CN104277126A - Method for purifying hydroxyethyl starch - Google Patents
Method for purifying hydroxyethyl starch Download PDFInfo
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- CN104277126A CN104277126A CN201310290621.3A CN201310290621A CN104277126A CN 104277126 A CN104277126 A CN 104277126A CN 201310290621 A CN201310290621 A CN 201310290621A CN 104277126 A CN104277126 A CN 104277126A
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Abstract
The invention provides a method for purifying hydroxyethyl starch. The method comprises the following steps: (1) mixing an aqueous solution of hydroxyethyl starch obtained by an activated carbon adsorption step in a hydroxyethyl starch preparation process with one or more than of sulfurous acid, hydrosulphite and sulfite, thereby obtaining a mixed solution; and (2) performing ultrafiltration on the mixed solution obtained in the step (1), separating, thereby obtaining the purified hydroxyethyl starch. The method disclosed by the invention has the positive effects that the method can reduce the content of bacterial endotoxin in the finished product hydroxyethyl starch, and the inherent quality of the product is greatly improved; the difference of molecular dimension in the finished hydroxyethyl starch is reduced, and the quality of the finished product is improved; and moreover, the method is easy to operate, pollution-free, rapid and easy to implement and suitable for industrial production, and the quality of the finished product is stable.
Description
Technical field
The invention belongs to pharmacy field, in particular to a kind of method of purification of hydroxyethylamyle.
Background technology
Hydroxyethylamyle (HES) uses usually in the patient of those massive blood losses, has and suppresses the effect of Ink vessel transfusing erythrocyte aggregation; Be mainly used in improving microcirculation disturbance, clinical in hypovolemic shock, as rhomboembolia type illness such as shocks in hemorrhagic shock, burn property and operation.HES can keep the Q volume of blood of patient, prevents their circulation from collapsing simultaneously.Because hydroxyethylamyle itself is formed by starch transformation, its structure is similar with glycogen, and irritated incidence is far below dextran, and the virus infection of lifeless matter goods threatens, and medical expense is lower again and be day by day subject to clinical welcome.
The chemical name of hydroxyethylamyle is 6-(2-hydroxyethyl) starch; English Hydroxyethyl Starch by name; Structural formula is as shown in the formula shown in I:
Formula I
Hydroxyethylamyle is white or off-white powder, and odorless is tasteless, has stronger water absorbability.Soluble in the hot water, dissolve in cold water slowly, insoluble in methyl alcohol and ether.Specific optical rotation is+175 ° ~+195 °.
The hydroxyethylamyle huge number used at present both at home and abroad, by molecular weight divide have low (Mw<100kDa), in (Mw is between 100kDa ~ 300kDa), high (Mw>300kDa) three kinds; Divide by replacement level and have low (Ms is between 0.3 ~ 0.6) and high (Ms>0.6) two kinds.For a long time, the hydroxyethylamyle that domestic enterprise produces has molecular-weight average to be 20,000 and 40,000 two kind, belong to Low Moleculor Hydroxyethylstarch, concentration is 6%, all applies with 0.5% sodium chloride injection compatibility, both all within the scope of kidney threshold (70,000 molecular weight), therefore series products enters after in body and drains rapidly through kidney, and the dilatation time is short, and dilatation is not steady, often can not reach the effect of Q volume of blood expansion, also just cannot realize the object recovering Hemodynamics balance.Untoward reaction simultaneously has report repeatly, does not abroad produce.Due to the aspect such as security and curative effect, the HES of early stage lower molecular weight high substitution value is substituted by middle-molecular-weihydroxyethyl low degree of substitution HES just gradually.130/0.4 by reducing molecular weight and the molecular weight distribution that narrows, and reduces and replace level and change replacement mode (C2/C6), have good security and capacity enlargement effect clinically.
