CN104277126B - The method of purification of hetastarch - Google Patents
The method of purification of hetastarch Download PDFInfo
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- CN104277126B CN104277126B CN201310290621.3A CN201310290621A CN104277126B CN 104277126 B CN104277126 B CN 104277126B CN 201310290621 A CN201310290621 A CN 201310290621A CN 104277126 B CN104277126 B CN 104277126B
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Abstract
The invention provides the method for purification of a kind of hetastarch.The method includes: 1) is mixed with one or more in sulfurous acid, bisulfites, sulphite by the aqueous solution of the hetastarch obtained by the steps of activated carbon adsorption of hetastarch preparation technology, obtains mixed solution；And 2) mixed solution that step 1) obtained carries out ultrafiltration, the hetastarch of isolated purification.The method of the present invention has following good effect: the method for the present invention can reduce bacteria endotoxin content in hetastarch finished product, substantially increases product inherent quality；Reduce the difference of molecular size in hetastarch finished product, improve the quality of finished product；Easily operated, pollution-free, and end product quality is stable, method is convenient easy to implement, is suitable for industrialized great production.
Description
Technical field
The invention belongs to pharmaceutical field, in particular to the method for purification of a kind of hetastarch.
Background technology
Hetastarch (HES) generally uses in the patient of those massive blood losses, has suppression Ink vessel transfusing erythrocyte aggregation
Effect；It is mainly used in improving microcirculation disturbance, is clinically used for hypovolemic shock, such as hemorrhagic shock, burn property and operation
The rhomboembolia type illness such as middle shock.HES can keep the blood volume of patient, prevents their circulation from collapsing simultaneously.Due to hydroxyl
Hydroxyethyl starch itself is to be formed by starch transformation, and its structure is similar with glycogen, and allergy incidence rate is far below dextran, inanimate object
The virus infection of goods threatens, and medical expense is the most relatively low and is increasingly subject to clinical welcome.
The chemical name of hetastarch is 6-(2-hydroxyethyl) starch；English entitled Hydroxyethyl Starch；
Structural formula is as shown in following formula I:
Formulas I
Hetastarch is white or off-white powder, and odorless is tasteless, has stronger hygroscopicity.It is the most soluble,
Cold water dissolve slowly, insoluble in methanol and ether.Specific optical rotation is+175 °～+195 °.
The hetastarch huge number used at present both at home and abroad, divide by molecular weight have low (Mw < 100kDa), in (Mw
Between 100kDa～300kDa), high (Mw > 300kDa) three kinds；Divide have low (Ms between 0.3～0.6) and height (Ms by replacing level
> 0.6) two kinds.For a long time, the hetastarch that domestic enterprise produces has mean molecule quantity to be 20,000 and 4 WANLIANG kinds, belongs to low point
Sub-hetastarch, concentration is 6%, and all with 0.5% sodium chloride injection compatibility application, (7 very much in the range of kidney threshold for both of which
Son amount), to drain rapidly through kidney after therefore series products entrance is internal, the dilatation time is short, and dilatation is unstable, tends not to reach blood
The effect of Capacity Expansion, the most just cannot realize recovering the purpose of hematodinamics balance.Untoward reaction simultaneously has been reported that repeatly, abroad
Do not produce.Due to the aspect such as safety and curative effect, the HES of low-molecular-weight high substituted degree in early days the most gradually by point
Son amount low degree of substitution HES substitutes.130/0.4, by reducing molecular weight and the molecular weight distribution that narrows, reduces replacement level and change takes
For mode (C2/C6), there is good safety and capacity enlargement effect clinically.
In the prior art, hetastarch is produced typically with starch as starting material；Through hydrolyzing, be etherified, adsorb, surpassing
The steps such as filter and spray drying.Such as, the customary preparation methods of hetastarch of the prior art is: starch adds a certain amount of
Purified water, hydrochloric acid or enzyme, be hydrolyzed at a certain temperature, controls hydrolysis degree, stops when hydrolysis reaches suitable molecular weight
Sealing solution, makees catalyst with sodium hydroxide, makes starch and oxirane carry out ethoxyl etherification to be etherified, uses afterwards
(such as) activated carbon removes impurity and decolouring, is removed by the impurity such as the hetastarch of small-molecular-weight and salt by ultrafilter membrane,
Afterwards by being spray-dried prepared hetastarch finished product.
