CN106928288B - A kind of preparation method of dihydrostreptomycin sulfate - Google Patents
A kind of preparation method of dihydrostreptomycin sulfate Download PDFInfo
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- CN106928288B CN106928288B CN201710169961.9A CN201710169961A CN106928288B CN 106928288 B CN106928288 B CN 106928288B CN 201710169961 A CN201710169961 A CN 201710169961A CN 106928288 B CN106928288 B CN 106928288B
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/238—Cyclohexane rings substituted by two guanidine radicals, e.g. streptomycins
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention discloses a kind of preparation methods of dihydrostreptomycin sulfate, belong to the process for producing of semisynthetic antibiotics, it is handled including acid, ion exchange, the absorption of macropore primary amine resins, hydrogenation, Two-step ion-exchanging, mixed bed purification, active carbon processing, nanofiltration membrane concentration, active carbon decoloring, ultrafiltration membrane treatment and spray drying step, The present invention reduces the consumption of oxalic acid in preparation process, improve the utilization rate of reducing agent, reduce production cost, improve production efficiency, the needs of industrialized production can be met well, improve the product purity of dihydrostreptomycin sulfate, quality pass rate and total recovery.
Description
Technical field
The present invention relates to a kind of preparation method of compound, especially a kind of preparation method of dihydrostreptomycin sulfate belongs to
In the process for producing of semisynthetic antibiotics.
Background technique
Streptomysin (Streptomycin) is that Sai Erman Waksman divides from streptomyces griseus culture solution in nineteen forty-four
A kind of alkaline antibiotic come is separated out, there is anti-binding bacillus characteristic, fungicide can also be used as in veterinary drug and pesticide.Its molecule
Structure is made of being connected as streptidine, streptose with N- methyl-L- gucosamine three parts with glycosidic bond, and molecular formula is
C21H39N7O12.It is alcoholic extract hydroxyl group that dihydrostreptomycin sulfate, which is by the aldehyde radical hydrogenating reduction of streptomysin, and is translated into sulfate shape
Formula can overcome the problems, such as that streptomysin stability is poor well, and its antimicrobial spectrum is similar with streptomysin.
Dihydrostreptomycin can be generated by wet streptomycete direct fermentation, but due to being free of aldehyde radical, nothing in dihydrostreptomycin
Method carries out absorption purification by macropore primary amine groups resin or D401 chelating resin, and product purity is caused to be difficult to improve.It is general at present
It all over using semi-synthesis method to prepare dihydrostreptomycin, that is, first passes through streptomycete fermentation and obtains streptomysin, then by aldehyde radical therein
It is restored, the restoring method mainly used has hydrogen catalytic reaction method, electrolytic reduction and reduction-state hydrogen reduction method.Wherein,
Hydrogen catalytic method must be in high temperature, high pressure and have catalyst under conditions of carries out, the high requirements on the equipment, and preparation difficulty is also larger.
Electrolytic reduction is that streptomysin is placed in cathode can, plays reduction by being subject to appropriate electric current, but the method needs to consume
A large amount of electric energy, and reaction efficiency is lower.
Reduction-state hydrogen reduction method production dihydrostreptomycin can carry out at normal temperatures and pressures, but existing preparation process is universal
There are oxalic acid consumptions it is high, reducing agent utilization rate is low, product purity is poor, qualification rate is low and unstable quality the problems such as.
Summary of the invention
The technical problem to be solved by the invention is to provide a kind of preparation methods of dihydrostreptomycin sulfate, can be in room temperature
It is reacted under normal pressure, reduces consumption of oxalic acid, reduce production cost, improve reducing agent utilization rate and production efficiency, and can reach very high
Product purity, quality pass rate and total recovery.
In order to solve the above technical problems, the technical scheme adopted by the invention is that:
A kind of preparation method of dihydrostreptomycin sulfate is provided, is included the following steps:
A. after streptomycin fermentation liquid being carried out sour processing, 60~85 DEG C are heated to, then insoluble by centrifugation or filtering removal
Then object adjusts pH to 7.0~8.5 with sodium hydroxide, streptomysin stoste is made；
B. by after the weak-acid cation-exchange resin adsorption saturation of streptomysin stoste, with soft water, salt-free water or purified water
Washing, then eluted with dilute sulfuric acid, streptomycin sulphate eluent is made；
C. it after streptomysin eluent being saturated with macropore primary amine groups resin adsorption, with salt-free water or purifying water washing and presses
It is dry, then recycled and parsed with dilute sulfuric acid, streptomycin sulphate desorbed solution is made；
D. after streptomycin sulphate desorbed solution being adjusted pH to 6.5~8.0 with sodium hydroxide, reducing agent is added, then use sulfuric acid
PH to 7.0~7.5 is adjusted, streptomycin sulphate hydride is made；
E. by after the weak-acid cation-exchange resin adsorption saturation of streptomycin sulphate hydride, with soft water, salt-free water or
Water washing is purified, then is eluted with dilute sulfuric acid, dihydrostreptomycin sulfate eluent is made；
F. dihydrostreptomycin sulfate eluent forward direction is passed through mixed-bed ion exchange resin, dihydrostreptomycin sulfate is made
Purify liquid；
G. after dihydrostreptomycin sulfate purification liquid being adjusted pH to 4.0~6.0 with calcium hydroxide, mass volume ratio, which is added, is
0.5~2.0% injection active carbon, gained filtrate is liquid after dihydrostreptomycin sulfate filter after filtering；
H. liquid nanofiltration membrane, which is concentrated, after dihydrostreptomycin sulfate being filtered is made dihydrostreptomycin sulfate concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 1.0~5.0%, mistake is added
Gained filtrate is dihydrostreptomycin sulfate decoloration concentrate after filter；
J. the ultrafiltration membrance filter for being 4000~8000D by dihydrostreptomycin sulfate decoloration concentrate molecular cut off, system
Obtain dihydrostreptomycin sulfate finished product concentrate；
K. dihydrostreptomycin sulfate finished product concentrate is spray-dried, dihydrostreptomycin sulfate finished powder is made.
