CN101012246A - Ion exchange purifying method of aminoglycoside antibiotics - Google Patents
Ion exchange purifying method of aminoglycoside antibiotics Download PDFInfo
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- CN101012246A CN101012246A CN 200610135346 CN200610135346A CN101012246A CN 101012246 A CN101012246 A CN 101012246A CN 200610135346 CN200610135346 CN 200610135346 CN 200610135346 A CN200610135346 A CN 200610135346A CN 101012246 A CN101012246 A CN 101012246A
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Abstract
The invention discloses an ionic exchanging purifying method of amino glycoside antibiotics, which comprises the following steps: adopting cationic exchange resin to adsorb the solution of amino glycoside antibiotics until saturing with pH value at 6.0-7.7; washing non-reacted residual liquid and weak adsorbing impurity through wash as at least 2 times as resin quantity (V/V); using 3-7 times eluent with density at 0.5-1.5mol/L to elute amino glycoside antibiotics at 1-3 times resin quantity/h speed; recycling solvent under -0.06--0.095Mpa at 50-70 deg.c; condensing in the vacuum; drying to obtain the product.
Description
Technical field
The present invention relates to a kind of antibiotic extracting method, more specifically relate to a kind of method that contains the aminoglycoside antibiotics of 2-deoxystreptamine in the Zeo-karb purifying molecules structure that adopts.
Background technology
Aminoglycoside antibiotics (hereinafter to be referred as AGS) 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.Such microbiotic has advantages such as has a broad antifungal spectrum, good effect, stable in properties and production technique are simple, and many pathogenic bacterium are had the characteristics of post antibiotic effect (PAE), occupies suitable share on market.Therefore, the preparation method of research aminoglycoside antibiotics has certain directive significance and vast market prospect.
The aminoglycoside antibiotics that contains the 2-deoxystreptamine structure is a kind of water-soluble, polynary weakly alkaline microbiotic.Usually, contain 3~5 amino and 1~2 methylamino-in the molecule, in the aqueous solution, have multistage dissociation equilibrium.Therefore, aminoglycoside antibiotics can exist with different electrochemical states in the water solution system of different pH values, and the different valence state ion presents multistage dissociation equilibrium state, along with stepwise dissociation appears in the pH value of solution from high to low.During higher pH value, aminoglycoside antibiotics exists with the zeroth order form; When the pH value is neutral, then exist with the low price cationic form; When the pH value is acid, then exist with the high-valence cationic form.
Because the aminoglycoside antibiotics biological organic bases that is polynary weakly alkaline, according to the ion-exchange theory, under alkaline condition, pH value>8.0 o'clock especially, aminoglycoside antibiotics mainly exists with molecularity, can select for use macroporous adsorbent resin to carry out separation and purification; But under acid and neutrallty condition, aminoglycoside antibiotics is to exist with the positively charged ion state, should adopt Zeo-karb to extract aminoglycoside antibiotics.
Ion exchange resin mainly is to be raw material with materials such as vinylbenzene, vinylformic acid or phenolic aldehyde, through synthetic solid-state polymer compound is the hydrophobicity skeleton, have characteristics such as be insoluble to general acid-base solution, good stability, physical strength height, the water-swellable rate is low, exchange capacity is big, small-molecule substances such as organic acid, microbiotic should use the ion exchange resin of hydrophobic structure to separate.
The main Zeo-karb commodity of domestic production circulation can be divided into condensation polymer type resin and polyaddition type resin according to the type of polyreaction; Divide cation exchange resin product such as then mainly containing polystyrene, acrylic acid series, phenolic aldehyde system, epoxy system, vinylpyridine system, urea aldehyde system and vinyl chloride according to the chemical constitution of resin matrix.
