CN106928288A - A kind of preparation method of dihydrostreptomycin sulfate - Google Patents
A kind of preparation method of dihydrostreptomycin sulfate Download PDFInfo
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- CN106928288A CN106928288A CN201710169961.9A CN201710169961A CN106928288A CN 106928288 A CN106928288 A CN 106928288A CN 201710169961 A CN201710169961 A CN 201710169961A CN 106928288 A CN106928288 A CN 106928288A
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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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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention discloses a kind of preparation method of dihydrostreptomycin sulfate, belong to the process for producing of semisynthetic antibiotics, including acid treatment, ion exchange, macropore primary amine resins are adsorbed, hydrogenation, Two-step ion-exchanging, mixed bed is purified, activated carbon treatment, NF membrane is concentrated, activated carbon decolorizing, 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 need for industrialized production being met well, improve the product purity of dihydrostreptomycin sulfate, up-to-standard 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, category
In the process for producing of semisynthetic antibiotics.
Background technology
Streptomysin (Streptomycin) is that Sai Erman Waksmans divide in nineteen forty-four from streptomyces griseus nutrient solution
A kind of alkaline antibiotic for coming is separated out, with anti-binding bacillus characteristic, also can be used as bactericide in veterinary drug and agricultural chemicals.Its molecule
Structure is connected with glycosidic bond with the part of N- methyl-L- gucosamines three by streptidine, streptose and formed, and molecular formula is
C21H39N7O12.It by the aldehyde radical hydrogenating reduction of streptomysin is alcoholic extract hydroxyl group that dihydrostreptomycin sulfate is, and is translated into sulfate shape
Formula, can well overcome the problem of streptomysin stability difference, and its antimicrobial spectrum is similar with streptomysin.
Dihydrostreptomycin can be produced by wet streptomycete direct fermentation, but due to being free of aldehyde radical, therefore nothing in dihydrostreptomycin
Method carries out absorption purification by macropore primary amine groups resin or D401 chelating resins, causes product purity to be difficult to improve.It is general at present
All over using semi-synthesis method to prepare dihydrostreptomycin, that is, first pass through streptomycete fermentation and obtain streptomysin, then by aldehyde radical therein
Reduced, the main restoring method for using has hydrogen catalytic reaction method, electrolytic reduction and reduction-state hydrogen reduction method.Wherein,
Hydrogen catalytic method must be carried out in high temperature, high pressure and under conditions of having catalyst, higher to equipment requirement, prepare difficulty also larger.
Electrolytic reduction is that streptomysin is placed in cathode can, and reduction is played by being subject to appropriate electric current, but the method needs consumption
Substantial amounts of electric energy, and reaction efficiency is relatively low.
Reduction-state hydrogen reduction method production dihydrostreptomycin can be carried out at normal temperatures and pressures, but existing preparation technology is universal
There are problems that oxalic acid consumption is high, reducing agent utilization rate is low, product purity is poor, qualification rate is low and quality.
The content of the invention
The technical problem to be solved in the invention is to provide a kind of preparation method of dihydrostreptomycin sulfate, can be in normal temperature
Reacted under normal pressure, reduce consumption of oxalic acid, reduce production cost, improve reducing agent utilization rate and production efficiency, and can reached very high
Product purity, up-to-standard rate and total recovery.
In order to solve the above technical problems, the technical solution adopted in the present invention is：
There is provided a kind of preparation method of dihydrostreptomycin sulfate, comprise the following steps：
A. after streptomycin fermentation liquid being carried out into acid treatment, 60~85 DEG C are heated to, then it is insoluble by being centrifuged or filtering removal
Thing, then adjusts pH to 7.0~8.5 with NaOH, and streptomysin stoste is obtained；
B. by streptomysin stoste with weak-acid cation-exchange resin adsorption saturation after, with soft water, salt-free water or purified water
Washing, then eluted with dilute sulfuric acid, streptomycin sulphate eluent is obtained；
C. by streptomysin eluent with macropore primary amine groups resin adsorption saturation after, water washing and pressed with salt-free water or purifying
It is dry, then parsing is circulated with dilute sulfuric acid, streptomycin sulphate desorbed solution is obtained；
D. after streptomycin sulphate desorbed solution being adjusted into pH to 6.5~8.0 with NaOH, reducing agent is added, then use sulfuric acid
PH is to 7.0~7.5 for regulation, and streptomycin sulphate hydride is obtained；
E. by streptomycin sulphate hydride with weak-acid cation-exchange resin adsorption saturation after, with soft water, salt-free water or
Purifying water washing, then eluted with dilute sulfuric acid, dihydrostreptomycin sulfate eluent is obtained；
F. dihydrostreptomycin sulfate eluent forward direction is passed through mixed-bed ion exchange resin, dihydrostreptomycin sulfate is obtained
Purification liquid；
G. after dihydrostreptomycin sulfate purification liquid being adjusted into pH to 4.0~6.0 with calcium hydroxide, addition mass volume ratio is
0.5~2.0% injection active carbon, gained filtrate is liquid after dihydrostreptomycin sulfate filter after filtering；
H. the concentration of liquid NF membrane is obtained dihydrostreptomycin sulfate concentrate after dihydrostreptomycin sulfate is filtered；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 1.0~5.0%, mistake are added
Gained filtrate is dihydrostreptomycin sulfate decolouring concentrate after filter；
J. by the ultrafiltration membrance filter that dihydrostreptomycin sulfate decolouring concentrate molecular cut off is 4000~8000D, system
Obtain dihydrostreptomycin sulfate finished product concentrate；
K. dihydrostreptomycin sulfate finished product concentrate is spray-dried, dihydrostreptomycin sulfate finished powder is obtained.