In the preparation of hetastarch, owing to starch had once been infected with a large amount of antibacterial in production, storage, transportation, this
After a little bacterial death, cellular lysate is stored in feed liquid, has lipopolysaccharide (LPS) and lipoid A in lysate, also known as endotoxin, for heat
The active part in source, their relative molecular weight is generally 1-2.5 ten thousand KD, easily associates into the association body of 50-100KD in water,
This kind of material has stronger thermostability and chemical stability, is difficult to be eliminated (100 DEG C, heating 1h also will not be destroyed).In
Toxin can cause human body heating, microcirculation disturbance, endotoxin shock and disseminated inravascular coagulation etc., will bring to Clinical practice
Potential safety hazard, even causes malpractice.
And as injection raw material, the bacterial endotoxin index of medium molecular weight hydroxyethyl starch be one very important
Quality index, bacterial endotoxin index quality criteria requirements to be met, and for the consideration of drug safety, at present in
The bacterial endotoxin index aspect of molecular weight hydroxyethyl starch, its upper limit is about 50EU/g, and becoming that it is reduced as best one can
Gesture is more and more obvious.
In the preparation method of existing hetastarch, the removal of bacterial endotoxin mainly by etherification step it
After, remove bacterial endotoxin by activated carbon adsorption and ultrafiltration.
Wherein, although activated carbon adsorption has preferably on bacteria endotoxin content in absorption bacterial endotoxin, reduction medicinal liquid
Effect, but absorption may eventually reach certain saturated extent of adsorption (≤75%), and if in order to meet the more antibacterial endogenous toxins of absorption
The purpose of element and take the way adding activated carbon also can cause the loss of principal agent composition more, affect yield, so medicinal liquid to be made
In bacterial endotoxin be reduced to reduced levels, the method has its limitation.
And although ultrafiltration can remove substantial amounts of bacterial endotoxin, but for hetastarch (particularly Middle molecule
Amount hetastarch) for, due to molecular weight distribution (15000-400000) and the bacterial endotoxin molecular weight distribution of this product
(thousand of to hundreds of thousands) have major part to overlap, in this way for removing the bacterial endotoxin in medicinal liquid in actual applications
Also it is restricted.
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides the method for purification of a kind of hetastarch.
Specifically, the present invention includes:
(1) method of purification of a kind of hetastarch, comprising:
1) by the aqueous solution of hetastarch that obtained by the steps of activated carbon adsorption of hetastarch preparation technology with
One or more mixing in sulfurous acid, bisulfites, sulphite, obtain mixed solution；And
2) mixed solution step 1) obtained carries out ultrafiltration, the hetastarch of isolated purification.
(2) according to the method described in (1), wherein, in the mixed solution that step 1) obtains, sulfurous acid, bisulfite
And/or the total concentration of inferior sulfate radical is 0.05-1.0mol/L.
(3) according to method described in (2), wherein, in the mixed solution that step 1) obtains, described sulfurous acid, sulfurous
The total concentration of acid hydrogen radical and/or inferior sulfate radical is 0.08-0.8mol/L.
(4) according to the method described in (1), wherein, described bisulfites is sodium sulfite.
(5) according to the method described in (1), wherein, described sulphite is ammonium sulfite and/or sodium sulfite.
(6) according to the method described in (1), wherein, the mixing described in step 1) is carried out under agitation.
(7) according to method described in (1), wherein, step 2) described in ultrafiltration in ultrafilter membrane used be 150,000 to retain point
The ultrafilter membrane of son amount and/or the ultrafilter membrane of 100,000 molecular cut offs；It is preferably the ultrafilter membrane of 100,000 molecular cut offs.
