CN1974585A - Membrane separating and purifying process for aminoglycoside antibiotics - Google Patents
Membrane separating and purifying process for aminoglycoside antibiotics Download PDFInfo
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- CN1974585A CN1974585A CN 200610135343 CN200610135343A CN1974585A CN 1974585 A CN1974585 A CN 1974585A CN 200610135343 CN200610135343 CN 200610135343 CN 200610135343 A CN200610135343 A CN 200610135343A CN 1974585 A CN1974585 A CN 1974585A
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Abstract
The present invention provides membrane separating and purifying process for aminoglycoside antibiotics. The process includes the membrane separation of aminoglycoside antibiotics solution at the pressure of 0.1-0.5 MPa to depurate, the membrane separation and concentration of the solution with macromolecular impurity eliminated at the pressure of 0.6-1.5 MPa to obtain concentrated solution of 9-20 Baume deg at 60 deg.c, and the spray drying of the concentrated solution to obtain aminoglycoside antibiotics product. The present invention has novel and simple technological process, high product quality, low power consumption and low production cost.
Description
Technical field
The present invention relates to a kind of antibiotic green chemical industry production method, more specifically relate to a kind of method that adopts membrane separation technique to prepare the aminoglycoside antibiotics that contains 2-deoxystreptamine in the molecular structure.
Background technology
Aminoglycoside antibiotics is to contain aminosugar in the class formation with glycosidic link form and aminosugar hexalin bonded compound, is the important microbiotic of finding after penicillin early of a class.The sum of the natural and semi-synthetic aminoglycoside antibiotics of having reported at present is above 3000 kinds, wherein the natural aminoglycoside antibiotics of microorganisms has nearly 200 kinds, have clinical use value 30 surplus kind, as Streptomycin sulphate, Xin Meisu, kantlex, gentamicin, micronomicin, ribostamycin, tobramycin and sisomicin etc., also have some semisynthetic microbiotic such as amikacin, amikacin, netilmicin and Etimicin etc. to come out one after another, and be used to clinical.
Molecular structure according to aminoglycoside antibiotics can be divided into streptamine derivative (as Streptomycin sulphate), the 2-deoxystreptamine derivative (comprises 4, the kantlex of 6-disubstituted derivative, tobramycin, gentamicin, micronomicin and sisomicin; 4, the Xin Meisu of 5-disubstituted derivative, paromycin and ribostamycin etc.; The destomycins of monosubstituted derivative) and amino-hexanol derivative (as sorbistin) etc.
At present, the clinical aminoglycoside antibiotics that uses is the derivative that contains 2-deoxystreptamine in the molecular structure more than 85%, and all lists China national essential drugs register mostly in.Owing to have the simple advantage of has a broad antifungal spectrum, good effect, stable in properties and production technique, and there are the characteristics of post antibiotic effect, aminoglycoside antibiotics to be widely used in around clinical treatment septicemia, bacterial endocarditis, serious respiratory tract infection, kidney and urinary tract infections, skin histology and soft tissue infection, burn and the operation property infectation of bacteria etc. to many pathogenic bacterium.The aminoglycoside antibiotics bulk drug that China produces accounts for 70% of world wide production.Therefore, the preparation method of research aminoglycoside antibiotics has certain directive significance and vast market prospect.
Membrane separation technique is according to the size in filter membrane aperture or the difference of the molecular weight of material size held back, under certain working pressure condition, material permeance or tunicle is held back, thereby reached the purpose of separating substances.As a kind of emerging high efficiency separation means, membrane separation technique is considered to be one of the most rising new and high technology of 21 century, has been widely used in food, medicine, chemical industry, biotechnology field.
Summary of the invention
The object of the present invention is to provide the membrane separating and purifying process of aminoglycoside antibiotics, this method not only helps containing being further purified and preserving of material of aminoglycoside antibiotics, and technology is simple, production energy consumption is little, be convenient to implement.
The membrane separating and purifying process of aminoglycoside antibiotics of the present invention is achieved in that the solution that contains aminoglycoside antibiotics, membrane separation for removing impurities under 0.1～0.5MPa working pressure condition, filtrate membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 0.6～1.5MPa working pressure condition behind the removal macromole impurity is spray dried to the aminoglycoside antibiotics product.
