according to claim 1, it is characterised in that Lincomycin Hydrochloride purity >=99.5%, moisture≤5%.
8. method according to claim 1, it is characterised in that step is as follows：
Step 1, continuous chromatography post on fermented filtrate of lincomycin, obtains eluent；
Step 2, eluent obtains lincomycin sterling by concentration, crystallizing and drying；
Wherein, upper continuous chromatography post, resin are selected from described in step 1：Macroporous absorbent resin HZ-802, resin particle diameter 50~
100 mesh, the uniformity more than 95%；
Wherein, eluent described in step 2 is as follows by concentration, the process dried：Concentration is used and is concentrated under reduced pressure, vacuum 0.02
~0.15Mpa, operation temperature are 35~90 DEG C, and it is 25%~70% to be concentrated into lincomycin mass concentration, obtains concentrate；It is dense
The method that contracting liquid is crystallized with acetone obtains solid；
Wherein, continuous chromatography is selected from：Disk conveying type continuous chromatography piece-rate system or the separation of Simulation moving bed formula continuous chromatography
System；
Wherein, upper continuous chromatography post described in step 1, by paragraphs below district's groups into：
A, feed zone (14-17#)：
Charging is divided into two groups of parallel feeds in the region, and by flow control, raw material initially enters 14# mouths and 15# mouths, is connecting
17# mouths and 16# mouths, material liquid pass through resin column, and product is attracted on resin, detection 14# column outlets feed liquid and material liquid one
Causing, be then determined as supersaturated absorption, the feed liquid that 17# mouths come out with 16# mouths is middle material, carries out applying mechanically charging,
B, water wash zone (10-13#) after feeding：
4 valve ports in the region connect in a series arrangement, after adsorption zone, after resin column adsorption saturation, turn to and wash material
Area, there is excessive material liquid in resin column, eluted remaining feed liquid in pillar and impurity B, C with water, the feed liquid eluted
Carry out applying mechanically charging into middle material,
C, secondary feeds area (18-20#)
The valve port in the region is is connected in series, and because adsorption zone supersaturation is adsorbed, part material liquid is also contained in Xi Liao areas, so setting
Put secondary feeds area, can so ensure the complete absorption of product, increase product yield, simultaneously because impurity B and woods can A setting
Adsorption rate on fat is different, is adjusted by flow velocity, and impurity B is eluted out, but can also take out of part woods can A,
D, product parsing area (7-9#)
In the region, using mode is connected in series, behind Xi Liao areas, the impurity B, C in resin column are seldom, using just
Butanol gets off product completion parsing, and the region soon rotates previous minute, it is necessary to detect 7# outlets in pillar, it is ensured that 7#
Outlet does not contain the product A or A of product containing very small amount, then representative products parse completely, another to detect production life cycle sample, confirms under parsing
The product design and purity come,
E, Xi Chun areas (2-6#)
In the region, using mode is connected in series, because n-butanol density ratio water is small, so being cleaned using anti-water inlet, so
Cleaning performance can be relatively good, reduce cleaning water consumption, the region before rotation 1 minute, it is necessary to detect 2# outlet wash water, detection
Whether butanol is contained, to judge whether Xi Chun areas clean up,
F, nip (1#) under resin
Because Xi Chun areas are using anti-water inlet cleaning way, so resin can be got on by top, will be pushed back in 1# posts using water under resin
Fall, it is ensured that the using effect of next cycle charging, use high flux flushing, because resin column cleans up, the regional water
Can be with Reusability.
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