In the prior art, producing hydroxyethylamyle is generally starting material with starch; Through steps such as hydrolysis, etherificate, absorption, ultrafiltration and spraying dry.Such as, the customary preparation methods of hydroxyethylamyle of the prior art is: starch adds a certain amount of purified water, hydrochloric acid or enzyme, be hydrolyzed at a certain temperature, controlled hydrolysis degree, hydrolysis is stopped when hydrolysis reaches suitable molecular weight, catalyzer is made with sodium hydroxide, starch and oxyethane is made to carry out ethoxyl etherification to carry out etherificate, (such as) gac is used to remove impurity and decolouring afterwards, by ultra-filtration membrane by impurity removings such as the hydroxyethylamyle of small-molecular-weight and salt, obtain hydroxyethylamyle finished product finally by spraying dry.
In the preparation of hydroxyethylamyle, because starch had once been infected with a large amount of bacterium in production, storage, transportation, after these bacterial death, cellular lysate is stored in feed liquid, lipopolysaccharides (LPS) and lipoid A is had in lysate, also known as intracellular toxin, for the active part of thermal source, their relative molecular weight is generally 1-2.5 ten thousand KD, the association body of 50-100KD is easily associated in water, this kind of material has stronger thermotolerance and chemical stability, is not easily eliminated (100 DEG C, heating 1h also can not be destroyed).Intracellular toxin can cause human body heating, microcirculation disturbance, endotoxin shock and disseminated inravascular coagulation etc., will bring potential safety hazard, and even cause malpractice to Clinical practice.
And as injection raw material, the bacterial endotoxin index of medium molecular weight hydroxyethyl starch is a very important quality index, bacterial endotoxin index not only will meet quality criteria requirements, and for the consideration of drug safety, at present in the bacterial endotoxin index of medium molecular weight hydroxyethyl starch, its upper limit is about 50EU/g, and the trend it reduced as best one can is also more and more obvious.
In the preparation method of existing hydroxyethylamyle, the removal of bacterial endotoxin, mainly by after etherification step, removes bacterial endotoxin by charcoal absorption and ultrafiltration process.
Wherein, although charcoal absorption, in attracts bacteria intracellular toxin, reduction liquid, bacteria endotoxin content has better effects, but absorption finally can reach certain saturated extent of adsorption (≤75%), and if take the loss adding also to cause main ingredient composition into the way of gac in order to the object of the more bacterial endotoxins of satisfied absorption, affect yield, so the bacterial endotoxin in liquid will be made to be reduced to lower level, the method has its limitation.
And although ultrafiltration process can remove a large amount of bacterial endotoxins, but for hydroxyethylamyle (particularly medium molecular weight hydroxyethyl starch), because the molecular weight distribution (15000-400000) of this product and bacterial endotoxin molecular weight distribution (several thousand to hundreds of thousands of) have major part to overlap, in this way the bacterial endotoxin in removing liquid is also restricted in actual applications.
Summary of the invention
In order to solve the problems of the technologies described above, the invention provides a kind of method of purification of hydroxyethylamyle.
Specifically, the present invention includes:
(1) method of purification for hydroxyethylamyle, it comprises:
1) aqueous solution of the hydroxyethylamyle charcoal absorption step by hydroxyethylamyle preparation technology obtained mixes with one or more in sulfurous acid, hydrosulphite, sulphite, obtains mixing solutions; And
2) mixing solutions step 1) obtained carries out ultrafiltration, is separated the hydroxyethylamyle obtaining purifying.
(2) method Gen Ju (1), wherein, in the mixing solutions that step 1) obtains, the total concn of sulfurous acid, bisulfite and/or inferior sulfate radical is 0.05-1.0mol/L.
(3) method Gen Ju (2), wherein, in the mixing solutions that step 1) obtains, the total concn of described sulfurous acid, bisulfite and/or inferior sulfate radical is 0.08-0.8mol/L.
(4) method Gen Ju (1), wherein, described hydrosulphite is sodium bisulfite.
(5) method Gen Ju (1), wherein, described sulphite is ammonium sulphite and/or S-WAT.