The present invention adopts membrane separation technique to prepare aminoglycoside antibiotics, its advantage is: than existing separation purification method, but adopt membrane separation technique high-level efficiency, less energy-consumption ground to remove in the aminoglycoside antibiotics solution small molecular weight impurities such as macromole impurity component such as protein, polysaccharide and inorganic salt, can reach the purpose of obvious raising aminoglycoside antibiotics purity and quality.
Embodiment
The solution that contains aminoglycoside antibiotics, membrane separation for removing impurities under 0.1～0.5MPa working pressure condition, after removing macromole impurity such as protein and polysaccharide, filtrate is the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 0.6～1.5MPa working pressure condition, is spray dried to the aminoglycoside antibiotics product.
It is 50000～80000 separatory membrane that above-mentioned membrane separation for removing impurities process is preferentially selected molecular weight cut-off for use, and separatory membrane is preferentially selected polysulfone membrane, polyvinylidene fluoride film or polyacrylonitrile film for use.
It is 500～3000 separatory membrane that above-mentioned membrane separation concentrated compression process is preferentially selected molecular weight cut-off for use, and separatory membrane is preferentially selected aromatic polyamide membrane, sulfonated polysulfone membrane or polysulfone membrane for use.
The above-mentioned solution that contains aminoglycoside antibiotics is one or more in microorganism synthetic aminoglycoside antibiotics fermentating liquid filtrate, aminoglycoside antibiotics crystalline mother solution and aminoglycoside antibiotics extracting solution, elutriant or the destainer.
Physical and chemical parameter measuring method of the present invention is as follows:
(1) aminoglycoside antibiotics Determination on content: adopting high performance liquid chromatography, is derivatization reagent with o-phthalaldehyde(OPA) and Thiovanic acid, and aminoglycoside antibiotics is carried out column front derivation.Condition determination: Agilent 1100 type high performance liquid chromatographs (DAD diode-array detector), Waters Nova-Pak C
18Chromatographic column (Φ 4.6 * 150mm, 5 μ m), moving phase is methyl alcohol: water: acetate (include sodium heptanesulfonate 12mmol/L, pH6.3)=70: 25: 5 (V/V/V), flow velocity 1.0ml/min, 30 ℃ of column temperatures, sample size 20 μ L detect wavelength 250nm.With various aminoglycoside antibiotics standard substance (purity 99%) (available from Sigma company) is contrast.
(2) determination of polysaccharide adopts the phenolsulfuric acid method, is contrast with glucose or D-semi-lactosi.Protein content determination adopts FoLin-phenol method, is contrast with the bSA.Inorganic ion content is measured and is adopted kit measurement, wherein SO
4 2-Mensuration adopt the bariumchloride precipitator method, Cl
-Measure and adopt the Silver Nitrate precipitator method, Ca
2+And Mg
2+Mensuration adopt methyl thymol blue complexometry.
(3) the spraying drying condition is: feeding liquid concentration 9～20 degree Beaume (60 ℃), 160～250 ℃ of PG-5 type spray-drier inlet temperatures, 60～110 ℃ of temperature outs, centrifugal head operating pressure 1.6～3.0kgf/cm
2
Preparation method's of the present invention embodiment is presented below:
Embodiment 1
The pH value is 7.36, micronomicin concentration is the fermentating liquid filtrate of 0.72g/L, and adopting molecular weight cut-off is 50000 polysulfone membrane, membrane separation for removing impurities under 0.5MPa working pressure condition; After removing macromole impurity such as protein and polysaccharide, it is 3000 polysulfone membrane that filtrate is selected molecular weight cut-off for use, the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 1.5MPa working pressure condition; Be spray dried to the micronomicin product.After measured, the rate of recovery 92.2% of micronomicin, purity are 72.0%.
Embodiment 2
The pH value is 8.32, tobramycin concentration is the extracting solution of 176.2g/L, and adopting molecular weight cut-off is 60000 polysulfone membrane, membrane separation for removing impurities under 0.25MPa working pressure condition; After removing macromole impurity such as protein and polysaccharide, it is 500 aromatic polyamide membrane that filtrate is selected molecular weight cut-off for use, the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 1.5MPa working pressure condition; Be spray dried to the tobramycin product.After measured, the rate of recovery 91.6% of tobramycin, purity are 69.9%.
