CN105132512B - A kind of method that impurity tailing peak is reduced in terramycin production - Google Patents
A kind of method that impurity tailing peak is reduced in terramycin production Download PDFInfo
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- CN105132512B CN105132512B CN201510584831.2A CN201510584831A CN105132512B CN 105132512 B CN105132512 B CN 105132512B CN 201510584831 A CN201510584831 A CN 201510584831A CN 105132512 B CN105132512 B CN 105132512B
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- terramycin
- impurity
- zymotic fluid
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- tailing peak
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Abstract
A kind of method that impurity tailing peak is reduced in being produced the invention discloses terramycin.The production process includes the following steps：It ferments, acidification dilutes, filtering, decoloration, crystallize, separation and drying, key are：Improve the controlling value of the content of ammonia nitrogen in ferment middle and later stage fermentation liquid；Reduce the controlling value that potency is diluted when zymotic fluid dilution；Shorten crystallization time；Shorten the replacement cycle of decolorizing resin；Increase the washing amount of Separation Performance in Oxytetracycline.The present invention uses above-mentioned technological means by comprehensive, optimizes terramycin production technology, experiments have shown that, by using the method for the present invention, the impurity tailing peak of product is reduced, its control 3.5 hereinafter, improving product quality.
Description
Technical field
The present invention relates to a kind of production method of terramycin, impurity tailing peak is reduced in especially a kind of terramycin production
Method.
Background technology
Terramycin is the secondary metabolite of streptomyces rimosus during the fermentation.NH in its molecular structural formula2It replaces
At CH3As impurity tailing peak.
It is soybean cake powder, corn steep liquor, ammonium sulfate and ammonium hydroxide to produce the culture medium main nitrogen used in terramycin；Carbon source is to form sediment
Powder, starch milk.Using purebred sinking, air agitation three grade fermemtation culture.It is stirred, ventilates in incubation, and certain
Make streptomyces rimosus mass propagation under cultivation temperature and pressure, promotes to generate terramycin in its bio-metabolic process.Fermentation ends
Afterwards, terramycin is present in into the cell.Fermentation finishes, and zymotic fluid is squeezed into souring tank, and oxalic acid and hydrochloric acid acidification is added, adjusts pH
Value is added cleanser yellow sodium prussiate, is diluted with low unit filtrate, and zinc sulfate is added after dilution is good.Dilution is squeezed into plate
Frame filters, and the filtrate of high unit basin is squeezed into decoloration filtrate tank with pump.Filtrate is passed through decolorizing resin tank by filtrate tank and is taken off
Color, destainer carry out continuous crystallisation by crystallizing tank after filtering.Crystal solution utilizes the effect of shutting off of filter cloth by separating plate frame
Mother liquor is filtered out, and terramycin crystal stays in and achievees the purpose that separation in sheet frame.The drying of wet crystal uses pneumatic conveying drying mode.
The moisture content of wet crystal is down to range as defined in standard.Then terramycin dry powder is carried out being packaged to be finished product.
Currently, some technological parameters of terramycin production are：1, the content control of ammonia nitrogen exists in ferment middle zymotic fluid
(so-called fermentation " early period ", " mid-term " and " later stage " is in 0.150-0.160g/ml for 0.080-0.100g/ml, later stage control
By what is divided within fermentation 50 hours, after 50 to 100 hours and 100 hours)；2, the control of dilution potency exists when zymotic fluid dilutes
13000u/ml-15000u/ml；3, crystallization time is more than 50 minutes；4, the replacement cycle of decolorizing resin is more than 3 years；5, separation soil
The washing amount of mycin is less than per 20 tons of frame.