Technical solution of the present invention further improvement is that：Acid treatment is by 6~16kg/m in step a3Ratio by grass
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 resins.
Technical solution of the present invention further improvement is that：The concentration of the dilute sulfuric acid is 5.0~10.0%, the weak acid
Property cationic ion-exchange resin be carboxylic acid type cation exchange resin, and be sodium form.
Technical solution of the present invention further improvement is that：The carboxylic acid type ion exchange resin is 110 resins, D152 trees
Any one in fat or D150 resins.
Technical solution of the present invention further improvement is 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 is that：Reducing agent described in step d be potassium borohydride or sodium borohydride,
Additional proportion is the units of 5.0~8.0g/ hundred million, add pre reduction agent be dissolved in 0.05 for 10~15% by mass volume ratio~
In the NaOH of 2.0g/ml, potassium hydroxide or ammonia spirit.
Technical solution of the present invention further improvement is that：The mixed-bed ion exchange resin is Hydrogen, is crosslinked by height
Degree storng-acid cation exchange resin and weak-base anion-exchange resin are by volume 1:0.3~1 mixing composition.
Technical solution of the present invention further improvement is that：The occupation mode of the mixed-bed ion exchange resin is 2~4
Individual 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 in 16 resins or 1 × 14 resin, weak-base anion-exchange resin is 703 resins.
Technical solution of the present invention further improvement is that：The nanofiltration retaining molecular weight is 300~500D or 150D,
The milipore filter is any one in doughnut, Flat Membrane or rolled film.
Technical solution of the present invention further improvement is that：The spray drying is using two streaming air-current atomising devices or three streams
Formula air-current atomising device.
By adopting the above-described technical solution, the technological progress that the present invention is obtained is：
The present invention goes the removal of impurity to be reduced to streptomysin again after disturbing as far as possible first by streptomysin preliminary purification, improves
Reducing agent utilization rate, the process for isolating and purifying is coordinated jointly using different kinds of ions exchanger resin and filter membrane, progressively removes the removal of impurity, color
Element, bacterial endotoxin and pyrogen etc., with reactions steps it is reasonable, easy to operate, repeatable recycle and energy-conserving and environment-protective
Feature, the need for can meeting industrialized production well, and is finally obtained high-purity, qualification rate high and high-quality stability
Dihydrostreptomycin sulfate product, can at normal temperatures and pressures react, 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.
Precipitation is generated using only the calcium ions and magnesium ions in a small amount of oxalic acid and zymotic fluid in step a of the present invention, regulation pH mainly leads to
Persulfuric acid is because sulfuric acid is lower than oxalic acid price and acid stronger therefore common to zymotic fluid using the two kinds of acid of oxalic acid and sulfuric acid
It is acidified, a large amount of oxalic acid can be saved, is reduced acidifying cost.After being adjusted to pH 2.5~3.5 and be heated to 60~85 DEG C, can
The impurity such as the acidic protein in zymotic fluid are condensed, and streptomysin activity will not be destroyed, then by centrifugation or plate-frame filtering,
The solid suspension that effectively can remain in removal zymotic fluid, insoluble mycelia, culture based draff and other are various insoluble
Impurity.The supernatant after the clarified solution after filtering or centrifugation is finally neutralized to pH7.0~8.5 with NaOH, makes cation
Exchanger resin absorption reaches more preferable effect.
The carboxylic acid type cation exchange resin used in step b of the present invention can be effectively adsorbed in the streptomysin point of alkalescence
Son, resin uses sodium form, the one kind in preferably 110 resins, D152 resins or D150 resins, 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, can effectively to strepto-
Element carries out enrichment method, and concentration can improve 15~20 times after wash-out.Streptomysin turns into the form of sulfate after wash-out, and property is more
Stabilization.