Technical solution of the present invention further improvement lies in that: in step a acid processing be by 6~16kg/m3Ratio will be careless
Acid is added in streptomycin fermentation liquid, then with sulphur acid for adjusting pH to 2.5~3.5；The macropore primary amine groups resin be D303 or
D318 resin.
Technical solution of the present invention further improvement lies in that: the concentration of the dilute sulfuric acid be 5.0~10.0%, the weak acid
Property cation exchange resin be carboxylic acid type cation exchange resin, and be sodium form.
Technical solution of the present invention further improvement lies in that: the carboxylic acid type ion exchange resin be 110 resins, D152 tree
Any one of rouge or D150 resin.
Technical solution of the present invention further improvement lies in that: the concentration of dilute sulfuric acid described in step b and e be 5.0~
6.5%, the concentration of dilute sulfuric acid described in step c is 7.0~9.0%.
Technical solution of the present invention further improvement lies in that: reducing agent described in step d be potassium borohydride or sodium borohydride,
Additional proportion is 5.0~8.0g/, hundred million unit, be added pre reduction agent by mass volume ratio be 10~15% be dissolved in 0.05~
In the sodium hydroxide of 2.0g/ml, potassium hydroxide or ammonia spirit.
Technical solution of the present invention further improvement lies in that: the mixed-bed ion exchange resin be Hydrogen, by height be crosslinked
Degree storng-acid cation exchange resin and weak-base anion-exchange resin are the mixing composition of 1:0.3~1 by volume.
Technical solution of the present invention further improvement lies in that: the usage mode of the mixed-bed ion exchange resin be 2~4
A mixed-bed ion exchange resin is used in series, the high-crosslinking-degree storng-acid cation exchange resin be 1 × 25 resin, 1 ×
Any one of 16 resins or 1 × 14 resin, weak-base anion-exchange resin are 703 resins.
Technical solution of the present invention further improvement lies in that: the nanofiltration retaining molecular weight be 300~500D or 150D,
The ultrafiltration membrane is any one of doughnut, plate membrane or rolled film.
Technical solution of the present invention further improvement lies in that: it is described spray drying using two streaming air-current atomising devices or three stream
Formula air-current atomising device.
By adopting the above-described technical solution, the technological progress achieved by the present invention is:
The present invention first by streptomysin preliminary purification, as far as possible again restores streptomysin after the interference of removal impurity, improves
Reducing agent utilization rate, the process isolated and purified are cooperated jointly using different kinds of ions exchanger resin and filter membrane, gradually remove impurity, color
Element, bacterial endotoxin and pyrogen etc. have reaction step is reasonable, easy to operate, repeatable to be recycled and energy-saving and environment-friendly
Feature can meet the needs of industrialized production well, and high-purity, high qualification rate and high quality stability is finally made
Dihydrostreptomycin sulfate product can react at normal temperatures and pressures, reduce consumption of oxalic acid, reduce production cost, improve reducing agent
Utilization rate and production efficiency have a clear superiority compared with traditional preparation method.
The calcium ions and magnesium ions being used only in a small amount of oxalic acid and fermentation liquid in step a of the present invention, which generate, to be precipitated, and is adjusted pH and is mainly led to
Persulfuric acid, since sulfuric acid is lower than oxalic acid price and acid stronger, using two kinds of acid of oxalic acid and sulfuric acid jointly to fermentation liquid
It is acidified, a large amount of oxalic acid can be saved, reduce acidification cost.It, can after being adjusted to 2.5~3.5 by pH and be heated to 60~85 DEG C
The impurity such as the acidic protein in fermentation liquid are coagulated, and streptomysin activity will not be destroyed, then pass through centrifugation or plate-frame filtering,
Remaining solid suspension in fermentation liquid, insoluble mycelia, culture based draff can be effectively removed and other are various insoluble
Impurity.The supernatant after filtered clarified solution or centrifugation is finally neutralized to pH7.0~8.5 with sodium hydroxide, makes cation
Exchanger resin absorption reaches better effect.