(8) according to method described in (1), wherein, step 2) described in separation include: by the middle-molecular-weihydroxyethyl hydroxyl of isolated
Hydroxyethyl starch is dried, thus obtains hetastarch finished product.
(9) according to the method described in (8), wherein, described dry including is spray-dried；Baking temperature is preferably 150-
180℃。
(10) according to method described in any one in (1)-(9), wherein, described hetastarch is middle-molecular-weihydroxyethyl hydroxyl
Hydroxyethyl starch.
The method that the present invention provides has the advantage that and good effect:
The method of the present invention can reduce bacteria endotoxin content in hetastarch finished product, makes contained antibacterial endogenous toxin in finished product
Element level has substantially reduction before not using this method, substantially increase product inherent quality.Additionally, the method for the present invention also reduces
The difference of the molecular size in hetastarch finished product, improves the quality of finished product.The method of the present invention is easily operated, without dirty
Dye, and end product quality is stable, is suitable for industrialized great production.
Detailed description of the invention
Below by way of the description of detailed description of the invention, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art are according to the basic thought of the present invention, and various modifications may be made or improves, but without departing from this
The basic thought of invention, the most within the scope of the present invention.
In this article, " bacterial endotoxin " includes such a heteromultimer, and its essence is lipopolysaccharide
(lipopolysaccharide, LpS), including lipoid A (lipidA), core polysaccharide, O-specific antigen polysaccharide (O-
Antigen) three ingredients.Wherein lipoid A is by phosphoglucose amine disaccharidase main chain and the length of the most covalently bound 10-18 carbon
Chain fatty acid forms, and contains hydrophobic center and hydrophilic edge the most simultaneously, is a kind of double property molecule, is again soda acid both sexes
Molecule.The antibacterial of different genera, is respectively provided with basically identical lipoid A skeleton, is part the most conservative in endotoxin.And class
Fat A has complete endotoxic characteristic, is the active center of LPS, and the harm to health is the most maximum.Core polysaccharide is by connecting
The kernel portion composition of the outer core part of O-specificity chain and connection lipoid A.Outer core part is mainly made up of hexose and heptose, tool
Having higher sugared heterologous, the difference of some gram negative bacteria core component mostly occurs the hexose molecule in this structure division
On.Kernel portion is the most stable, mainly by KDO(2-ketone group-3-deoxidation-D. manna alcohol type-ketooctulosonic acid) and heptose structure
Become.O-specificity chain is repeated oligomerisation sugar unit by 4～40 and forms, and each oligomerisation sugar unit is made up of 3-8 monosaccharide molecule.
O-specificity chain has strain specific, and some endotoxin does not exist O-specificity chain, and this has no effect on and damage its biology
Activity.The structure of the special chain of O-is the most labile part in endotoxin molecule, such as: its monosaccharide molecule can be by second phthalein
Glycosylation, it is possible to the number of conversion repetitive.The special chain of O-of different strain is different, and therefore its antigen has the spy of strain
The opposite sex.On epicyte, the effect of self-protection is played in the active change of endotoxin kind, is adapted to the change of surrounding.
Under the conditions of common pH, the saccharide residue in endotoxin molecule is by partial phosphorylation (pK1=l.3, pK2=8.2, pI=3.1), phosphoric acid
Foundation group and KDO carry a large amount of negative charge, and therefore endotoxin molecule shows elecrtonegativity the most in the solution.
In this article, " medium molecular weight hydroxyethyl starch " refers to that weight average molecular weight is 110000-150000 dalton, replaces
Degree is the hetastarch of 0.36-0.45.