(6) method Gen Ju (1), wherein, the mixing described in step 1) is carried out under agitation.
(7) method Gen Ju (1), wherein, step 2) described in ultrafiltration in ultra-filtration membrane used be the ultra-filtration membrane of 150,000 molecular weight cut-offs and/or the ultra-filtration membrane of 100,000 molecular weight cut-offs; Be preferably the ultra-filtration membrane of 100,000 molecular weight cut-offs.
(8) method Gen Ju (1), wherein, step 2) described in separation comprise: carry out drying by being separated the medium molecular weight hydroxyethyl starch obtained, thus obtain hydroxyethylamyle finished product.
(9) method Gen Ju (8), wherein, described drying comprises spraying dry; Drying temperature is preferably 150-180 DEG C.
(10) according to the method in (1)-(9) described in any one, wherein, described hydroxyethylamyle is medium molecular weight hydroxyethyl starch.
Method tool provided by the invention has the following advantages and positively effect:
Method of the present invention can reduce bacteria endotoxin content in hydroxyethylamyle finished product, and making has obvious reduction before contained bacterial endotoxin level does not use this method in finished product, substantially increases product inner quality.In addition, method of the present invention also reduces the difference of the molecular size in hydroxyethylamyle finished product, improves the quality of finished product.Method easy handling of the present invention, pollution-free, and final product quality is stablized, and is applicable to industrialized production.
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
In this article, " bacterial endotoxin " comprises so a kind of heteromultimer, its essence is lipopolysaccharides (lipopolysaccharide, LpS), comprises lipoid A (lipidA), core polysaccharide, O-specific antigens polysaccharide (O-antigen) three integral parts.Wherein lipoid A is made up of the longer chain fatty acid of phosphoglucose amine disaccharide main chain and covalently bound 10-18 carbon with it, and namely simultaneously containing hydrophobic center and hydrophilic edge, being a kind of two property molecule, is again soda acid amphipathic molecule.The bacterium of different genera, all has basically identical lipoid A skeleton, is part the most conservative in intracellular toxin.And lipoid A has complete endotoxic characteristic, be the active centre of LPS, also maximum to the harm of HUMAN HEALTH.Core polysaccharide is made up of with the kernel portion being connected lipoid A the outer core part connecting O-specificity chain.Outer core part is primarily of hexose and heptose composition, and have higher sugared heterology, the difference of some Gram-negative bacteria core component mostly occurs on the hexose molecule in this structure division.Kernel portion is then relatively stable, primarily of KDO(2-ketone group-3-deoxidation-D. sweet dew alcohol type-octulosonic acid) and heptose formation.O-specificity chain repeats 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 intracellular toxin does not exist O-specificity chain, and this does not affect and damage its biological activity.The structure of the special chain of O-is the most labile part in intracellular toxin molecule, as: its monosaccharide molecule can by the glycosylation of second phthalein, the also number of convertible repeating unit.The special chain of O-of different strain is different, and therefore its antigen has the specificity of bacterial classification.On epicyte, the effect of self-protection is played in the active change of intracellular toxin kind, can adapt to the change of surrounding environment.Under common pH condition, the saccharide residue in intracellular toxin molecule is by partial phosphorylation (pK
1=l.3, pK
2=8.2, pI=3.1), phosphate groups and KDO carry a large amount of negative charge, and therefore intracellular toxin molecule generally shows electronegativity in the solution.
In this article, " medium molecular weight hydroxyethyl starch " refers to that weight-average molecular weight is 110000-150000 dalton, and substitution value is the hydroxyethylamyle of 0.36-0.45.