Because aminoglycoside antibiotics is polynary weakly alkaline biology organic bases, under acid and neutrallty condition, mainly is to exist with the positively charged ion state, its vitriol is soluble in water, is insoluble to organic solvent.Therefore, contain H to being adsorbed on the aminoglycoside antibiotics on the Zeo-karb, can adopting
+, K
+, Na
+, NH
4 +Eluent Deng mineral ion carries out wash-out, and this eluent can be acidity, neutrality or basic solution.
Summary of the invention
The object of the present invention is to provide the ion exchange purifying method of aminoglycoside antibiotics, not only equipment is simple for this method, good separating effect, product yield height, and resin long service life, production cost are low.
The ion exchange purifying method of aminoglycoside antibiotics of the present invention is achieved in that the solution that contains aminoglycoside antibiotics, under pH value 6.0~7.7 conditions, extremely saturated with cationic exchange resin adsorption, remove not take place the debris and the more weak impurity of adsorptive power of ion-exchange earlier with the washing that is no less than 2 times of amount of resin (V/V), use the eluent of 0.5~1.5mol/L concentration of 3~7 times of amount of resin (V/V) again, with 1~3 times of amount of resin/hour flow velocity (V/V) wash-out aminoglycoside antibiotics component, elutriant-0.06~-0.095MPa, under 50~70 ℃ of conditions, through decompression and solvent recovery, vacuum concentration, be dried to the aminoglycoside antibiotics product.
Than existing preparation method, the present invention adopts ion-exchange techniques purification aminoglycoside antibiotics, and following remarkable advantage is arranged:
1. the active ion in the functional group of strongly acidic cation-exchange is-SO
3H, pK
a<1, the pH value is little to its elutive power influence; Elutive power is main relevant with the concentration and the valence state of eluent, and the concentration of eluent and valence state are high more, and it is just big more to the elutive power that is adsorbed on material on the strongly acidic cation-exchange.But the active ion in the functional group of weak-type Zeo-karb is-COOH pK
a=4.0~5.6, the pH value is bigger to its elutive power influence; Elutive power is not only relevant with the concentration and the valence state of eluent, and prior influence factor is the pH value of eluent, as the pH of eluent value<pK
aThe time, cause the functional group of weak-type Zeo-karb not dissociate and present molecularity, lost the ability that exchanges with positively charged ion, the material that is adsorbed on the resin is eluted easily.
2. waiting under the volumetric molar concentration condition, the ordering of the avidity of various ion pair resins size is as follows: when adopting strongly acidic cation-exchange, and H
+<AGs
+<Li
+<K
+=Na
+<NH
4 +<Ro
+<Cs
+<Ag
+<Ti
+<AGs
2+, select NH for use
4OH, NH
4Cl, (NH
4)
2SO
4Deng containing NH
4 +Solution can reach the purpose of wash-out aminoglycoside antibiotics component; When adopting the weak-type Zeo-karb, AGs
+<Li
+<K
+=Na
+<NH
4 +<Ro
+<Cs
+<Ag
+<Ti
+<AGs
2+<H
+, adopt HCl, H
2SO
4Deng the easier purpose that reaches wash-out aminoglycoside antibiotics component of dilute acid soln.
3. adopting the main foundation of ion exchange technique separation and purification aminoglycoside antibiotics is that ion exchange resin is different to the avidity of aminoglycoside antibiotics and impurity.Ion exchange resin depends primarily on the influence of other impurity in the functional group characteristics of physico-chemical property, resin of aminoglycoside antibiotics and the solution to the avidity of aminoglycoside antibiotics.Owing to except that the aminoglycoside antibiotics ion, also have K in the aminoglycoside antibiotics fermented liquid
+, Na
+, NH
4 +, Ca
2+, Mg
2+Deng positively charged ion, and amphotericeledrolyte such as the amino acid that under acidic conditions, exists, protein with the positively charged ion state, when selecting ion exchange technique separation and purification aminoglycoside antibiotics, can take 2 strategies: 1. select mineral ion and foreign protein avidity stronger, and resin and the condition more weak to aminoglycoside antibiotics avidity, impurity is attracted on the resin when upper prop, and aminoglycoside antibiotics flows out in a large number, plays the purpose that aminoglycoside antibiotics and impurity separate.2. or on the contrary, selection is stronger to aminoglycoside antibiotics avidity, and to more weak resin and conditions of impurity avidity such as mineral ion, amino acid and protein, aminoglycoside antibiotics is adsorbed on the resin in a large number, mode by desorption then is with certain density eluent wash-out aminoglycoside antibiotics component.1. plant strategy and compare with the, 2. the plant strategy not only can reach efficiently separating of aminoglycoside antibiotics and impurity, and the aminoglycoside antibiotics component is had tangible enrichment concentrated effect.