Carboxylic acid type cation exchange resin used in step b of the present invention can effectively adsorb the streptomysin point in alkalinity
Son, resin use sodium form, one of preferably 110 resins, D152 resin or D150 resin, the suction with object streptomysin
The advantage that attached selectivity is strong, the rate of adsorption is high, and be passed through forward or backwards.Streptomysin stoste is by carboxylic acid type cation
After exchanger resin, the impurity such as most of inorganic ions, protein and pigment can be removed.Solubility is very in dilute sulfuric acid for streptomysin
Height, elution rate is fast, and use cost is low.After resin is washed with water, eluted using a small amount of dilute sulfuric acid, it can be effectively to strepto-
Element carries out enrichment method, and concentration can be improved 15~20 times after elution.Streptomysin becomes the form of sulfate after elution, and property is more
Stablize.
It is used in step c and streptomysin eluent is first subjected to absorption purification with macropore primary amine groups resin D303 or D318, then
The method for restoring aldehyde radical therein with reducing agent can effectively improve product purity, and reduce the use of reducing agent.Macropore
With the streptomysin in streptomysin eluent containing aldehyde radical schiff base reaction can occur for primary amine groups resin, carry out selective suction to it
It is attached, but cannot be reacted with other impurity without aldehyde radical, such as streptamine, streptidine, double hydrogen streptoses, to make to be inhaled
Attached impurity penetrates, and has the function that effectively remove impurity.And if not only can before reduction step is advanceed to adsorption step
Waste reducing agent, and due to being free of aldehyde radical in the dihydrostreptomycin after reduction, then it can not be by macropore primary amine groups resin adsorption.
Washing uses salt-free water or purified water, without the use of soft water, prevents the sodium ion contained in soft water from influencing macropore primary amine groups resin
Adsorption effect.
Reducing agent sodium borohydride or potassium borohydride used in step d to the hydrogenation effect of streptomycin sulphate desorbed solution very
Good, the conversion ratio of reaction is very high, can reach the level not less than 99.5%.And concentration and the purification step reducing agent of front
Utilization rate be further enhanced, reduce the waste of reducing agent, additional amount of the reducing agent in streptomycin sulphate desorbed solution
Hundred million unit of only 5.0~8.0g/.Sodium borohydride or potassium borohydride property in alkaline solution are more stable, therefore before use
It is first dissolved in the sodium hydroxide, potassium hydroxide or ammonia spirit of 0.05~2.0g/ml by mass volume ratio for 10~15%, energy
Enough better play the effect for inhibiting it to hydrolyze.Reaction reduction effect when pH range is 6.5~8.0 is best.
Step e of the invention has reached and has separated by carrying out secondary ion exchange to streptomycin sulphate hydride
Except the purpose of the foreign ion introduced in step of hydrogenation.Streptomycin sulphate hydride with sulphur acid for adjusting pH to 7.0~7.5 when adsorb
Effect is best, and the carboxylic acid type resin cation of used sodium form is preferably appointing in 110 resins, D152 resin or D150 resin
One kind can effectively adsorb dihydrostreptomycin sulfate, with suitable soft water, salt-free water or purifying washing after the completion of absorption
Resin is washed, then with dilute sulfuric acid is eluted dihydrostreptomycin sulfate from resin to get to purifying.
The present invention use dilute sulfuric acid rather than dilute hydrochloric acid carried out by parse agent, cation exchange resin regenerative agent and acid pH tune
Save agent, to prevent from introducing chloride ion impurities in system, avoid portioned product and remaining chloride ion generate streptomycin hydrochloride or
Dihydrostreptomycin hydrochloride adversely affects sulfuric acid purity salt and yield bring.It is wherein directed to different resins, in step b and e
Elution effect is best when middle dilute sulfuric acid concentration is 5.0~6.5%, and in the circulation parsing of step c, the concentration of dilute sulfuric acid is preferably
7.0~9.0%.
Step f further removes salt refining, sulphur to streptomycin sulphate eluent by the mixed-bed ion exchange resin of Hydrogen
Pantostrep eluent is passed through the direction of mixed-bed ion exchange resin as forward direction, avoids the zwitterion mixed
Lamination occurs for exchanger resin.The present invention is exchanged using high-crosslinking-degree storng-acid cation exchange resin with weakly-basic anion
Resin uniformly mixes in exchanger, achievees the effect that cation and anion exchange while carrying out, reaction efficiency is high.High-crosslinking-degree strong acid
Property cation exchange resin be preferably any one of 1 × 25 resin, 1 × 16 resin or 1 × 14 resin, weakly-basic anion is handed over
Changing resin is preferably 703 resins.Mixed bed purifies liquid out, and there are two more important indexs, i.e. ash content and pH, under normal circumstances,
After pH is provided lower than standard, there are also certain desalination ability, the present invention to use 2~4 concatenated purifying techniques of mixed bed for bed,
The ion exchange resin in mixed bed can be made full use of, the utilization rate of mixed bed is improved, it helps improves product quality.It is high
1:0.3~1 is mixed by volume in exchanger for degree of cross linking storng-acid cation exchange resin and weak-base anion-exchange resin
It is optimum proportioning when conjunction, the comprehensive utilization ratio highest of two kinds of resins can thoroughly adsorb foreign ion remaining in eluent
Removal, water outlet desalination rate are very high.