By carefully studying and testing discovery, the factor for influencing terramycin product impurity tailing peak mainly has following a few sides
Face：
1, zymotic fluid quality.In fermentation process, ammonia nitrogen, later stage is utilized early period to generate ammonia nitrogen, the reacting condition thalline of ammonia nitrogen
Growth metabolism situation.Early period, ammonia-nitrogen content controlled too low, illustrated that the fast of bacterial metabolism, nutriment cannot meet thalline life
Long, later stage ammonia nitrogen does not go up, and impurity is relatively more, influences tailing peak.
2, volume is diluted.It is large volume to dilute fixing fabric structure in 7000-11000u/ml, and dilution volume is in 12000-
14000u/ml is small size.The solubility of tailing peak is bigger than terramycin in water phase, and large volume dilution volume is larger, tailing peak
Dissolving it is relatively more；Small size dilutes small volume, and the dissolving of tailing peak is relatively fewer, therefore reduces dilution potency, favorably
In reduction tailing peak.
3, crystallization time.Terramycin has its crystallization rate, when crystalline mother solution unit is basically unchanged, it is believed that crystallization is
It finishes, should be centrifuged.The inappropriate extension of crystallization time, crystallization from mother liquor the impurity such as adsorption comet peak and it is dirty
Dye, makes tailing peak increase.It is again higher just more bad for the second-rate long pH of destainer crystallization time.Therefore it should strictly control
Crystallization time processed had not only ensured yield but also had reduced tailing peak.
4, the quality of decolorizing resin and long-term excess load use.The quality of decolorizing resin：The granulation uniformity of decolorizing resin,
Exchange capacity and mechanical strength all have an impact tailing peak.If resin demand is very little, filtrate flux is often excessive, is chronically at super
Load condition, resin are easy fatigue, are not easy to restore decoloring ability, this is unfavorable to reducing tailing peak.
5, the washing amount of Separation Performance in Oxytetracycline.With salt-free water washing when because of Separation Performance in Oxytetracycline, leaching requirement is few, and part tailing peak is residual
It stays in terramycin, increases leaching requirement, so that part tailing peak is entered mother liquor, the hangover in terramycin finished product can be effectively reduced
Peak.
Invention content
The technical problem to be solved by the present invention is to：The method that impurity tailing peak is reduced in a kind of production of terramycin is provided.
In order to solve the above-mentioned technical problem, the technical solution used in the present invention is：
The method that impurity tailing peak is reduced in a kind of production of terramycin, the production process include the following steps：Fermentation, acidification
It dilutes, filtering, decoloration, crystallize, separation and drying, key are：
A, the controlling value of the content of ammonia nitrogen in ferment middle and later stage fermentation liquid is improved；
B, the controlling value that potency is diluted when zymotic fluid dilution is reduced；
C, shorten crystallization time；
D, shorten the replacement cycle of decolorizing resin；
E, increase the washing amount of Separation Performance in Oxytetracycline.
As the preferred technical solution of the present invention, it is：
The content of ammonia nitrogen is controlled in 0.110-0.140g/ml in ferment middle zymotic fluid.
The control of dilution potency is in 11000u/ml-13000u/ml when zymotic fluid dilutes.
Crystallization time was controlled at 40-50 minutes.
The replacement cycle of decolorizing resin controls in 1.5-3.
The washing amount of Separation Performance in Oxytetracycline is controlled at every frame 20-25 tons.
Advantageous effect obtained by the present invention：
The factor for influencing terramycin product impurity tailing peak is more, uses above-mentioned technological means by comprehensive, optimizes soil
Mycin production technology, experiments have shown that, by using the method for the present invention, the impurity tailing peak of product is reduced, its control is existed
3.5 hereinafter, improve product quality.
The present invention is described in further details With reference to embodiment.