4. made full use of under pH value 6.0~7.7 conditions Zeo-karb to the avidity of targeted activity material aminoglycoside antibiotics and difference to the avidity of impurity such as protein, polysaccharide, amino acid, pigment, inorganic salt, and certain density eluent solution different to the elutive power that is adsorbed on aminoglycoside antibiotics and impurity such as protein, amino acid, inorganic salt on the ion exchange resin, really reached the high efficiency separation of aminoglycoside antibiotics and impurity.
Embodiment
The ion exchange purifying method of aminoglycoside antibiotics of the present invention, its method steps is: the solution that contains aminoglycoside antibiotics, under pH value 6.0~7.7 conditions, extremely saturated with cationic exchange resin adsorption, remove not take place the debris and the more weak impurity of adsorptive power of ion-exchange earlier with the washing that is no less than 2 times of amount of resin (V/V), use the negatively charged ion of 0.5~1.5mol/L concentration of 3~7 times of amount of resin (V/V) again, with 1~3 times of amount of resin/hour flow velocity (V/V) wash-out aminoglycoside antibiotics component, elutriant-0.06~-0.095MPa, under 50~70 ℃ of conditions, through decompression and solvent recovery, vacuum concentration, be dried to the aminoglycoside antibiotics product.
Wherein, the solution that contains aminoglycoside antibiotics can be to derive from biosynthetic aminoglycoside antibiotics fermented liquid, aminoglycoside antibiotics crystalline mother solution, aminoglycoside antibiotics extracting solution that other means obtain or in the elutriant one or more.
The Zeo-karb skeleton preferentially select polystyrene or polyacrylic acid for use.
Eluent is a kind of in inorganic salt solution, inorganic acid aqueous solution or the inorganic base aqueous solution, and the cation composition of eluent can be H
+, K
+, Na
+, NH
4 +Deng in the mineral ion one or more.
The physical and chemical parameter measuring method of prepared product 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 aminoglycoside antibiotics (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 10~20 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, adopt Amberlite IR-120 storng-acid cation exchange resin, with 1.06 times of amount of resin/hour last column flow rate (V/V), dynamic adsorption is to saturated, earlier with water (V/V) the flush away polar impurity that is no less than 2 times of amount of resin, use the 1.5mol/L NaCl solution (V/V) of 3 times of amount of resin again, with 2 times of amount of resin/hour flow velocity (V/V) wash-out micronomicin component, elutriant-0.06~-0.095MPa, under 50~70 ℃ of conditions, through decompression and solvent recovery, vacuum concentration, be spray dried to the micronomicin product.After measured, the rate of recovery 89.5% of micronomicin, purity 72.2%.
Embodiment 2
The pH value is 8.32, tobramycin concentration is the extracting solution of 176.2g/L, with hydrochloric acid soln adjust pH to 6.92, adopt 724 weakly acidic cation-exchange resins, under the mixing speed condition of 50r/min, Static Adsorption is to saturated, earlier with water (V/V) the flush away polar impurity that is no less than 2 times of amount of resin, use the 0.75mol/L HCl solution (V/V) of 4 times of amount of resin again, with 3 times of amount of resin/hour flow velocity (V/V) wash-out tobramycin component, elutriant-0.06~-0.095MPa, under 50~70 ℃ of conditions, through decompression and solvent recovery, vacuum concentration, be spray dried to the tobramycin product.After measured, the rate of recovery 88.9% of tobramycin, purity 72.8%.