In this article, " hydroxyethylamyle preparation technology " refers to starch to be starting material, obtains the process of hydroxyethylamyle through hydrolysis, etherificate, absorption, ultrafiltration and drying and other steps:
Wherein, hydrolyzed starch generally adopts acid hydrolysis or enzymic hydrolysis, preferred acid hydrolysis of the present invention; Usually, acid is hydrochloric acid, and hydrolysis temperature is 85-95 DEG C, adopts viscosity method to detect hydrolysis process;
Wherein, etherificate generally adopts oxyethane or chloroethanol as etherifying agent, optimization ethylene oxide of the present invention; Etherificate is generally carried out in the basic conditions (pH is 12-14), and etherification temperature is 17-24 DEG C, and etherification time is 4-8h;
Wherein, absorption is general adopts gac to be sorbent material;
Wherein, ultrafiltration is that filtration medium refines feed liquid with ultra-filtration membrane, and the selection of ultra-filtration membrane is determined by molecular weight product.Preferred target is the ultra-filtration membrane of 100,000 and/or 150,000 molecular weight cut-offs is that filtration medium carries out ultrafiltration;
Wherein, drying generally adopts drying under reduced pressure, constant pressure and dry, lyophilize, spraying dry etc.; Preferably spray drying of the present invention.
In order to reduce the bacterial endotoxin index of hydroxyethylamyle, present inventor has performed large quantitative analysis and production process monitoring, found that: in existing hydroxyethylamyle production technique, inferior sulfate radical is added in hydroxyethylamyle feed liquid ultrafiltration step forward direction feed liquid, endotoxic dissolving environment can be changed, reduce the association in the solution of intracellular toxin macromole, be conducive to intracellular toxin to be removed when ultrafiltration, the bacterial endotoxin level of final production medium molecular weight hydroxyethyl starch out also can obviously reduce, thus improves the quality of products.The present inventor on this basis, thus obtains technical scheme of the present invention further.
Specifically, the invention provides:
A method of purification for hydroxyethylamyle, it comprises:
1) aqueous solution of the hydroxyethylamyle charcoal absorption step by hydroxyethylamyle preparation technology obtained mixes with one or more in sulfurous acid, hydrosulphite, sulphite, obtains mixing solutions; And
2) mixing solutions step 1) obtained carries out ultrafiltration, is separated the hydroxyethylamyle obtaining purifying.
Preferably, in the mixing solutions that step 1) obtains, the total concn of sulfurous acid, bisulfite and/or inferior sulfate radical is 0.05-1.0mol/L.
Preferably, in the mixing solutions that step 1) obtains, the total concn of sulfurous acid, bisulfite and/or inferior sulfate radical is 0.08-0.8mol/L.
Preferably, described hydrosulphite is sodium bisulfite.
Preferably, described sulphite is ammonium sulphite and/or S-WAT.
Preferably, the mixing described in step 1) is carried out under agitation.
Preferably, step 2) described in ultrafiltration in ultra-filtration membrane used be the ultra-filtration membrane of 150,000 molecular weight cut-offs and/or the ultra-filtration membrane of 100,000 molecular weight cut-offs; Be preferably the ultra-filtration membrane of 100,000 molecular weight cut-offs.
Preferably, step 2) described in separation comprise: carry out drying by being separated the medium molecular weight hydroxyethyl starch obtained, thus obtain hydroxyethylamyle finished product.It is further preferred that described drying comprises spraying dry; Drying temperature is preferably 150-180 DEG C.
Preferably, described hydroxyethylamyle is medium molecular weight hydroxyethyl starch.
A kind of embodiment of the present invention can be:
A preparation method for hydroxyethylamyle, the method comprises: use sulfurous acid, hydrosulphite, sulphite hydrotropy intracellular toxin, and reduce the associations of macromole in water such as intracellular toxin, during ultrafiltration, intracellular toxin is easily removed;
Preferably, hydrotropy use sulfurous acid, bisulfite, inferior sulfate radical concentration sum be 0.05-1.0mol/L.
Preferably, sulfurous acid, bisulfite, inferior sulfate radical that hydrotropy uses, can sulfurous acid solution, sulphite, one or more in hydrosulphite.