The injection active carbon used in step g and step i has a clear superiority compared to other traditional decolorising agents.Injection is living
Property charcoal have that sterile, tasteless, non-toxic, with high purity, decoloration is fast, strong adsorption force and steady performance.And injection is living
Property charcoal can play good absorption property at low temperature, avoid heating and the double hydrogen strepto- activity of the sulfuric acid of non-refractory generated
Adverse effect also prevents the problem of medical fluid caused by heating darkens, increases decolorising agent dosage, while saving heating
Cost.Dihydrostreptomycin sulfate purifies liquid in pH to 4.0~6.0, and the adsorption effect of injection active carbon is best, in alkaline condition
Lower impurity content increases, and influences the quality of the pharmaceutical preparations.The present invention, which adjusts pH using calcium hydroxide, can play neutralization free acid well
Effect, and remove acid ion, and use cost is lower.Injection active carbon is suitable for continuous processing, and handles behaviour
Make simply, the present invention is handled with injection active carbon respectively before and after nanofiltration membrane concentration step, injection active carbon mass volume ratio point
Not Wei 0.5~2.0% and 1.0~5.0% when, can sufficiently adsorb the impurity and pigment in medical fluid, further increase the pure of product
Degree and color grade, medical fluid light transmittance can reach 95% or more after processing.The nanofiltration membrane and ultrafiltration filter membrane that the present invention uses are recyclable
It uses, reduces the use cost of film, and being effectively treated by previous step, impurity is considerably less in medical fluid, to filter membrane
It pollutes extremely low.
The nanofiltration membrane that liquid is 300~500D or 150D by molecular cut off after the present invention filters dihydrostreptomycin sulfate
Afterwards, it can be concentrated and is purified, for it is more than wherein divalent ion and molecular weight be higher than molecular cut off it is organic
Object, pigment and peculiar smell have good removal ability.Decolourize the ultrafiltration membrance filter that concentrate molecular cut off is 4000~8000D
Afterwards, pyrogen, the bacterial endotoxin etc. in medical fluid can be effectively removed, medicine inspection criterion of acceptability is reached.Hyperfiltration membrane assembly is excellent
The type of choosing is any one of doughnut, plate membrane, rolled film.Compared to traditional way of distillation, absorption method and heat damage
The methods of, nanofiltration membrane and ultrafiltration membrane treatment method have obviously in terms for the treatment of effect, reduction energy consumption and reduction
Advantage.
After two streamings of dihydrostreptomycin sulfate finished product concentrate or three streaming air-current atomising devices are spray-dried by step k,
The dihydrostreptomycin sulfate finished product of final obtained white powder, product impurity content are substantially reduced, dihydrostreptomycin sulfate salt
Purity can reach 97% or more level, be significantly higher than 95% professional standard, and quality is stablized, product qualification rate is
100%.Final products total recovery can reach 70~75% level, and the product compared to conventional preparation techniques 60% or so is total
Yield is significantly improved.
Specific embodiment
Here is certain specific embodiments of the invention, to invention is further described in detail, but not with
This limits protection scope of the present invention.
A kind of preparation method of dihydrostreptomycin sulfate of the invention, specific implementation step are as follows:
A. 6~16kg/m is pressed3Ratio oxalic acid is added in streptomycin fermentation liquid, then with sulphur acid for adjusting pH to 2.5~
3.5,60~85 DEG C are heated to, then by centrifugation or filtering removal insoluble matter, then adjust pH to 7.0~8.5 with sodium hydroxide,
Streptomysin stoste is made；
B. by after streptomysin stoste 110 resin of sodium form, D152 resin or D150 resin adsorption saturation, with soft water, salt-free
Water or purifying water washing, then eluted with 5.0~6.5% dilute sulfuric acid, streptomycin sulphate eluent is made；
C. by after the macropore primary amine groups resin D303 adsorption saturation of streptomysin eluent, with salt-free water or water washing is purified simultaneously
It press dry, then recycles parsing with 7.0~9.0% dilute sulfuric acid, streptomycin sulphate desorbed solution is made；
D. after streptomycin sulphate desorbed solution being adjusted pH to 6.5~8.0 with sodium hydroxide, according to 5.0~8.0g/, hundred million unit
Ratio reducing agent potassium borohydride or sodium borohydride is added, then with sulphur acid for adjusting pH to 7.0~7.5, streptomycin sulphate is made
Hydride.The sodium hydroxide of 0.05~2.0g/ml, hydroxide are dissolved in for 10~15% by mass volume ratio before reducing agent addition
In potassium or ammonia spirit.