Embodiment 3
The pH value is 7.56, Xin Meisu concentration is the fermentating liquid filtrate of 12.9g/L, with hydrochloric acid soln adjust pH to 6.05, adopt Dowex 50 storng-acid cation exchange resins, with 0.98 times of amount of resin/hour last column flow rate (V/V), dynamic adsorption is to saturated, with water (V/V) the flush away polar impurity that is no less than 2 times of amount of resin, use 1.0 mol/L NH of 7 times of amount of resin more earlier
4OH solution (V/V), with 1 times of amount of resin/hour flow velocity (V/V) wash-out Xin Meisu component, elutriant-0.06~-0.095MPa, 50~70 ℃ of conditions under, through decompression and solvent recovery, vacuum concentration, be spray dried to the Xin Meisu product.After measured, the rate of recovery 91.0% of Xin Meisu, purity 73.9%.
Embodiment 4
The pH value is 7.23, sisomicin concentration is the fermentating liquid filtrate of 1.1g/L, behind hydrochloric acid soln adjust pH to 6.83, adopt Amberlite IRC-50 weakly acidic cation-exchange resin, with 0.56 times of amount of resin/hour last column flow rate (V/V), dynamic adsorption is to saturated, with water (V/V) the flush away polar impurity that is no less than 2 times of amount of resin, use the 0.50mol/L H of 3 times of amount of resin more earlier
2SO
4Solution (V/V), with 3 times of amount of resin/hour flow velocity (V/V) wash-out sisomicin component, elutriant-0.06~-0.095MPa, 50~70 ℃ of conditions under, through decompression and solvent recovery, vacuum concentration, be spray dried to the sisomicin product.After measured, the rate of recovery 89.5% of sisomicin, purity 71.3%.
Embodiment 5
The pH value is 9.54, kantlex concentration is the crystalline mother solution of 257.2g/L, with hydrochloric acid soln adjust pH to 5.99, adopt 732 storng-acid cation exchange resins, under the mixing speed condition of 75r/min, Static Adsorption is to saturated, with water (V/V) the flush away polar impurity that is no less than 2 times of amount of resin, use the 1.5mol/L NH of 7 times of amount of resin more earlier
4OH solution (V/V), with 1 times of amount of resin/hour flow velocity (V/V) wash-out kantlex component, elutriant-0.06~-0.095MPa, 50~70 ℃ of conditions under, through decompression and solvent recovery, vacuum concentration, be spray dried to the kantlex product.After measured, the rate of recovery 89.6% of kantlex, purity 73.3%.
Embodiment 6
The pH value is 7.58, kantlex concentration is the fermentating liquid filtrate of 8.0g/L, adopt 734 storng-acid cation exchange resins, with 0.96 times of amount of resin/hour last column flow rate (V/V), dynamic adsorption is to saturated, with water (V/V) the flush away polar impurity that is no less than 2 times of amount of resin, use the 0.8mol/L HCl of 6 times of amount of resin: NH more earlier
4Cl (1: 2) solution (V/V), with 2 times of amount of resin/hour flow velocity (V/V) wash-out kantlex component, elutriant-0.06~-0.095MPa, 50~70 ℃ of conditions under, through decompression and solvent recovery, vacuum concentration, be spray dried to the kantlex product.After measured, the rate of recovery 90.4% of kantlex, purity 71.7%.