A kind of specific embodiments of the present invention can be:
The method of purification of hydroxyethylamyle of the present invention can be included in the preparation method of following hydroxyethylamyle, and wherein, the preparation method of described medium molecular weight hydroxyethyl starch comprises the following steps:
1) Starch Hydrolysis: take purified water as solvent, dissolve starch when heated and stirred, and then add mineral acid and to be hydrolyzed reaction;
2) hydroxyethyl etherificate: add basic catalyst and etherifying agent by step 1) products therefrom, under vacuum protection, carries out etherification reaction;
3) decolorization adsorption: by step 2) products therefrom adds the miscible agent of water and ethanol, and fully stir, leave standstill; Get upper liquid, add gac, carry out decolouring clarification;
4) ultrafiltration: step 3) products therefrom is used sulfurous acid, hydrosulphite, sulphite hydrotropy intracellular toxin, reduces the associations of macromole in water such as intracellular toxin, crosses ultra-filtration membrane and carries out ultrafiltration;
5) drying is separated: step 4) products therefrom is carried out separation dry, obtain hydroxyethylamyle finished product.
When preferably: above-mentioned steps 1), water is solvent, water is purified water, and its weight ratio in mixed system is 70-90%; Heating temperature is 85-95 DEG C; The mineral acid added is concentrated hydrochloric acid (as analytical pure concentrated hydrochloric acid), and concentration is 36-38 % by weight, and its weight ratio in mixed system is 0.1%-2%; Carry out there being the situation of stirring.
The basic catalyst that preferably: above-mentioned steps 2) hydroxyethyl etherificate adds is concentration is 10%-20%(% by weight) sodium hydroxide solution, its weight ratio in mixed system is 0.5%-2.5%; Etherifying agent is oxyethane, and its weight ratio in mixed system is 1.7%-3.5%; The time of etherificate is 4-8h, and temperature of reaction is 17-24 DEG C; Carry out vacuum protection during etherificate, and carry out under the condition of Keep agitation.
Preferably: the above-mentioned steps 3) miscible agent for water and ethanol that adds of decolouring, its weight ratio in mixed system is 24.5%-33.6%; The weight ratio of the gac added in mixed system is 0.1%-0.3%; Decoloration device adopts stainless steel closed delivery Plate Filtration device, filtrate clarification reach 2010 pharmacopeia annex IX B " clarity test procedure " 0.5 level number below; Carry out there being the situation of stirring.
Preferably: above-mentioned steps 4) ultra-filtration membrane that employing 100,000 retains relative molecular mass (KD) that is chosen as of the film of ultrafiltration screens final molecular weight, completes feed liquid and refines; Or 150,000 ultra-filtration membranes retaining relative molecular mass (KD) screen final molecular weight, complete feed liquid and refine.
Separation drying preferably: above-mentioned steps 5) adopts spraying dry; Drying temperature is preferably 150-180 DEG C.
A kind of specific embodiments of the present invention can be:
1) be hydrolyzed: in the reactor of 3L, add water 650-700ml, under stirring, add starch 200g, add concentrated hydrochloric acid 2.7-50ml, be warming up to 90 DEG C, insulation 89-92 DEG C, by viscosity method controlled hydrolysis process, when hydrolysis reaches process stipulation requirement, stop hydrolysis.Fast cooling is to 19-23 DEG C.
2) hydroxyethyl etherificate: sodium hydroxide 6-25g is dissolved in 110-140ml water, is cooled to 19-23 DEG C.Under stirring, by sodium hydroxide solution, slowly join in hydrolysis mixture, temperature 19-23 DEG C, vacuumize, slowly pass into oxyethane 18-35g, confined reaction 5-8h.React complete, adjust pH5.5-7.5 with concentrated hydrochloric acid.
3) decolour, adsorb, under stirring, add the water of 350-500ml and the miscible agent of ethanol (volume ratio 1:3), fully stir, leave standstill; Get upper liquid, add gac 2.0-4.0g, 55-70 DEG C of insulated and stirred 50-65min, after filtration, adds water to 1400-1800ml.