In this article, " hetastarch preparation technology " refers to starch as starting material, through hydrolyzing, be etherified, adsorbing,
Ultrafiltration and drying and other steps obtain the process of hetastarch:
Wherein, hydrolysis starch typically uses acid hydrolysis or enzyme hydrolysis, and preferred acid of the present invention hydrolyzes；Generally, acid is hydrochloric acid, water
Solve temperature and be 85-95 DEG C, use viscosity method detection hydrolysis process；
Wherein, etherificate is general use oxirane or 2-chloroethyl alcohol as etherifying agent, optimization ethylene oxide of the present invention；Etherificate one
As carry out (pH is 12-14) in the basic conditions, etherification temperature is 17-24 DEG C, and etherification time is 4-8h；
Wherein, absorption general employing activated carbon is adsorbent；
Wherein, ultrafiltration is to be that filter medium refines feed liquid with ultrafilter membrane, and the selection of ultrafilter membrane is determined by molecular weight product.Excellent
The ultrafilter membrane selecting target to be 100,000 and/or 150,000 molecular cut offs is that filter medium carries out ultrafiltration；
Wherein, be dried typically use drying under reduced pressure, constant pressure and dry, lyophilization, spray drying etc.；The present invention preferably sprays
It is dried.
In order to reduce the bacterial endotoxin index of hetastarch, present inventor has performed substantial amounts of analysis and production process
Monitoring, found that: in existing hetastarch production technology, in hetastarch feed liquid ultrafiltration step forward direction feed liquid
Add inferior sulfate radical, it is possible to change endotoxic dissolving environment, reduce the association in the solution of endotoxin macromole, in being conducive to
Toxin is removed when ultrafiltration, and the bacterial endotoxin level of final production medium molecular weight hydroxyethyl starch out also can substantially drop
Low, thus improve product quality.The present inventor on this basis, thus has obtained technical scheme further.
Specifically, the invention provides:
A kind of method of purification of hetastarch, comprising:
1) by the aqueous solution of hetastarch that obtained by the steps of activated carbon adsorption of hetastarch preparation technology with
One or more mixing in sulfurous acid, bisulfites, sulphite, obtain mixed solution；And
2) mixed solution step 1) obtained carries out ultrafiltration, the hetastarch of isolated purification.
Preferably, in the mixed solution that step 1) obtains, sulfurous acid, bisulfite and/or inferior sulfate radical total
Concentration is 0.05-1.0mol/L.
Preferably, in the mixed solution that step 1) obtains, sulfurous acid, bisulfite and/or inferior sulfate radical total
Concentration is 0.08-0.8mol/L.
Preferably, described bisulfites is sodium sulfite.
Preferably, described sulphite is ammonium sulfite and/or sodium sulfite.
Preferably, the mixing described in step 1) is carried out under agitation.
Preferably, step 2) described in ultrafiltration in the used ultrafilter membrane that ultrafilter membrane is 150,000 molecular cut offs and/or
The ultrafilter membrane of 100000 molecular cut offs；It is preferably the ultrafilter membrane of 100,000 molecular cut offs.
Preferably, step 2) described in separation include: the medium molecular weight hydroxyethyl starch of isolated is dried,
Thus obtain hetastarch finished product.It is further preferred that described dry including is spray-dried；Baking temperature is preferably 150-
180℃。
Preferably, described hetastarch is medium molecular weight hydroxyethyl starch.
A kind of embodiment of the present invention may is that
The preparation method of a kind of hetastarch, the method includes: use sulfurous acid, bisulfites, sulphite to help
Molten endotoxin, reduces the macromole associations in water such as endotoxin, and during ultrafiltration, endotoxin is readily removable；
Preferably, the sulfurous acid of hydrotropy use, bisulfite, the concentration sum of inferior sulfate radical are 0.05-1.0mol/
L。
Preferably, the sulfurous acid of hydrotropy use, bisulfite, inferior sulfate radical, can be sulfurous acid solution, sulfurous acid
One or more in salt, bisulfites.