Specific implementation mode
Embodiment 1,
Terramycin is the secondary metabolite of streptomyces rimosus during the fermentation.During the fermentation, with corn steep liquor, sulphur
Sour ammonium and ammonium hydroxide are nitrogen source；Carbon source is starch, starch milk.Using purebred sinking, air agitation three grade fermemtation culture.Incubation
In be stirred, ventilate.It is passed through the amount of ammonium hydroxide by control to control the content of ammonia nitrogen in zymotic fluid, mid-term control is small every 8
When be passed through ammonium hydroxide 350ml, ammonia-nitrogen content mid-term is controlled in 0.115g/ml；And make cracking chain under certain cultivation temperature and pressure
Mould mass propagation promotes to generate terramycin in its bio-metabolic process.After fermentation, terramycin is present in into the cell.
Fermentation finishes, and zymotic fluid is squeezed into souring tank, and oxalic acid and hydrochloric acid acidification is added, adjusts pH value, cleanser is added
Yellow sodium prussiate is diluted with low unit filtrate, and zymotic fluid dilutes potency control to 12500u/ml；Sulfuric acid is added after dilution is good
Zinc.Dilution is squeezed into plate-frame filtering, the filtrate of high unit basin is squeezed into decoloration post filtrate tank with pump.Filtrate is by filtrate tank
It is passed through and produces 122 using Kunshan#Decolorizing resin tank is decolourized (122#The decolorizing resin replacement cycle is 2 years), destainer is after filtering
By crystallizing tank crystallize within continuous 50 minutes, crystal solution is filtered out mother liquor using the effect of shutting off of filter cloth by separating plate frame,
Then it is washed, washing amount is controlled to 20 tons of every frame, so that terramycin crystal is stayed in sheet frame and is detached.The drying of wet crystal
Using pneumatic conveying drying mode.The moisture content of wet crystal is down to range as defined in standard.Then terramycin dry powder pack
To finished product.Finished product tailing peak is average 3.46.
Embodiment 2
Terramycin is the secondary metabolite of streptomyces rimosus during the fermentation.During the fermentation, with corn steep liquor, sulphur
Sour ammonium and ammonium hydroxide are nitrogen source；Carbon source is starch, starch milk.Using purebred sinking, air agitation three grade fermemtation culture.Incubation
In be stirred, ventilate.It is passed through the amount of ammonium hydroxide by control to control the content of ammonia nitrogen in zymotic fluid, mid-term control is small every 8
When be passed through ammonium hydroxide 360ml, ammonia-nitrogen content mid-term is controlled in 0.125g/ml；And make cracking chain under certain cultivation temperature and pressure
Mould mass propagation promotes to generate terramycin in its bio-metabolic process.After fermentation, terramycin is present in into the cell.
Fermentation finishes, and zymotic fluid is squeezed into souring tank, and oxalic acid and hydrochloric acid acidification is added, adjusts pH value, cleanser is added
Yellow sodium prussiate is diluted with low unit filtrate, and zymotic fluid dilutes potency control to 12000u/ml；Sulfuric acid is added after dilution is good
Zinc.Dilution is squeezed into plate-frame filtering, the filtrate of high unit basin is squeezed into decoloration post filtrate tank with pump.Filtrate is by filtrate tank
It is passed through and produces 122 using Kunshan#Decolorizing resin tank is decolourized (122#The decolorizing resin replacement cycle is 2 years), destainer is after filtering
By crystallizing tank crystallize within continuous 40 minutes, crystal solution is filtered out mother liquor using the effect of shutting off of filter cloth by separating plate frame,
Then it is washed, washing amount is controlled to 25 tons of every frame, so that terramycin crystal is stayed in sheet frame and is detached.The drying of wet crystal
Using pneumatic conveying drying mode.The moisture content of wet crystal is down to range as defined in standard.Then terramycin dry powder pack
To finished product.Finished product tailing peak is average 3.39.