Embodiment 3
The pH value is 7.56, Xin Meisu concentration is the fermentating liquid filtrate of 12.9g/L, and adopting molecular weight cut-off is 80000 polysulfone membrane, membrane separation for removing impurities under 0.1MPa working pressure condition; After removing macromole impurity such as protein and polysaccharide, it is 500 sulfonated polysulfone membrane that filtrate is selected molecular weight cut-off for use, the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 1.5MPa working pressure condition; Be spray dried to the Xin Meisu product.After measured, the rate of recovery 93.8% of Xin Meisu, purity are 68.2%.
Embodiment 4
The pH value is 7.23, sisomicin concentration is the fermentating liquid filtrate of 1.1g/L, and adopting molecular weight cut-off is 80000 polyvinylidene fluoride film, membrane separation for removing impurities under 0.1MPa working pressure condition; After removing macromole impurity such as protein and polysaccharide, it is 3000 polysulfone membrane that filtrate is selected molecular weight cut-off for use, the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 0.6MPa working pressure condition; Be spray dried to the sisomicin product.After measured, the rate of recovery 92.2% of sisomicin, purity are 69.2%.
Embodiment 5
The pH value is 9.54, kantlex concentration is the crystalline mother solution of 257.2g/L, and adopting molecular weight cut-off is 70000 polyvinylidene fluoride film, membrane separation for removing impurities under 0.2MPa working pressure condition; After removing macromole impurity such as protein and polysaccharide, it is 800 aromatic polyamide membrane that filtrate is selected molecular weight cut-off for use, the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 0.9MPa working pressure condition; Be spray dried to the kantlex product.After measured, the rate of recovery 92.3% of kantlex, purity are 69.9%.
Embodiment 6
The pH value is 7.58, kantlex concentration is the fermentating liquid filtrate of 8.0g/L, and adopting molecular weight cut-off is 50000 polyvinylidene fluoride film, membrane separation for removing impurities under 0.5MPa working pressure condition; After removing macromole impurity such as protein and polysaccharide, it is 800 sulfonated polysulfone membrane that filtrate is selected molecular weight cut-off for use, the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 0.75MPa working pressure condition; Be spray dried to the kantlex product.After measured, the rate of recovery 93.1% of kantlex, purity are 69.1%.
Embodiment 7
The pH value is 7.39, gentamicinC
1aConcentration is the fermentating liquid filtrate of 1.2g/L, and the employing molecular weight cut-off is 60000 polyacrylonitrile film, membrane separation for removing impurities under 0.35MPa working pressure condition; After removing macromole impurity such as protein and polysaccharide, it is 3000 polysulfone membrane that filtrate is selected molecular weight cut-off for use, the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 0.65MPa working pressure condition; Be spray dried to gentamicinC
1aProduct.After measured, gentamicinC
1aThe rate of recovery 93.3%, purity be 67.8%.
Embodiment 8
The pH value is 7.38, ribostamycin concentration is the fermentating liquid filtrate of 2.0g/L, and adopting molecular weight cut-off is 50000 polyacrylonitrile film, membrane separation for removing impurities under 0.5MPa working pressure condition; After removing macromole impurity such as protein and polysaccharide, it is 3000 aromatic polyamide membrane that filtrate is selected molecular weight cut-off for use, the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 0.6MPa working pressure condition; Be spray dried to the ribostamycin product.After measured, the rate of recovery 92.6% of ribostamycin, purity are 68.0%.
Embodiment 9
The pH value is 9.5, sisomicin concentration is the ammoniacal liquor elutriant of 186.7g/L, and adopting molecular weight cut-off is 80000 polyacrylonitrile film, membrane separation for removing impurities under 0.1MPa working pressure condition; After removing macromole impurity such as protein and polysaccharide, it is 3000 sulfonated polysulfone membrane that filtrate is selected molecular weight cut-off for use, the membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 0.6MPa working pressure condition; Be spray dried to the sisomicin product.After measured, the rate of recovery 91.3% of sisomicin, purity are 64.8%.
Above embodiment is intended to further describe for example the present invention, rather than limits the present invention by any way.
The present invention is novel, and technology is simple, the extraction efficiency height, and production cost is low, has bigger generalization.