A kind of specific embodiments of the present invention may is that
The method of purification of the hetastarch of the present invention can be included in the preparation method of following hetastarch, wherein,
The preparation method of described medium molecular weight hydroxyethyl starch comprises the following steps:
1) Starch Hydrolysis: with purified water as solvent, dissolves starch in the case of heated and stirred, then adds mineral acid
Be hydrolyzed reaction；
2) ethoxy etherificate: by adding base catalyst and etherifying agent in step 1) products therefrom, under vacuum protection, enter
Row etherification reaction；
3) decolorization adsorption: by step 2) products therefrom adds water and the miscible agent of ethanol, and it is sufficiently stirred for, stands；Take upper strata
Liquid, adds activated carbon, carries out decolouring clarification；
4) ultrafiltration: step 3) products therefrom is used sulfurous acid, bisulfites, sulphite hydrotropy endotoxin, reduces
The association in water of the macromole such as endotoxin, crosses ultrafilter membrane and carries out ultrafiltration；
5) separation is dried: step 4) products therefrom carries out separation and is dried, obtain hetastarch finished product.
When in preferably: above-mentioned steps 1), water is solvent, water is purified water, and its weight ratio in mixed system is 70-
90%；Heating-up temperature is 85-95 DEG C；The mineral acid added is concentrated hydrochloric acid (such as analytical pure concentrated hydrochloric acid), and concentration is 36-38 weight %,
Its weight ratio in mixed system is 0.1%-2%；Carry out in the situation having stirring.
Preferably: above-mentioned steps 2) ethoxy etherificate add base catalyst be concentration be 10%-20%(weight %)
Sodium hydroxide solution, its weight ratio in mixed system is 0.5%-2.5%；Etherifying agent is oxirane, and it is in mixed system
Weight ratio is 1.7%-3.5%；The time of etherificate is 4-8h, and reaction temperature is 17-24 DEG C；Vacuum protection is carried out during etherificate, and
Carry out under conditions of continuously stirred.
Preferably: above-mentioned steps 3) decolouring add for water and the miscible agent of ethanol, its weight in mixed system
Ratio is 24.5%-33.6%；The activated carbon added weight ratio in mixed system is 0.1%-0.3%；Decoloration device uses stainless
Steel closed delivery plate-and-frame filtration device, filtrate clarification reach 2010 pharmacopeia annex IX B " clarity inspection technique " 0.5 level number with
Under；Carry out in the situation having stirring.
Preferably: above-mentioned steps 4) film of ultrafiltration be chosen as use 100,000 ultrafiltration retaining relative molecular mass (KD)
Final molecular weight is screened by film, completes feed liquid and refines；Or 150,000 retain the ultrafilter membrane of relative molecular mass (KD) to
Whole molecular weight screens, and completes feed liquid and refines.
Separation preferably: above-mentioned steps 5) is dried employing and is spray-dried；Baking temperature is preferably 150-180 DEG C.
A kind of specific embodiments of the present invention may is that
1) hydrolysis: add water 650-700ml in the reactor of 3L, under stirring, adds starch 200g, adds concentrated hydrochloric acid
2.7-50ml, is warming up to 90 DEG C, is incubated 89-92 DEG C, controls hydrolysis process with viscosity method, when hydrolysis reaches process stipulation requirement,
Stop hydrolysis.Fast cooling is to 19-23 DEG C.
2) ethoxy etherificate: sodium hydroxide 6-25g is dissolved in 110-140ml water, is cooled to 19-23 DEG C.Under stirring, will
Sodium hydroxide solution, is slowly added in hydrolysis mixture, temperature 19-23 DEG C, evacuation, is slowly passed through oxirane 18-
35g, confined reaction 5-8h.React complete, adjust pH5.5-7.5 with concentrated hydrochloric acid.
3) decolour, adsorb, under stirring, add water and the miscible agent of ethanol (volume ratio 1:3) of 350-500ml, fully stir
Mix, stand；Take upper liquid, add activated carbon 2.0-4.0g, 55-70 DEG C of insulated and stirred 50-65min, after filtration, add water to
1400-1800ml。
4) ultrafiltration: adding sulfurous acid or its salt, making sulfurous acid, bisulfite, the concentration sum of inferior sulfate radical is 0.08-
0.8mol/L, is sufficiently stirred for 1.5h, and filtrate is with the ultrafilter membrane ultrafiltration of 100,000 molecular weight.
5) it is dried, by the HES solution after ultrafiltration, 150-180 DEG C of spray drying, obtains sample.