Embodiment 3
Terramycin is the secondary metabolite of streptomyces rimosus during the fermentation.During the fermentation, with corn steep liquor, sulphur
Sour ammonium and ammonium hydroxide are nitrogen source；Carbon source is starch, starch milk.Using purebred sinking, air agitation three grade fermemtation culture.Incubation
In be stirred, ventilate.It is passed through the amount of ammonium hydroxide by control to control the content of ammonia nitrogen in zymotic fluid, mid-term control is small every 8
When be passed through ammonium hydroxide 365ml, ammonia-nitrogen content mid-term is controlled in 0.140g/ml；And make cracking chain under certain cultivation temperature and pressure
Mould mass propagation promotes to generate terramycin in its bio-metabolic process.After fermentation, terramycin is present in into the cell.
Fermentation finishes, and zymotic fluid is squeezed into souring tank, and oxalic acid and hydrochloric acid acidification is added, adjusts pH value, cleanser is added
Yellow sodium prussiate is diluted with low unit filtrate, and zymotic fluid dilutes potency control to 11000u/ml；Sulfuric acid is added after dilution is good
Zinc.Dilution is squeezed into plate-frame filtering, the filtrate of high unit basin is squeezed into decoloration post filtrate tank with pump.Filtrate is by filtrate tank
It is passed through and produces 122 using Kunshan#Decolorizing resin tank is decolourized (122#The decolorizing resin replacement cycle is 1.5 years), destainer is through filtering
By crystallizing tank crystallize within continuous 40 minutes afterwards, crystal solution is filtered mother liquor using the effect of shutting off of filter cloth by separating plate frame
Go out, then washed, washing amount is controlled to 30 tons of every frame, so that terramycin crystal is stayed in sheet frame and is detached.Wet crystal
It is dry to use pneumatic conveying drying mode.The moisture content of wet crystal is down to range as defined in standard.Then terramycin dry powder is wrapped
Dress obtains finished product.Finished product tailing peak is average 3.31.
Claims (1)
1. a kind of method for reducing impurity tailing peak in terramycin production, the production process include the following steps：Ferment, be acidified it is dilute
It releases, filter, decolourize, crystallize, detach and dries, it is characterised in that：
A, the controlling value of the content of ammonia nitrogen in ferment middle and later stage fermentation liquid is improved；
B, the controlling value that potency is diluted when zymotic fluid dilution is reduced；
C, shorten crystallization time；
D, shorten the replacement cycle of decolorizing resin；
E, increase the washing amount of Separation Performance in Oxytetracycline；
The content of ammonia nitrogen is controlled in 0.110-0.140g/ml in ferment middle zymotic fluid；
The control of dilution potency is in 11000u/ml-13000u/ml when zymotic fluid dilutes；
Crystallization time was controlled at 40-50 minutes；
The replacement cycle of decolorizing resin controls in 1.5-3；
The washing amount of Separation Performance in Oxytetracycline is controlled at every frame 20-25 tons.
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| CN106380422B (en) * | 2016-08-29 | 2018-04-03 | 河北健民淀粉糖业有限公司 | A kind of method that low phosphorus content terramycin finished product is extracted from Performance in Oxytetracycline Fermentation Broth |
| CN106119332A (en) * | 2016-08-29 | 2016-11-16 | 河北健民淀粉糖业有限公司 | A kind of oxytetracycline production technology |
| CN116621724B (en) * | 2023-07-21 | 2023-10-27 | 山东国邦药业有限公司 | Oxytetracycline extraction method for reducing content of impurity 2-acetyl-2-desamidooxytetracycline |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB718020A (en) * | 1950-06-01 | 1954-11-10 | Pfizer & Co C | Improvements in or relating to the recovery of the antibiotic oxytetracycline |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB718020A (en) * | 1950-06-01 | 1954-11-10 | Pfizer & Co C | Improvements in or relating to the recovery of the antibiotic oxytetracycline |
Non-Patent Citations (2)
| Title |
|---|
| "土霉素结晶工艺改进的研究";田彩霞等;《中国抗生素杂志》;20060331;第31卷(第3期);1.2,2.3,2.4 * |
| "降低土霉素杂质的工艺研究";辛占昌等;《中国医药工业杂志》;19991231;第30卷(第11期);3.1 * |
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