E. by after streptomycin sulphate hydride 110 resin of sodium form, D152 resin or D150 resin adsorption saturation, use is soft
Water, salt-free water or purifying water washing, then eluted with 5.0~6.5% dilute sulfuric acid, dihydrostreptomycin sulfate eluent is made；
F. dihydrostreptomycin sulfate eluent forward direction is passed through 2~4 concatenated Hydrogen mixed-bed ion exchange resins, mixed
It closes bed ion exchange resin to use, dihydrostreptomycin sulfate is made and purifies liquid；The mixed-bed ion exchange resin is by 1 × 25 tree
Any one of rouge, 1 × 16 resin or 1 × 14 resin are that 1:0.3~1 mixes composition with 703 resins by volume.
G. after dihydrostreptomycin sulfate purification liquid being adjusted pH to 4.0~6.0 with calcium hydroxide, mass volume ratio, which is added, is
0.5~2.0% injection active carbon, gained filtrate is liquid after dihydrostreptomycin sulfate filter after filtering；
H. the nanofiltration membrane concentration that liquid molecular cut off is 300~500D or 150D after dihydrostreptomycin sulfate being filtered is made
Dihydrostreptomycin sulfate concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 1.0~5.0%, mistake is added
Gained filtrate is dihydrostreptomycin sulfate decoloration concentrate after filter；
J. the ultrafiltration membrance filter for being 4000~8000D by dihydrostreptomycin sulfate decoloration concentrate molecular cut off, system
Obtain dihydrostreptomycin sulfate finished product concentrate；The ultrafiltration membrane is any one of doughnut, plate membrane or rolled film.
K. dihydrostreptomycin sulfate finished product concentrate is sprayed with two streaming air-current atomising devices or three streaming air-current atomising devices
It is dry, dihydrostreptomycin sulfate finished powder is made.
Embodiment 1
A kind of preparation method of dihydrostreptomycin sulfate of the present embodiment, specific implementation step are as follows:
A. 6kg/m is pressed3Ratio by oxalic acid be added streptomycin fermentation liquid in, then with sulphur acid for adjusting pH to 2.5, be heated to
60 DEG C, then by centrifugation or filtering removal insoluble matter, then adjust pH to 7.0 with sodium hydroxide, streptomysin stoste is made；
B. by streptomysin stoste with 110 resin adsorption of sodium form be saturated after, washed and pressed dry with soft water, then with 5.0% it is dilute
Sulfuric acid elution, is made streptomycin sulphate eluent；
C. by after macropore primary amine groups resin D303 or the D318 adsorption saturation of streptomysin eluent, with purifying water washing, then
Parsing is recycled with 8.0% dilute sulfuric acid, streptomycin sulphate desorbed solution is made；
D. it after streptomycin sulphate desorbed solution being adjusted pH to 6.5 with sodium hydroxide, is added according to the ratio of hundred million unit of 5.0g/
Reducing agent potassium borohydride, reducing agent are first dissolved in 0.05% sodium hydroxide solution by mass volume ratio for 10% before being added,
Then with sulphur acid for adjusting pH to 7.0, streptomycin sulphate hydride is made；
E. after streptomycin sulphate hydride being saturated with sodium form D152 resin adsorption, with salt-free water washing, then with 5.5%
Dilute sulfuric acid elution, is made dihydrostreptomycin sulfate eluent；
F. dihydrostreptomycin sulfate eluent forward direction is passed through two concatenated Hydrogen mixed-bed ion exchange resins, be made
Dihydrostreptomycin sulfate purifies liquid；The mixed-bed ion exchange resin is by 1 × 25 resin and 703 resins 1:0.3 by volume
Mixing composition；
G. after dihydrostreptomycin sulfate purification liquid being adjusted pH to 4.0 with calcium hydroxide, it is 0.5% that mass volume ratio, which is added,
Injection active carbon, after filtering gained filtrate be dihydrostreptomycin sulfate filter after liquid；
H. liquid is concentrated with the nanofiltration membrane that molecular cut off is 150D after dihydrostreptomycin sulfate being filtered is made the double hydrogen chains of sulfuric acid
Mycin concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 1.0%, institute after filtering is added
Obtaining filtrate is dihydrostreptomycin sulfate decoloration concentrate；
J. dihydrostreptomycin sulfate decoloration concentrate is filtered with the hollow fiber ultrafiltration membrane that molecular cut off is 4000D,
Dihydrostreptomycin sulfate finished product concentrate is made.
K. two streaming air-current atomising devices of dihydrostreptomycin sulfate finished product concentrate are spray-dried, the double hydrogen chains of sulfuric acid is made
Mycin finished powder.