Used in step c first carries out absorption purification by streptomysin eluent with macropore primary amine groups resin D303 or D318, then
The method that aldehyde radical therein is reduced with reducing agent, can effectively improve product purity, and reduce the use of reducing agent.Macropore
Primary amine groups resin can occur schiff base reaction with the streptomysin containing aldehyde radical in streptomysin eluent, and selective suction is carried out to it
It is attached, but can not be reacted with other impurity without aldehyde radical, such as streptamine, streptidine, double hydrogen streptoses, so that can not be inhaled
Attached impurity is passed through, and is reached and is effectively gone deimpurity effect.And if before reduction step is advanceed into adsorption step, not only can
Reducing agent is wasted, and due to being free of aldehyde radical in the dihydrostreptomycin after reduction, then cannot be by macropore primary amine groups resin adsorption.
Washing uses salt-free water or purified water, without using soft water, prevents the sodium ion contained in soft water from influenceing macropore primary amine groups resin
Adsorption effect.
The reducing agent sodium borohydride that is used in step d or potassium borohydride to the hydrogenation effect of streptomycin sulphate desorbed solution very
Good, the conversion ratio of reaction is very high, can reach the level for being not less than 99.5%.And concentration above and purification step reducing agent
Utilization rate be further enhanced, reduce the waste of reducing agent, addition of the reducing agent in streptomycin sulphate desorbed solution
The units of only 5.0~8.0g/ hundred million.Sodium borohydride or the potassium borohydride property in alkaline solution are more stablized, therefore using preceding
It is first 10~15% to be dissolved in the NaOH of 0.05~2.0g/ml, potassium hydroxide or ammonia spirit by mass volume ratio, energy
It is hydrolyzed enough preferably to play a part of suppression.Reaction reduction effect when pH scopes are 6.5~8.0 is optimal.
Step e of the invention carries out secondary ion exchange by streptomycin sulphate hydride, has reached separation and has gone
Except the purpose of the foreign ion of introducing in step of hydrogenation.Streptomycin sulphate hydride sulphur acid for adjusting pH is adsorbed to when 7.0~7.5
Preferably, the carboxylic acid type resin cation of the sodium form for being used is preferably appointing in 110 resins, D152 resins or D150 resins to effect
One kind, can effectively be adsorbed to dihydrostreptomycin sulfate, with appropriate soft water, salt-free water or purifying washing after the completion of absorption
Resin is washed, then dihydrostreptomycin sulfate is eluted from resin with dilute sulfuric acid, that is, purified.
The present invention is adjusted using parsing agent, cationic ion-exchange resin regenerative agent and acid pH carried out by dilute sulfuric acid rather than watery hydrochloric acid
Section agent, to prevent from introducing chloride ion impurities in system, it is to avoid portioned product with residual chlorion generation streptomycin hydrochloride or
The adverse effect that dihydrostreptomycin hydrochloride brings to sulfuric acid purity salt and yield.Different resins is wherein directed to, in step b and e
Preferably, in the circulation parsing of step c, the concentration of dilute sulfuric acid is preferably wash-out effect when middle dilute sulfuric acid concentration is 5.0~6.5%
7.0~9.0%.
Step f further removes salt refining, sulphur by the mixed-bed ion exchange resin of Hydrogen to streptomycin sulphate eluent
The direction that Pantostrep eluent is passed through mixed-bed ion exchange resin is forward direction, it is to avoid the zwitterion for mixing
There is lamination in 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, reaches cation and anion exchange while the effect for carrying out, and reaction efficiency is high.High-crosslinking-degree strong acid
Property cationic ion-exchange resin be preferably in 1 × 25 resin, 1 × 16 resin or 1 × 14 resin any one, weakly-basic anion is handed over
Change resin and be preferably 703 resins.Mixed bed goes out to purify liquid two more important indexs, i.e. ash content and pH, generally,
After pH specifies less than standard, bed also has certain desalination ability, and the present invention uses 2~4 purifying techniques of mixed beds series connection,
The ion exchange resin in mixed bed can be made full use of, the utilization rate of mixed bed is improved, it helps improve product quality.It is high
Degree of cross linking storng-acid cation exchange resin and weak-base anion-exchange resin are by volume 1 in exchanger:0.3~1 mixes
It is optimum proportioning during conjunction, two kinds of comprehensive utilization ratio highests of resin can thoroughly adsorb the foreign ion of remaining in eluent
Removal, water outlet desalination rate is 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 lived
Property charcoal has that aseptic, tasteless, non-toxic, purity is high, decolouring is fast, absorption affinity is strong and steady performance.And injection is lived
Property charcoal can at low temperature play good absorption property, it is to avoid heating is produced to the double hydrogen strepto-s activity of sulfuric acid of non-refractory
Harmful effect, also prevent the liquid that causes of heating and darkens, and increase the problem of decolorising agent consumption, 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 alkalescence condition
Lower impurity content increases, and influences the quality of the pharmaceutical preparations.The present invention adjusts pH and can play neutralization free acid well using calcium hydroxide
Effect, and remove acid ion, and use cost is lower.Injection active carbon is suitable for continuous processing, and treatment behaviour
Make simple, the present invention is processed with injection active carbon respectively before and after NF membrane concentration step, injection active carbon mass volume ratio point
Not Wei 0.5~2.0% and 1.0~5.0% when, can fully adsorb the impurity and pigment in liquid, further improve product it is pure
Degree and color level, liquid light transmittance can reach more than 95% after treatment.The NF membrane and ultrafiltration filter membrane that the present invention is used are recycled
Use, reduce the use cost of film, and by effective treatment of previous step, impurity is considerably less in liquid, to filter membrane
Pollution is extremely low.