In order to be better understood from the present invention, further explain and describe present invention below by way of example, but these examples
Son is not to be construed as limiting the scope of the invention.
In example below, pharmaceutical grade starch is available from Zhengzhou Lv Bo chemical products company limited；Activated carbon is available from all
City Zhong Li Trade Co., Ltd.；Oxirane is available from Chengdu, Sichuan chemical inc.
In example below, the detection of bacterial endotoxin of hetastarch finished product detects by the following method: China
The dynamic turbidimetric of the bacterial endotoxins test of the E part of pharmacopeia annex Ⅺ.The computational methods of yield are: yield=finished product weight
Amount ÷ amylopectin weight × 100%.
Example 1
1) hydrolysis
In the reactor of 10L, add water 3300ml, under stirring, add pharmaceutical grade starch 1000g, add concentrated hydrochloric acid
25ml, is warming up to 90 DEG C, is incubated 89-92 DEG C, every 10 minutes sampling once, rapid estimated viscosity, when the delivery time 1 point 25 seconds
Time, stopping heating, fast cooling is to 19-20 DEG C.
2) etherificate
Solid sodium hydroxide 35g is dissolved in 590ml water, is cooled to 19-20 DEG C.By gained NaOH solution at stirring condition
Under be slowly added in the hydrolysis mixture that step 1) obtains, temperature is maintained at 19-20 DEG C, airtight etherificate tank, and evacuation slowly leads to
Enter oxirane 90g, confined reaction 8 hours, react complete.
3) absorption
PH7.5 is adjusted with concentrated hydrochloric acid.Under stirring, add water and the miscible agent of ethanol (volume ratio 1:3) of 1750ml, fully stir
Mix, stand；Take upper liquid, with 15.0g activated carbon as adsorbent, 55 DEG C of insulated and stirred 65 minutes, filter, thus will be etherified feed liquid
Middle impurity and small part bacterial endotoxin remove.
4) ultrafiltration
Step 3) gained filtrate is added water to 7500ml, then is divided into A, B, C tri-parts (2500*3).It is separately added into sulfurous acid
Hydrogen sodium 0g, 12.88g, 128.81g, be sufficiently stirred for 1.5h, and filtrate is with the ultrafilter membrane ultrafiltration of 100,000 molecular weight.
5) it is dried
HES solution after ultrafiltration, at 160-170 DEG C of spray drying, collects to obtain sample.
Specific experiment result sees table 1.
Example 2
1) hydrolysis
In the reactor of 10L, add water 3500ml, under stirring, add pharmaceutical grade starch 1000g, add concentrated hydrochloric acid
250ml, is warming up to 90 DEG C, is incubated 89-92 DEG C, and once, rapid estimated viscosity, when the delivery time is at 1 point 20 in sampling in every 10 minutes
During the second, stopping heating, fast cooling is to 21-23 DEG C.
2) etherificate
Solid sodium hydroxide 125g is dissolved in 700ml water, is cooled to 19-20 DEG C.By gained NaOH solution at stirring bar
Being slowly added under part in the hydrolysis mixture that step 1) obtains, temperature is maintained at 21-23 DEG C, airtight etherificate tank, evacuation, slowly
It is passed through oxirane 115g, confined reaction 5 hours, reacts complete.
3) absorption
PH5.5 is adjusted with concentrated hydrochloric acid.Under stirring, add water and the miscible agent of ethanol (volume ratio 1:3) of 2500ml, fully stir
Mix, stand；Take upper liquid, with 20.0g activated carbon as adsorbent, 60 DEG C of insulated and stirred 55 minutes, filter, thus will be etherified feed liquid
Middle impurity and small part bacterial endotoxin remove.
4) ultrafiltration
Step 3) gained filtrate is added water to 9000ml, then is divided into A, B, C tri-parts (3000*3).It is separately added into sulfurous acid
Ammonium monohydrate 0g, 40.25g, 321.97g, be sufficiently stirred for 1.5h, and filtrate is with the ultrafilter membrane ultrafiltration of 100,000 molecular weight.