Embodiment 2
A kind of preparation method of dihydrostreptomycin sulfate of the present embodiment, specific implementation step are as follows:
A. 16kg/m is pressed3Ratio oxalic acid is added in streptomycin fermentation liquid, then with sulphur acid for adjusting pH to 3.5, heating
To 85 DEG C, then by centrifugation or filtering removal insoluble matter, pH to 8.5 then is adjusted with sodium hydroxide, streptomysin stoste is made；
B. after streptomysin stoste being saturated with sodium form D152 resin adsorption, with salt-free water washing, with 5.0% dilute sulfuric acid dip
It is de-, streptomycin sulphate eluent is made；
C. it after streptomysin eluent being saturated with macropore primary amine groups resin D318 resin adsorption, with salt-free water washing and presses
It is dry, then parsing is recycled with 6.0% dilute sulfuric acid, streptomycin sulphate desorbed solution is made；
D. it after streptomycin sulphate desorbed solution being adjusted pH to 8.0 with sodium hydroxide, is added according to the ratio of hundred million unit of 6.0g/
Reducing agent sodium borohydride, reducing agent are first dissolved in 2.0% potassium hydroxide solution by mass volume ratio for 15% before being added, so
Afterwards with sulphur acid for adjusting pH to 7.5, streptomycin sulphate hydride is made；
E. after streptomycin sulphate hydride being saturated with sodium form D150 resin adsorption, with purifying water washing, then with 8.5%
Dilute sulfuric acid elution, is made dihydrostreptomycin sulfate eluent；
F. dihydrostreptomycin sulfate eluent forward direction is passed through three concatenated Hydrogen mixed-bed ion exchange resins, be made
Dihydrostreptomycin sulfate purifies liquid；1:1 is mixed by volume by 1 × 16 resin and 703 resins for the mixed-bed ion exchange resin
It is combined into；
G. after dihydrostreptomycin sulfate purification liquid being adjusted pH to 6.0 with calcium hydroxide, it is 2.0% that mass volume ratio, which is added,
Injection active carbon, after filtering gained filtrate be dihydrostreptomycin sulfate filter after liquid；
H. the nanofiltration membrane that liquid molecular cut off is 300~500D after dihydrostreptomycin sulfate being filtered, which is concentrated, is made sulfuric acid pair
Hydrogen streptomysin concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 5.0%, institute after filtering is added
Obtaining filtrate is dihydrostreptomycin sulfate decoloration concentrate；
J. dihydrostreptomycin sulfate decoloration concentrate is filtered with the flat plate ultrafiltration membrane that molecular cut off is 8000D, is made
Dihydrostreptomycin sulfate finished product concentrate；
K. three streaming air-current atomising devices of dihydrostreptomycin sulfate finished product concentrate are spray-dried, the double hydrogen chains of sulfuric acid is made
Mycin finished powder.
Embodiment 3
A kind of preparation method of dihydrostreptomycin sulfate of the present embodiment, specific implementation step are as follows:
A. 9kg/m is pressed3Ratio by oxalic acid be added streptomycin fermentation liquid in, then with sulphur acid for adjusting pH to 3.0, be heated to
75 DEG C, then by centrifugation or filtering removal insoluble matter, then adjust pH to 8.0 with sodium hydroxide, streptomysin stoste is made；
B. after streptomysin stoste being saturated with sodium form D150 resin adsorption, with purifying water washing, then with 6.0% dilute sulfuric acid
Streptomycin sulphate eluent is made in elution；
C. it by after the macropore primary amine groups resin D303 adsorption saturation of streptomysin eluent, with salt-free water washing and press dry, then
Parsing is recycled with 7.0% dilute sulfuric acid, streptomycin sulphate desorbed solution is made；
D. it after streptomycin sulphate desorbed solution being adjusted pH to 7.0 with sodium hydroxide, is added according to the ratio of hundred million unit of 7.0g/
Reducing agent potassium borohydride, reducing agent are first dissolved in 1.5% ammonia spirit for 12% by mass volume ratio before being added, are then used
Streptomycin sulphate hydride is made to 7.2 in sulphur acid for adjusting pH.
E. after streptomycin sulphate hydride being saturated with 110 resin adsorption of sodium form, with purifying water washing, then with 6.5%
Dilute sulfuric acid elution, is made dihydrostreptomycin sulfate eluent；
F. dihydrostreptomycin sulfate eluent forward direction is passed through four concatenated Hydrogen mixed-bed ion exchange resins, be made
Dihydrostreptomycin sulfate purifies liquid；The mixed-bed ion exchange resin is by 1 × 14 resin and 703 resins 1:0.5 by volume
Mixing composition；
G. after dihydrostreptomycin sulfate purification liquid being adjusted pH to 5.0 with calcium hydroxide, it is 1.0% that mass volume ratio, which is added,
Injection active carbon, after filtering gained filtrate be dihydrostreptomycin sulfate filter after liquid；
H. liquid is concentrated with the nanofiltration membrane that molecular cut off is 150D after dihydrostreptomycin sulfate being filtered is made the double hydrogen chains of sulfuric acid
Mycin concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 2.0%, institute after filtering is added
Obtaining filtrate is dihydrostreptomycin sulfate decoloration concentrate；
J. dihydrostreptomycin sulfate decoloration concentrate is filtered with the rolling ultrafiltration membrane that molecular cut off is 6000D, is made
Dihydrostreptomycin sulfate finished product concentrate；
K. two streaming air-current atomising devices of dihydrostreptomycin sulfate finished product concentrate are spray-dried, the double hydrogen chains of sulfuric acid is made
Mycin finished powder.