Liquid is 300~500D by molecular cut off or the NF membrane of 150D after the present invention filters dihydrostreptomycin sulfate
Afterwards, it can be concentrated and is purified, it is organic higher than molecular cut off for ion and molecular weight more than wherein divalence
Thing, pigment and peculiar smell have good removal ability.Decolouring concentrate molecular cut off is the ultrafiltration membrance filter of 4000~8000D
Afterwards, pyrogen, bacterial endotoxin in liquid etc. can be effectively removed, medicine inspection criterion of acceptability is reached.Hyperfiltration membrane assembly is excellent
The type of choosing is any one in doughnut, Flat Membrane, rolled film.Compared to traditional way of distillation, absorption method and heat damage
Etc. method, NF membrane and ultrafiltration membrane treatment method have substantially at aspects such as treatment effect, reduction energy consumption and reduction operation complexities
Advantage.
After with two streamings or three streaming air-current atomising devices be spray-dried dihydrostreptomycin sulfate finished product concentrate by step k,
The dihydrostreptomycin sulfate finished product of final prepared white powder, product impurity content is substantially reduced, dihydrostreptomycin sulfate salt
Purity can reach more than 97% level, be significantly higher than 95% professional standard, and steady quality, product percent of pass 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, is used to be described in further detail the present invention, but not with
This is limited protection scope of the present invention.
A kind of preparation method of dihydrostreptomycin sulfate of the invention, its specific implementation step is as follows：
A. 6~16kg/m is pressed3Ratio by oxalic acid add streptomycin fermentation liquid in, then with sulphur acid for adjusting pH to 2.5~
3.5,60~85 DEG C are heated to, then by being centrifuged or filtering removal insoluble matter, pH then is adjusted to 7.0~8.5 with NaOH,
Streptomysin stoste is obtained；
B. by the streptomysin stoste resin of sodium form 110, D152 resins or D150 resin adsorption saturations after, with soft water, salt-free
Water or purifying water washing, then eluted with 5.0~6.5% dilute sulfuric acid, prepared streptomycin sulphate eluent；
C. by streptomysin eluent with macropore primary amine groups resin D303 adsorption saturations after, with salt-free water or purifying water washing simultaneously
Press dry, then parsing is circulated with 7.0~9.0% dilute sulfuric acid, streptomycin sulphate desorbed solution is obtained；
D. after streptomycin sulphate desorbed solution being adjusted into pH to 6.5~8.0 with NaOH, according to the units of 5.0~8.0g/ hundred million
Ratio add reducing agent potassium borohydride or sodium borohydride, then with sulphur acid for adjusting pH to 7.0~7.5, be obtained streptomycin sulphate
Hydride.Reducing agent by mass volume ratio is 10~15% to be dissolved in the NaOH of 0.05~2.0g/ml, hydroxide before adding
In potassium or ammonia spirit.
E. by the streptomycin sulphate hydride resin of sodium form 110, D152 resins or D150 resin adsorption saturations after, with soft
Water, salt-free water or purifying water washing, then eluted with 5.0~6.5% dilute sulfuric acid, prepared dihydrostreptomycin sulfate eluent；
F. dihydrostreptomycin sulfate eluent forward direction is passed through 2~4 Hydrogen mixed-bed ion exchange resins of series connection, is mixed
Close bed ion exchange resin to use, dihydrostreptomycin sulfate purification liquid is obtained；The mixed-bed ion exchange resin is by 1 × 25 tree
Any one in fat, 1 × 16 resin or 1 × 14 resin is by volume 1 with 703 resins:0.3~1 mixing composition.