4) ultrafiltration: add sulfurous acid or its salt, the concentration sum making sulfurous acid, bisulfite, inferior sulfate radical is 0.08-0.8mol/L, fully stirs 1.5h, and filtrate is with the ultra-filtration membrane ultrafiltration of 100,000 molecular weight.
5) dry, by the HES solution after ultrafiltration, 150-180 DEG C of spraying dry, obtains sample.
For a better understanding of the present invention, further explain and describe content of the present invention below by way of example, but these examples are not to be construed as limiting the scope of the invention.
In following example, pharmaceutical grade starch can derive from Zhengzhou Lv Bo Chemicals company limited; Gac can derive from Zhucheng Zhong Li Trade Co., Ltd.; Oxyethane can derive from Chengdu, Sichuan chemical inc.
In following example, the detection of bacterial endotoxin of hydroxyethylamyle finished product detects by the following method: the dynamic turbidimetric of the bacterial endotoxins test of the E part of Chinese Pharmacopoeia annex Ⅺ.The method of calculation of yield are: yield=finished weight ÷ amylopectin weight × 100%.
Example 1
1) be hydrolyzed
In the reactor of 10L, add water 3300ml, under stirring, add pharmaceutical grade starch 1000g, add concentrated hydrochloric acid 25ml, be warming up to 90 DEG C, insulation 89-92 DEG C, within every 10 minutes, sample once, rapid test viscosity, when the elution time at 1 point and 25 seconds time, stop 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.Gained NaOH solution slowly added under agitation in the hydrolysis mixture that step 1) obtains, temperature remains on 19-20 DEG C, and airtight etherificate tank, vacuumizes, and slowly passes into oxyethane 90g, and confined reaction 8 hours, reacts complete.
3) adsorb
PH7.5 is adjusted with concentrated hydrochloric acid.Under stirring, add the water of 1750ml and the miscible agent of ethanol (volume ratio 1:3), fully stir, leave standstill; Get upper liquid, with 15.0g gac for sorbent material, 55 DEG C of insulated and stirred 65 minutes, filter, thus by impurity in etherificate feed liquid and the removing of small part bacterial endotoxin.
4) ultrafiltration
Step 3) gained filtrate is added water to 7500ml, then is divided into A, B, C tri-parts (2500*3).Add sodium bisulfite 0g, 12.88g, 128.81g respectively, fully stir 1.5h, filtrate is with the ultra-filtration membrane ultrafiltration of 100,000 molecular weight.
5) dry
HES solution after ultrafiltration, at 160-170 DEG C of spraying dry, collects to obtain sample.
Specific experiment result is see table 1.
Example 2
1) be hydrolyzed
In the reactor of 10L, add water 3500ml, under stirring, add pharmaceutical grade starch 1000g, add concentrated hydrochloric acid 250ml, be warming up to 90 DEG C, insulation 89-92 DEG C, within every 10 minutes, sample once, rapid test viscosity, when the elution time at 1 point and 20 seconds time, stop 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.Gained NaOH solution slowly added under agitation in the hydrolysis mixture that step 1) obtains, temperature remains on 21-23 DEG C, and airtight etherificate tank, vacuumizes, and slowly passes into oxyethane 115g, and confined reaction 5 hours, reacts complete.
3) adsorb
PH5.5 is adjusted with concentrated hydrochloric acid.Under stirring, add the water of 2500ml and the miscible agent of ethanol (volume ratio 1:3), fully stir, leave standstill; Get upper liquid, with 20.0g gac for sorbent material, 60 DEG C of insulated and stirred 55 minutes, filter, thus by impurity in etherificate feed liquid and the removing of small part bacterial endotoxin.
4) ultrafiltration
Step 3) gained filtrate is added water to 9000ml, then is divided into A, B, C tri-parts (3000*3).Add ammonium sulphite monohydrate 0g, 40.25g, 321.97g respectively, fully stir 1.5h, filtrate is with the ultra-filtration membrane ultrafiltration of 100,000 molecular weight.