Embodiment 4
A kind of preparation method of dihydrostreptomycin sulfate of the present embodiment, specific implementation step are as follows:
A. 13kg/m is pressed3Ratio oxalic acid is added in streptomycin fermentation liquid, then with sulphur acid for adjusting pH to 3.0, heating
To 68 DEG C, then by centrifugation or filtering removal insoluble matter, pH to 7.5 then is adjusted with sodium hydroxide, streptomysin stoste is made；
B. it after streptomysin stoste being saturated with sodium form D152 resin adsorption, is washed with soft water, with 5.5% dilute sulfuric acid dip
It is de-, streptomycin sulphate eluent is made；
C. it by after the macropore primary amine groups resin D318 adsorption saturation of streptomysin eluent, with purifying water washing and press dry, then
Parsing is recycled with 9.0% dilute sulfuric acid, streptomycin sulphate desorbed solution is made；
D. it after streptomycin sulphate desorbed solution being adjusted pH to 7.0 with sodium hydroxide, is added according to the ratio of hundred million unit of 8.0g/
Reducing agent sodium borohydride, reducing agent are first dissolved in 1.0% sodium hydroxide solution by mass volume ratio for 14% before being added, so
Afterwards with sulphur acid for adjusting pH to 7.4, streptomycin sulphate hydride is made；
E. by streptomycin sulphate hydride with sodium form D152 resin adsorption be saturated after, washed with soft water, then with 6.0% it is dilute
Sulfuric acid elution, is made dihydrostreptomycin sulfate eluent；
F. dihydrostreptomycin sulfate eluent forward direction is passed through two concatenated Hydrogen mixed-bed ion exchange resins, be made
Dihydrostreptomycin sulfate purifies liquid；The mixed-bed ion exchange resin is by 1 × 25 resin and 703 resins 1:0.7 by volume
Mixing composition.
G. after dihydrostreptomycin sulfate purification liquid being adjusted pH to 5.5 with calcium hydroxide, it is 1.5% that mass volume ratio, which is added,
Injection active carbon, after filtering gained filtrate be dihydrostreptomycin sulfate filter after liquid；
H. the nanofiltration membrane that liquid molecular cut off is 300~500D after dihydrostreptomycin sulfate being filtered, which is concentrated, is made sulfuric acid pair
Hydrogen streptomysin concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 3.5%, institute after filtering is added
Obtaining filtrate is dihydrostreptomycin sulfate decoloration concentrate；
J. dihydrostreptomycin sulfate decoloration concentrate is filtered with the hollow fiber ultrafiltration membrane that molecular cut off is 5000D,
Dihydrostreptomycin sulfate finished product concentrate is made；
K. three streaming air-current atomising devices of dihydrostreptomycin sulfate finished product concentrate are spray-dried, the double hydrogen chains of sulfuric acid is made
Mycin finished powder.
In order to preferably verify feasibility and superiority of the invention, inventor is according to preparation described in Examples 1 to 4
Method and corresponding technological parameter are prepared for dihydrostreptomycin sulfate finished powder by raw material actual production of streptomycin fermentation liquid,
And sample detection is carried out to some committed steps during the preparation process.The body of streptomycin fermentation liquid used in Examples 1 to 4
Product, potency and total hundred million data and intermediate steps and the detection data of final products are as shown in Table 1 below.
Table 1
It can be seen that using the preparation method of dihydrostreptomycin sulfate provided by the invention, the double hydrogen chains of sulfuric acid produced
Mycin finished product powder purity can reach 97% or more level, average value 97.5%, significantly larger than industry quality standard regulation
Be not less than 95% requirement.And according to the Testing index of intermediate steps crucial in table 1 it can also be seen that the present invention can be bright
It is aobvious to improve pretreatment yield (average 98.9%) and hydrogenation conversion ratio (average 99.77%), reduce purification process
Content of ashes, each one-step reaction index can reach the requirement of professional standard.And the present invention can be such that product yield also obtains
It to raising, in Examples 1 to 4, is pre-processed from initial streptomycin fermentation liquid, to finally obtained dihydrostreptomycin sulfate finished product
The total recovery of powder, whole preparation process is not less than 71.8%, and average total recovery can reach 73.7% level, compared to biography
The total yield of products of system preparation process 60% or so has apparent improvement.