G. after dihydrostreptomycin sulfate purification liquid being adjusted into pH to 4.0~6.0 with calcium hydroxide, addition mass volume ratio is
0.5~2.0% injection active carbon, gained filtrate is liquid after dihydrostreptomycin sulfate filter after filtering；
H. liquid molecular cut off is 300~500D or the concentration of the NF membrane of 150D is obtained after dihydrostreptomycin sulfate is filtered
Dihydrostreptomycin sulfate concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 1.0~5.0%, mistake are added
Gained filtrate is dihydrostreptomycin sulfate decolouring concentrate after filter；
J. by the ultrafiltration membrance filter that dihydrostreptomycin sulfate decolouring concentrate molecular cut off is 4000~8000D, system
Obtain dihydrostreptomycin sulfate finished product concentrate；The milipore filter is any one in doughnut, Flat 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
Dry, dihydrostreptomycin sulfate finished powder is obtained.
Embodiment 1
A kind of preparation method of dihydrostreptomycin sulfate of the present embodiment, its specific implementation step is as follows：
A. 6kg/m is pressed3Ratio by oxalic acid add streptomycin fermentation liquid in, be then heated to 2.5 with sulphur acid for adjusting pH
60 DEG C, then by being centrifuged or filtering removal insoluble matter, pH then is adjusted to 7.0 with NaOH, streptomysin stoste is obtained；
B. by streptomysin stoste with the resin adsorption saturation of sodium form 110 after, washed with soft water and pressed dry, then with 5.0% it is dilute
Sulfuric acid is eluted, and streptomycin sulphate eluent is obtained；
C. by streptomysin eluent with macropore primary amine groups resin D303 or D318 adsorption saturation after, with purifying water washing, then
Parsing is circulated with 8.0% dilute sulfuric acid, streptomycin sulphate desorbed solution is obtained；
D. after streptomycin sulphate desorbed solution being adjusted into pH to 6.5 with NaOH, added according to the ratio of the units of 5.0g/ hundred million
Reducing agent potassium borohydride, reducing agent add before be first 10% to be dissolved in 0.05% sodium hydroxide solution by mass volume ratio,
Then with sulphur acid for adjusting pH to 7.0, streptomycin sulphate hydride is obtained；
E. by streptomycin sulphate hydride with sodium form D152 resin adsorption saturations after, use salt-free water washing, then with 5.5%
Dilute sulfuric acid is eluted, and dihydrostreptomycin sulfate eluent is obtained；
F. dihydrostreptomycin sulfate eluent forward direction is passed through two Hydrogen mixed-bed ion exchange resins of series connection, is obtained
Dihydrostreptomycin sulfate purifies liquid；The mixed-bed ion exchange resin is by 1 × 25 resin and 703 resins by volume 1:0.3
Mixing composition；
G. after dihydrostreptomycin sulfate purification liquid being adjusted into pH to 4.0 with calcium hydroxide, it is 0.5% to add mass volume ratio
Injection active carbon, after filtering gained filtrate be dihydrostreptomycin sulfate filter after liquid；
H. liquid molecular cut off is the NF membrane concentration double hydrogen chains of prepared sulfuric acid of 150D after dihydrostreptomycin sulfate is filtered
Mycin concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 1.0%, institute after filtering are added
It is dihydrostreptomycin sulfate decolouring concentrate to obtain filtrate；
J. by the hollow fiber ultrafiltration membrane filtering that dihydrostreptomycin sulfate decolouring concentrate molecular cut off is 4000D,
Dihydrostreptomycin sulfate finished product concentrate is obtained.
K. dihydrostreptomycin sulfate finished product concentrate is spray-dried with two streaming air-current atomising devices, the double hydrogen chains of sulfuric acid is obtained
Mycin finished powder.