5) dry
HES solution after ultrafiltration, at 150-160 DEG C of spraying dry, collects to obtain sample.
Specific experiment result is see table 1.
Example 3
1) be hydrolyzed
In the reactor of 10L, add water 3250ml, under stirring, add pharmaceutical grade starch 1000g, add concentrated hydrochloric acid 13.5ml, be warming up to 90 DEG C, insulation 89-92 DEG C, within every 10 minutes, sample once, rapid test viscosity, when the elution time at 1 point and 37 seconds time, stop 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.Gained NaOH solution slowly added under agitation in the hydrolysis mixture that step 1) obtains, temperature remains on 19-20 DEG C, and airtight etherificate tank, vacuumizes, and slowly passes into oxyethane 125g, and confined reaction 6.5 hours, reacts complete.
3) adsorb
PH5.8 is adjusted with concentrated hydrochloric acid.Under stirring, add the water of 1750ml and the miscible agent of ethanol (volume ratio 1:3), fully stir, leave standstill; Get upper liquid, with 10.0g gac for sorbent material, 70 DEG C of insulated and stirred 50 minutes, filter, thus by impurity in etherificate feed liquid and the removing of small part bacterial endotoxin.
4) ultrafiltration
Step 3) gained filtrate is added water to 7200ml, then is divided into A, B, C tri-parts (2400*3).Add sodium bisulfite 0g, 19.77g, 49.44g respectively, fully stir 1.5h, filtrate is with the ultra-filtration membrane ultrafiltration of 100,000 molecular weight.
5) dry
HES solution after ultrafiltration, at 170-180 DEG C of spraying dry, collects to obtain sample.
Specific experiment result is see table 1.
The result of example 1-3
Table 1: the result data of routine 1-3
Can find out according to data in table 1: along with the concentration of sulfurous acid, bisulfite and/or inferior sulfate radical improves within the specific limits, endotoxin content in product can be reduced preferably, improve the weight-average molecular weight of product simultaneously, the raising of the weight-average molecular weight of product shows that sample molecule size differences reduces, and quality is improved.
Claims (10)
1. a method of purification for hydroxyethylamyle, it comprises:
1) aqueous solution of the hydroxyethylamyle charcoal absorption step by hydroxyethylamyle preparation technology obtained mixes with one or more in sulfurous acid, hydrosulphite, sulphite, obtains mixing solutions; And
2) mixing solutions step 1) obtained carries out ultrafiltration, is separated the hydroxyethylamyle obtaining purifying.
2. method according to claim 1, wherein, in the mixing solutions that step 1) obtains, the total concn of sulfurous acid, bisulfite and/or inferior sulfate radical is 0.05-1.0mol/L.
3. method according to claim 2, wherein, in the mixing solutions that step 1) obtains, the total concn of described sulfurous acid, bisulfite and/or inferior sulfate radical is 0.08-0.8mol/L.
4. method according to claim 1, wherein, described hydrosulphite is sodium bisulfite.
5. method according to claim 1, wherein, described sulphite is ammonium sulphite and/or S-WAT.
6. method according to claim 1, wherein, the mixing described in step 1) is carried out under agitation.
7. method according to claim 1, wherein, step 2) described in ultrafiltration in ultra-filtration membrane used be the ultra-filtration membrane of 150,000 molecular weight cut-offs and/or the ultra-filtration membrane of 100,000 molecular weight cut-offs; Be preferably the ultra-filtration membrane of 100,000 molecular weight cut-offs.
8. method according to claim 1, wherein, step 2) described in separation comprise: carry out drying by being separated the medium molecular weight hydroxyethyl starch obtained, thus obtain hydroxyethylamyle finished product.
9. method according to claim 8, wherein, described drying comprises spraying dry; Drying temperature is preferably 150-180 DEG C.
10. according to the method in claim 1-9 described in any one, wherein, described hydroxyethylamyle is medium molecular weight hydroxyethyl starch.
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