Claims (7)
1. the membrane separating and purifying process of an aminoglycoside antibiotics, it is characterized in that: the solution that contains aminoglycoside antibiotics, membrane separation for removing impurities under 0.1～0.5MPa working pressure condition, filtrate membrane separation concentrated concentrated solution that shortens 9～20 degree Beaume (60 ℃) under 0.6～1.5MPa working pressure condition behind the removal macromole impurity is spray dried to the aminoglycoside antibiotics product.
2. the membrane separating and purifying process of aminoglycoside antibiotics according to claim 1, it is characterized in that: described spraying drying condition is: feeding liquid concentration 9～20 degree Beaume (60 ℃), 160～250 ℃ of PG-5 type spray-drier inlet temperatures, 60～110 ℃ of temperature outs, centrifugal head operating pressure 1.6～3.0kgf/cm
2
3. the membrane separating and purifying process of aminoglycoside antibiotics according to claim 1 is characterized in that: it is 50000～80000 separatory membrane that described membrane separation for removing impurities process is selected molecular weight cut-off for use.
4. the membrane separating and purifying process of aminoglycoside antibiotics according to claim 3, it is characterized in that: the separatory membrane of described membrane separation for removing impurities process is polysulfone membrane, polyvinylidene fluoride film or polyacrylonitrile film.
5. the membrane separating and purifying process of aminoglycoside antibiotics according to claim 1 is characterized in that: it is 500～3000 separatory membrane that described membrane separation concentrated compression process is selected molecular weight cut-off for use.
6. the membrane separating and purifying process of aminoglycoside antibiotics according to claim 5, it is characterized in that: the separatory membrane of described membrane separation concentrated compression process is aromatic polyamide membrane, sulfonated polysulfone membrane or polysulfone membrane.
7. the membrane separating and purifying process of aminoglycoside antibiotics according to claim 1, it is characterized in that: the solution that contains aminoglycoside antibiotics is one or more in microorganism synthetic aminoglycoside antibiotics fermentating liquid filtrate, aminoglycoside antibiotics crystalline mother solution and aminoglycoside antibiotics extracting solution, elutriant or the destainer.
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| CNB2006101353434A CN100463912C (en) | 2006-12-20 | 2006-12-20 | Membrane separating and purifying process for aminoglycoside antibiotics |
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| CN100463912C CN100463912C (en) | 2009-02-25 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012514A (en) * | 2012-12-24 | 2013-04-03 | 江西制药有限责任公司 | Membrane separation and extraction method for micronomicin sulfate |
| CN106317138A (en) * | 2016-08-25 | 2017-01-11 | 宁夏泰益欣生物科技有限公司 | Extraction method of neomycin sulfate |
| CN109705174A (en) * | 2019-02-19 | 2019-05-03 | 北大方正集团有限公司 | The extracting method of tobramycin |
| CN111004298A (en) * | 2019-12-20 | 2020-04-14 | 无锡福祈制药有限公司 | Preparation method of high-purity ribostamycin sulfate |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102146104B (en) * | 2011-01-31 | 2013-06-05 | 常州方圆制药有限公司 | Method for removing divalent metal ion from antibiotic etimicin liquid medicine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1268760C (en) * | 2003-10-29 | 2006-08-09 | 三达膜科技（厦门）有限公司 | Method for producing fermented nucleotide typed antibiotics by using membrane |
-
2006
- 2006-12-20 CN CNB2006101353434A patent/CN100463912C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012514A (en) * | 2012-12-24 | 2013-04-03 | 江西制药有限责任公司 | Membrane separation and extraction method for micronomicin sulfate |
| CN103012514B (en) * | 2012-12-24 | 2015-05-20 | 江西制药有限责任公司 | Membrane separation and extraction method for micronomicin sulfate |
| CN106317138A (en) * | 2016-08-25 | 2017-01-11 | 宁夏泰益欣生物科技有限公司 | Extraction method of neomycin sulfate |
| CN109705174A (en) * | 2019-02-19 | 2019-05-03 | 北大方正集团有限公司 | The extracting method of tobramycin |
| CN109705174B (en) * | 2019-02-19 | 2020-09-04 | 北大方正集团有限公司 | Method for extracting tobramycin |
| CN111004298A (en) * | 2019-12-20 | 2020-04-14 | 无锡福祈制药有限公司 | Preparation method of high-purity ribostamycin sulfate |
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| CN100463912C (en) | 2009-02-25 |
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