Claims (10)
1. a kind of preparation method of dihydrostreptomycin sulfate, it is characterised in that include the following steps:
A. after streptomycin fermentation liquid being carried out sour processing, 60~85 DEG C are heated to, then by centrifugation or filtering removal insoluble matter, so
PH to 7.0~8.5 is adjusted with sodium hydroxide afterwards, streptomysin stoste is made；
B. by after the weak-acid cation-exchange resin adsorption saturation of streptomysin stoste, with soft water, salt-free water or water washing is purified,
It is eluted again with dilute sulfuric acid, streptomycin sulphate eluent is made；
C. it after streptomycin sulphate eluent being saturated with macropore primary amine groups resin adsorption, with salt-free water or purifying water washing and presses
It is dry, then recycled and parsed with dilute sulfuric acid, streptomycin sulphate desorbed solution is made；
D. after streptomycin sulphate desorbed solution being adjusted pH to 6.5~8.0 with sodium hydroxide, reducing agent is added, then adjusted with sulfuric acid
Streptomycin sulphate hydride is made in pH to 7.0~7.5；
E. by after the weak-acid cation-exchange resin adsorption saturation of streptomycin sulphate hydride, with soft water, salt-free water or purifying
Water washing, then eluted with dilute sulfuric acid, dihydrostreptomycin sulfate eluent is made；
F. dihydrostreptomycin sulfate eluent forward direction is passed through mixed-bed ion exchange resin, dihydrostreptomycin sulfate purification is made
Liquid；
G. after dihydrostreptomycin sulfate purification liquid being adjusted pH to 4.0~6.0 with calcium hydroxide, it is 0.5 that mass volume ratio, which is added,
~2.0% injection active carbon, gained filtrate is liquid after dihydrostreptomycin sulfate filter after filtering；
H. liquid nanofiltration membrane, which is concentrated, after dihydrostreptomycin sulfate being filtered is made dihydrostreptomycin sulfate concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 1.0~5.0% is added, after filtering
Gained filtrate is dihydrostreptomycin sulfate decoloration concentrate；
J. the ultrafiltration membrance filter for being 4000~8000D by dihydrostreptomycin sulfate decoloration concentrate molecular cut off, is made sulphur
Pantostrep finished product concentrate；
K. dihydrostreptomycin sulfate finished product concentrate is spray-dried, dihydrostreptomycin sulfate finished powder is made.
2. a kind of preparation method of dihydrostreptomycin sulfate according to claim 1, it is characterised in that: in step a at acid
Reason is by 6~16kg/m3Ratio oxalic acid is added in streptomycin fermentation liquid, then with sulphur acid for adjusting pH to 2.5~3.5.
3. a kind of preparation method of dihydrostreptomycin sulfate according to claim 1, it is characterised in that: the faintly acid sun
Ion exchange resin is carboxylic acid type cation exchange resin, and is sodium form；The macropore primary amine groups resin is D303 or D318 tree
Rouge.
4. a kind of preparation method of dihydrostreptomycin sulfate according to claim 3, it is characterised in that: the carboxylic acid type from
Sub-exchange resin is any one of 110 resins, D152 resin or D150 resin.
5. a kind of preparation method of dihydrostreptomycin sulfate according to claim 1, it is characterised in that: institute in step b and e
The concentration for stating dilute sulfuric acid is 5.0~6.5%, and the concentration of dilute sulfuric acid described in step c is 7.0~9.0%.
6. a kind of preparation method of dihydrostreptomycin sulfate according to claim 1, it is characterised in that: described in step d
Reducing agent is potassium borohydride or sodium borohydride, and additional proportion is 5.0~8.0g/, hundred million unit, and pre reduction agent is added and presses quality volume
Than being dissolved in the sodium hydroxide, potassium hydroxide or ammonia spirit of 0.05~2.0g/ml for 10~15%.
7. a kind of preparation method of dihydrostreptomycin sulfate according to claim 1, it is characterised in that: the mixed bed from
Sub-exchange resin is Hydrogen, by volume by high-crosslinking-degree storng-acid cation exchange resin and weak-base anion-exchange resin
It mixes and forms for 1:0.3~1.
8. a kind of preparation method of dihydrostreptomycin sulfate according to claim 7, it is characterised in that: the mixed bed from
The usage mode of sub-exchange resin be 2~4 mixed-bed ion exchange resins be used in series, the high-crosslinking-degree highly acid sun from
Sub-exchange resin is any one of 1 × 25 resin, 1 × 16 resin or 1 × 14 resin, and weak-base anion-exchange resin is
703 resins.
9. a kind of preparation method of dihydrostreptomycin sulfate according to claim 1, it is characterised in that: the nanofiltration membrane
Molecular cut off is 300~500D or 150D, and the ultrafiltration membrane is any one of doughnut, plate membrane or rolled film.
10. a kind of preparation method of dihydrostreptomycin sulfate according to claim 1, it is characterised in that: described spraying dry
It is dry to use two streaming air-current atomising devices or three streaming air-current atomising devices.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB651832A (en) * | 1946-02-15 | 1951-04-11 | Merck & Co Inc | Process for preparing dihydrostreptomycin and acid salts thereof |
| RO114896B1 (en) * | 1996-01-11 | 1999-08-30 | Vlase Cristina Victorina | Process for preparing dihydrostreptomycin for pharmaceutical use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB651832A (en) * | 1946-02-15 | 1951-04-11 | Merck & Co Inc | Process for preparing dihydrostreptomycin and acid salts thereof |
| RO114896B1 (en) * | 1996-01-11 | 1999-08-30 | Vlase Cristina Victorina | Process for preparing dihydrostreptomycin for pharmaceutical use |
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| Title |
|---|
| 提高硫酸双氢链霉素产品质量的研究;严希康 等;《上海食品药品监管情报研究》;20060930(第82期);第30-33页 |
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