Embodiment 2
A kind of preparation method of dihydrostreptomycin sulfate of the present embodiment, its specific implementation step is as follows：
A. 16kg/m is pressed3Ratio by oxalic acid add streptomycin fermentation liquid in, then with sulphur acid for adjusting pH to 3.5, heating
To 85 DEG C, then by being centrifuged or filtering removal insoluble matter, pH then is adjusted to 8.5 with NaOH, streptomysin stoste is obtained；
B. by streptomysin stoste with sodium form D152 resin adsorption saturations after, salt-free water washing is used, with 5.0% dilute sulfuric acid dip
It is de-, streptomycin sulphate eluent is obtained；
C. by streptomysin eluent with macropore primary amine groups resin D318 resin adsorption saturations after, with salt-free water washing and press
It is dry, then circulate parsing, prepared streptomycin sulphate desorbed solution with 6.0% dilute sulfuric acid；
D. after streptomycin sulphate desorbed solution being adjusted into pH to 8.0 with NaOH, added according to the ratio of the units of 6.0g/ hundred million
Reducing agent sodium borohydride, reducing agent add before be first 15% to be dissolved in 2.0% potassium hydroxide solution by mass volume ratio, so
Afterwards with sulphur acid for adjusting pH to 7.5, streptomycin sulphate hydride is obtained；
E. by streptomycin sulphate hydride with sodium form D150 resin adsorption saturations after, with purifying water washing, then with 8.5%
Dilute sulfuric acid is eluted, and dihydrostreptomycin sulfate eluent is obtained；
F. dihydrostreptomycin sulfate eluent forward direction is passed through three Hydrogen mixed-bed ion exchange resins of series connection, is obtained
Dihydrostreptomycin sulfate purifies liquid；The mixed-bed ion exchange resin is by 1 × 16 resin and 703 resins by volume 1:1 mixes
It is combined into；
G. after dihydrostreptomycin sulfate purification liquid being adjusted into pH to 6.0 with calcium hydroxide, it is 2.0% to add mass volume ratio
Injection active carbon, after filtering gained filtrate be dihydrostreptomycin sulfate filter after liquid；
H. liquid molecular cut off is the prepared sulfuric acid pair of NF membrane concentration of 300~500D after dihydrostreptomycin sulfate is filtered
Hydrogen streptomysin concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 5.0%, institute after filtering are added
It is dihydrostreptomycin sulfate decolouring concentrate to obtain filtrate；
J. by the flat plate ultrafiltration membrane filtration that dihydrostreptomycin sulfate decolouring concentrate molecular cut off is 8000D, it is obtained
Dihydrostreptomycin sulfate finished product concentrate；
K. dihydrostreptomycin sulfate finished product concentrate is spray-dried with three streaming air-current atomising devices, the double hydrogen chains of sulfuric acid is obtained
Mycin finished powder.
Embodiment 3
A kind of preparation method of dihydrostreptomycin sulfate of the present embodiment, its specific implementation step is as follows：
A. 9kg/m is pressed3Ratio by oxalic acid add streptomycin fermentation liquid in, be then heated to 3.0 with sulphur acid for adjusting pH
75 DEG C, then by being centrifuged or filtering removal insoluble matter, pH then is adjusted to 8.0 with NaOH, streptomysin stoste is obtained；
B. by streptomysin stoste with sodium form D150 resin adsorption saturations after, with purifying water washing, then with 6.0% dilute sulfuric acid
Wash-out, is obtained streptomycin sulphate eluent；
C. by streptomysin eluent with macropore primary amine groups resin D303 adsorption saturations after, with salt-free water washing and press dry, then
Parsing is circulated with 7.0% dilute sulfuric acid, streptomycin sulphate desorbed solution is obtained；
D. after streptomycin sulphate desorbed solution being adjusted into pH to 7.0 with NaOH, added according to the ratio of the units of 7.0g/ hundred million
Reducing agent potassium borohydride, reducing agent add before be first 12% to be dissolved in 1.5% ammonia spirit by mass volume ratio, Ran Houyong
Sulphur acid for adjusting pH is obtained streptomycin sulphate hydride to 7.2.
E. by streptomycin sulphate hydride with the resin adsorption saturation of sodium form 110 after, with purifying water washing, then with 6.5%
Dilute sulfuric acid is eluted, and dihydrostreptomycin sulfate eluent is obtained；
F. dihydrostreptomycin sulfate eluent forward direction is passed through four Hydrogen mixed-bed ion exchange resins of series connection, is obtained
Dihydrostreptomycin sulfate purifies liquid；The mixed-bed ion exchange resin is by 1 × 14 resin and 703 resins by volume 1:0.5
Mixing composition；
G. after dihydrostreptomycin sulfate purification liquid being adjusted into pH to 5.0 with calcium hydroxide, it is 1.0% to add mass volume ratio
Injection active carbon, after filtering gained filtrate be dihydrostreptomycin sulfate filter after liquid；
H. liquid molecular cut off is the NF membrane concentration double hydrogen chains of prepared sulfuric acid of 150D after dihydrostreptomycin sulfate is filtered
Mycin concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 2.0%, institute after filtering are added
It is dihydrostreptomycin sulfate decolouring concentrate to obtain filtrate；
J. by the roll-to-roll ultrafiltration membrane filtration that dihydrostreptomycin sulfate decolouring concentrate molecular cut off is 6000D, it is obtained
Dihydrostreptomycin sulfate finished product concentrate；
K. dihydrostreptomycin sulfate finished product concentrate is spray-dried with two streaming air-current atomising devices, the double hydrogen chains of sulfuric acid is obtained
Mycin finished powder.