5) it is dried
HES solution after ultrafiltration, at 150-160 DEG C of spray drying, collects to obtain sample.
Specific experiment result sees table 1.
Example 3
1) hydrolysis
In the reactor of 10L, add water 3250ml, under stirring, add pharmaceutical grade starch 1000g, add concentrated hydrochloric acid
13.5ml, is warming up to 90 DEG C, is incubated 89-92 DEG C, and once, rapid estimated viscosity, when the delivery time is at 1 point 37 in sampling in every 10 minutes
During the second, stopping heating, fast cooling is to 19-20 DEG C.
2) etherificate
Solid sodium hydroxide 30g is dissolved in 550ml water, is cooled to 19-20 DEG C.By gained NaOH solution at stirring condition
Under be slowly added in the hydrolysis mixture that step 1) obtains, temperature is maintained at 19-20 DEG C, airtight etherificate tank, and evacuation slowly leads to
Enter oxirane 125g, confined reaction 6.5 hours, react complete.
3) absorption
PH5.8 is adjusted with concentrated hydrochloric acid.Under stirring, add water and the miscible agent of ethanol (volume ratio 1:3) of 1750ml, fully stir
Mix, stand；Take upper liquid, with 10.0g activated carbon as adsorbent, 70 DEG C of insulated and stirred 50 minutes, filter, thus will be etherified feed liquid
Middle impurity and small part bacterial endotoxin remove.
4) ultrafiltration
Step 3) gained filtrate is added water to 7200ml, then is divided into A, B, C tri-parts (2400*3).It is separately added into sulfurous acid
Hydrogen sodium 0g, 19.77g, 49.44g, be sufficiently stirred for 1.5h, and filtrate is with the ultrafilter membrane ultrafiltration of 100,000 molecular weight.
5) it is dried
HES solution after ultrafiltration, at 170-180 DEG C of spray drying, collects to obtain sample.
Specific experiment result sees table 1.
The result of example 1-3
Table 1: the result data of example 1-3
According to data in table 1 it can be seen that along with the concentration of sulfurous acid, bisulfite and/or inferior sulfate radical is necessarily
In the range of improve, it is possible to preferably reduce endotoxin content in product, improve the weight average molecular weight of product, the weight of product simultaneously
The raising of average molecular weight shows that sample molecule size difference reduces, and quality is improved.
Claims (9)
1. a method of purification for hetastarch, comprising:
1) by the aqueous solution of hetastarch obtained by the steps of activated carbon adsorption of hetastarch preparation technology and sulfurous
One or more mixing in acid, bisulfites, sulphite, obtain mixed solution, wherein, in step 1) mixing that obtains
In solution, the total concentration of sulfurous acid, bisulfite and/or inferior sulfate radical is 0.5-0.8mol/L；And
2) by step 1) mixed solution that obtains carries out ultrafiltration, the hetastarch of isolated purification.
Method the most according to claim 1, wherein, described bisulfites is sodium sulfite.
Method the most according to claim 1, wherein, described sulphite is ammonium sulfite and/or sodium sulfite.
Method the most according to claim 1, wherein, step 1) described in mixing carry out under agitation.
Method the most according to claim 1, wherein, step 2) described in ultrafiltration in ultrafilter membrane used be 150,000 to retain point
The ultrafilter membrane of son amount and/or the ultrafilter membrane of 100,000 molecular cut offs.
Method the most according to claim 1, wherein, step 2) described in ultrafiltration in ultrafilter membrane used be 100,000 to retain point
The ultrafilter membrane of son amount.
Method the most according to claim 1, wherein, step 2) described in separation include: by the middle-molecular-weihydroxyethyl of isolated
Hetastarch is dried, thus obtains hetastarch finished product.
Method the most according to claim 7, wherein, described dry including is spray-dried；Baking temperature is 150-180
℃。
9. according to the method described in any one in claim 1-7, wherein, described hetastarch is middle-molecular-weihydroxyethyl hydroxyl second
Base starch.
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