Embodiment 7
The pH value is 7.39, gentamicinC
1aConcentration is the fermentating liquid filtrate of 1.2g/L, adopt storng-acid cation exchange resin 732: 735 (2: 1) (V/V), with 0.98 times of amount of resin/hour last column flow rate (V/V), dynamic adsorption is to saturated, with water (V/V) the flush away polar impurity that is no less than 2 times of amount of resin, use the 1.5mol/L NH of 7 times of amount of resin more earlier
4Cl solution (V/V), with 1 times of amount of resin/hour flow velocity (V/V) wash-out gentamicinC
1aComponent, elutriant-0.06~-0.095MPa, 50~70 ℃ of conditions under, through decompression and solvent recovery, vacuum concentration, be spray dried to gentamicinC
1aProduct.After measured, gentamicinC
1aThe rate of recovery 90.6%, purity 73.2%.
Embodiment 8
The pH value is 7.38, ribostamycin concentration is the fermentating liquid filtrate of 2.0g/L, adopt 112 weakly acidic cation-exchange resins, under the mixing speed condition of 90r/min, Static Adsorption is to saturated, earlier with water (V/V) the flush away polar impurity that is no less than 2 times of amount of resin, use the 0.5mol/L HCl of 3 times of amount of resin: NaCl (2: 1) solution (V/V) again, with 2 times of amount of resin/hour flow velocity (V/V) wash-out ribostamycin component, elutriant-0.06~-0.095MPa, under 50~70 ℃ of conditions, through decompression and solvent recovery, vacuum concentration, be spray dried to the ribostamycin product.After measured, the rate of recovery 89.9% of ribostamycin, purity 71.9%.
Embodiment 9
The pH value is 9.05, sisomicin concentration is the ammoniacal liquor elutriant of 186.7g/L, with hydrochloric acid soln adjust pH to 7.71, adopt 001 * 13 storng-acid cation exchange resin, with 1.12 times of amount of resin/hour last column flow rate (V/V), dynamic adsorption is to saturated, with water (V/V) the flush away polar impurity that is no less than 2 times of amount of resin, use the 0.5mol/L (NH of 5 times of amount of resin more earlier
4)
2SO
4Solution (V/V), with 3 times of amount of resin/hour flow velocity (V/V) wash-out sisomicin component, elutriant-0.06~-0.095MPa, 50~70 ℃ of conditions under, become the sisomicin product through decompression and solvent recovery, vacuum concentration, vacuum spray drying.After measured, the rate of recovery 88.6% of sisomicin, purity 69.9%.
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 dissemination.
Claims (6)
1. the ion exchange purifying method of an aminoglycoside antibiotics, it is characterized in that: the solution that will contain aminoglycoside antibiotics, in the pH value is under 6.0~7.7 conditions, extremely saturated with cationic exchange resin adsorption, remove not take place the debris and the more weak impurity of adsorptive power of ion-exchange earlier with the washing that is no less than 2 times of amount of resin (V/V), use the eluent of 0.5~1.5mol/L concentration of 3~7 times of amount of resin (V/V) again, with 1~3 times of amount of resin/hour flow velocity (V/V) wash-out aminoglycoside antibiotics component, elutriant is at-0.06~0.095MPa, under 50~70 ℃ of conditions, through decompression and solvent recovery, vacuum concentration, be dried to the aminoglycoside antibiotics product.
2. the ion exchange purifying method of aminoglycoside antibiotics according to claim 1, it is characterized in that: described drying mode is a spraying drying, described spray-dired condition is: feeding liquid concentration 10~20 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 ion exchange purifying method of aminoglycoside antibiotics according to claim 1, it is characterized in that: described Zeo-karb skeleton is selected polystyrene or polyacrylic acid for use.
4. the ion exchange purifying method of aminoglycoside antibiotics according to claim 1 is characterized in that: eluent is a kind of in inorganic salt solution, inorganic acid aqueous solution or the inorganic base aqueous solution.
5. the ion exchange purifying method of aminoglycoside antibiotics according to claim 4, it is characterized in that: the cation composition of eluent is H
+, K
+, Na
+, NH
4 +In the mineral ion one or more.
6. the ion exchange purifying method 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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