Embodiment 4
A kind of preparation method of dihydrostreptomycin sulfate of the present embodiment, its specific implementation step is as follows：
A. 13kg/m is pressed3Ratio by oxalic acid add streptomycin fermentation liquid in, then with sulphur acid for adjusting pH to 3.0, heating
To 68 DEG C, then by being centrifuged or filtering removal insoluble matter, pH then is adjusted to 7.5 with NaOH, streptomysin stoste is obtained；
B. by streptomysin stoste with sodium form D152 resin adsorption saturations after, washed with soft water, with 5.5% dilute sulfuric acid dip
It is de-, streptomycin sulphate eluent is obtained；
C. by streptomysin eluent with macropore primary amine groups resin D318 adsorption saturations after, water washing and pressed dry with purifying, then
Parsing is circulated with 9.0% dilute sulfuric acid, streptomycin sulphate desorbed solution is obtained；
D. after streptomycin sulphate desorbed solution being adjusted into pH to 7.0 with NaOH, added according to the ratio of the units of 8.0g/ hundred million
Reducing agent sodium borohydride, reducing agent add before be first 14% to be dissolved in 1.0% sodium hydroxide solution by mass volume ratio, so
Afterwards with sulphur acid for adjusting pH to 7.4, streptomycin sulphate hydride is obtained；
E. by streptomycin sulphate hydride with sodium form D152 resin adsorption saturations after, washed with soft water, then with 6.0% it is dilute
Sulfuric acid is eluted, and dihydrostreptomycin sulfate eluent is obtained；
F. dihydrostreptomycin sulfate eluent forward direction is passed through two Hydrogen mixed-bed ion exchange resins of series connection, is obtained
Dihydrostreptomycin sulfate purifies liquid；The mixed-bed ion exchange resin is by 1 × 25 resin and 703 resins by volume 1:0.7
Mixing composition.
G. after dihydrostreptomycin sulfate purification liquid being adjusted into pH to 5.5 with calcium hydroxide, it is 1.5% to add mass volume ratio
Injection active carbon, after filtering gained filtrate be dihydrostreptomycin sulfate filter after liquid；
H. liquid molecular cut off is the prepared sulfuric acid pair of NF membrane concentration of 300~500D after dihydrostreptomycin sulfate is filtered
Hydrogen streptomysin concentrate；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 3.5%, institute after filtering are added
It is dihydrostreptomycin sulfate decolouring concentrate to obtain filtrate；
J. by the hollow fiber ultrafiltration membrane filtering that dihydrostreptomycin sulfate decolouring concentrate molecular cut off is 5000D,
Dihydrostreptomycin sulfate finished product concentrate is obtained；
K. dihydrostreptomycin sulfate finished product concentrate is spray-dried with three streaming air-current atomising devices, the double hydrogen chains of sulfuric acid is obtained
Mycin finished powder.
In order to preferably verify feasibility of the invention and superiority, inventor is according to the preparation described in embodiment 1~4
Method and corresponding technological parameter, dihydrostreptomycin sulfate finished powder is prepared for by raw material actual production of streptomycin fermentation liquid,
And in preparation process some committed steps have been carried out with sampling detection.The body of the streptomycin fermentation liquid that embodiment 1~4 is used
The detection data of product, potency and total hundred million data, and intermediate steps and final products is as shown in Table 1 below.
Table 1
As can be seen here, the preparation method of the dihydrostreptomycin sulfate for being provided using the present invention, the double hydrogen chains of the sulfuric acid for being produced
Mycin finished product powder purity can reach more than 97% level, and average value is 97.5%, significantly larger than industry quality standard regulation
The requirement for being not less than 95%.And according to the Testing index of crucial intermediate steps in table 1 it can also be seen that the present invention can be bright
((average 99.77%) reduces purification process to aobvious raising pretreatment yield for average 98.9%) and hydrogenation conversion ratio
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
To raising, in embodiment 1~4, pre-processed from initial streptomycin fermentation liquid, dihydrostreptomycin sulfate finished product is obtained to final
Powder, the total recovery of 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 the preparation technology 60% or so that unites has obvious improvement.
Claims (10)
1. a kind of preparation method of dihydrostreptomycin sulfate, it is characterised in that comprise the following steps：
A. after streptomycin fermentation liquid being carried out into acid treatment, 60~85 DEG C are heated to, then by being centrifuged or filtering removal insoluble matter, so
PH is adjusted to 7.0~8.5 with NaOH afterwards, and streptomysin stoste is obtained；
B. by streptomysin stoste with weak-acid cation-exchange resin adsorption saturation after, with soft water, salt-free water or purifying water washing,
Eluted with dilute sulfuric acid again, streptomycin sulphate eluent is obtained；
C. by streptomysin eluent with macropore primary amine groups resin adsorption saturation after, water washing and pressed dry with salt-free water or purifying, then
Circulated with dilute sulfuric acid and parsed, streptomycin sulphate desorbed solution is obtained；
D. after streptomycin sulphate desorbed solution being adjusted into pH to 6.5~8.0 with NaOH, reducing agent is added, then adjusted with sulfuric acid
PH is obtained streptomycin sulphate hydride to 7.0~7.5；
E. by streptomycin sulphate hydride with weak-acid cation-exchange resin adsorption saturation after, with soft water, salt-free water or purifying
Water washing, then eluted with dilute sulfuric acid, dihydrostreptomycin sulfate eluent is obtained；
F. dihydrostreptomycin sulfate eluent forward direction is passed through mixed-bed ion exchange resin, dihydrostreptomycin sulfate purification is obtained
Liquid；
G. after dihydrostreptomycin sulfate purification liquid being adjusted into pH to 4.0~6.0 with calcium hydroxide, it is 0.5 to add mass volume ratio
~2.0% injection active carbon, gained filtrate is liquid after dihydrostreptomycin sulfate filter after filtering；
H. the concentration of liquid NF membrane is obtained dihydrostreptomycin sulfate concentrate after dihydrostreptomycin sulfate is filtered；
I. in dihydrostreptomycin sulfate concentrate, the injection active carbon that mass volume ratio is 1.0~5.0%, institute after filtering are added
It is dihydrostreptomycin sulfate decolouring concentrate to obtain filtrate；
J. by the ultrafiltration membrance filter that dihydrostreptomycin sulfate decolouring concentrate molecular cut off is 4000~8000D, sulphur is obtained
Pantostrep finished product concentrate；
K. dihydrostreptomycin sulfate finished product concentrate is spray-dried, dihydrostreptomycin sulfate finished powder is obtained.
2. the preparation method of a kind of dihydrostreptomycin sulfate according to claim 1, it is characterised in that：In step a at acid
Reason is by 6~16kg/m3Ratio by oxalic acid add streptomycin fermentation liquid in, then with sulphur acid for adjusting pH to 2.5~3.5.
3. the preparation method of a kind 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 trees
Fat.
4. the preparation method of a kind of dihydrostreptomycin sulfate according to claim 3, it is characterised in that：The carboxylic acid type from
Sub-exchange resin is any one in 110 resins, D152 resins or D150 resins.
5. the preparation method of a kind of dihydrostreptomycin sulfate according to claim 1, it is characterised in that：Institute in step b and e
It is 5.0~6.5% to state the concentration of dilute sulfuric acid, and the concentration of dilute sulfuric acid described in step c is 7.0~9.0%.
6. the preparation method of a kind 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 the units of 5.0~8.0g/ hundred million, adds pre reduction agent to press quality volume
Than being dissolved in the NaOH of 0.05~2.0g/ml, potassium hydroxide or ammonia spirit for 10~15%.
7. the preparation method of a kind of dihydrostreptomycin sulfate according to claim 1, it is characterised in that：The mixed bed from
Sub-exchange resin is Hydrogen, by high-crosslinking-degree storng-acid cation exchange resin and weak-base anion-exchange resin by volume
It is 1:0.3~1 mixing composition.
8. the preparation method of a kind of dihydrostreptomycin sulfate according to claim 6, it is characterised in that：The mixed bed from
The occupation mode of sub-exchange resin is used in series for 2~4 mixed-bed ion exchange resins, high-crosslinking-degree highly acid sun from
Sub-exchange resin is any one in 1 × 25 resin, 1 × 16 resin or 1 × 14 resin, and weak-base anion-exchange resin is
703 resins.
9. the preparation method of a kind of dihydrostreptomycin sulfate according to claim 1, it is characterised in that：The NF membrane
Molecular cut off is 300~500D or 150D, and the milipore filter is any one in doughnut, Flat Membrane or rolled film.
10. the preparation method of a kind of dihydrostreptomycin sulfate according to claim 1, it is characterised in that：The spraying is dry
It is dry to use two streaming air-current atomising devices or three streaming air-current atomising devices.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501352A (en) * | 2017-08-29 | 2017-12-22 | 河北圣雪大成制药有限责任公司 | A kind of method that dihydrostreptomycin sulfate is prepared based on microreactor |
| CN110294775A (en) * | 2018-03-23 | 2019-10-01 | 安徽古特生物科技有限公司 | A kind of purification process of Creatine Phosphate Sodium |
| CN111793103A (en) * | 2020-06-09 | 2020-10-20 | 浙江普洛生物科技有限公司 | Extraction process of apramycin sulfate |
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| 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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| 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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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501352A (en) * | 2017-08-29 | 2017-12-22 | 河北圣雪大成制药有限责任公司 | A kind of method that dihydrostreptomycin sulfate is prepared based on microreactor |
| CN110294775A (en) * | 2018-03-23 | 2019-10-01 | 安徽古特生物科技有限公司 | A kind of purification process of Creatine Phosphate Sodium |
| CN110294775B (en) * | 2018-03-23 | 2021-11-26 | 安徽古特生物科技有限公司 | Purification method of creatine phosphate sodium |
| CN111793103A (en) * | 2020-06-09 | 2020-10-20 | 浙江普洛生物科技有限公司 | Extraction process of apramycin sulfate |
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