CN102887958B - Preparation method of hydroxyethyl starch - Google Patents
Preparation method of hydroxyethyl starch Download PDFInfo
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- CN102887958B CN102887958B CN201110202084.3A CN201110202084A CN102887958B CN 102887958 B CN102887958 B CN 102887958B CN 201110202084 A CN201110202084 A CN 201110202084A CN 102887958 B CN102887958 B CN 102887958B
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Abstract
The invention provides a preparation method of hydroxyethyl starch and is characterized in that the preparation method comprises the following steps of: adding a water solution into a reactor, pouring starch with stirring, adding sodium hydroxide or sodium carbonate, stirring and reacting at 30-50 DEG C, filtering to obtain alkaline activated starch for later use; adding an ethanol solution into the reactor, pouring the alkaline activated starch and sodium hydroxide, evenly stirring, sealing the reactor, vacuumizing, adding epoxy ethane, stirring, and filtering to obtain hydroxyethyl starch. By the adoption of the method, the amount of alkali during hydroxyethylation can be reduced, and even the alkali can not be added. Therefore, intensity of the reaction and side reaction are greatly reduced, the reaction condition is mild, and the quality is better controlled.
Description
Technical field
The present invention relates to a kind of preparation method, particularly a kind of preparation method of hydroxyethylamyle, belongs to technical field of pharmaceutical biotechnology.
Background technology
Hydroxyethylamyle (hydroxyethyl starch, HES) can be used for different fields, as papermaking, stamp, sizes mixing, and expands clinically, and become irreplaceable part clinically for Q volume of blood.The synthetic method of hydroxyethylamyle is many, be generally solution rheological problem, most employing first carries out hydroxyethylation in the basic conditions by after starch material hydrolysis to a certain extent, in fact this reactive mode destroys the structure of starch, have also been changed the composition of raw starch, as the composition of side chain and amylose starch, make reaction uneven and a lot of side reaction can be produced under this reaction conditions, thus bad control quality product; Another kind of mode directly drops into raw material, but the natural structure of this mode starch becomes dyssynthesis, and will carry out under very drastic conditions, the bad control of condition, quality product is also uncontrollable; Another mode is reacted after gelatinization or gelling starches, and this mode not only destroys starch structure, and the bad control of reaction stream sex change, and simultaneous reactions by product is also more.
Summary of the invention
The object of the invention is the preparation method of openly a kind of hydroxyethylamyle.
The present invention seeks to be achieved through the following technical solutions:
The preparation method of hydroxyethylamyle of the present invention comprises the steps:
A, prepare basic activated starch
In reactor, add the aqueous solution 30 ~ 50 parts by volume, stir lower input starch 5 ~ 15 weight part, filter after 30 ~ 50 DEG C of Water Unders are washed; Get 20 ~ 40 parts by volume water and add reactor, then add the starch after washing, add sodium hydroxide or sodium carbonate 0.05 ~ 0.15 weight part under stirring, under 30 ~ 50 DEG C of conditions, stirring reaction filtered after 60 ~ 150 minutes, obtained basic activated starch;
B, prepare hydroxyethylamyle
Add 85% ~ 95% ethanolic soln 20 ~ 40 parts by volume in the reactor, stir after dropping into the sodium hydroxide of basic activated starch 10 ~ 15 weight part and 0 ~ 0.15 weight part, reactor is airtight, vacuumize, add oxyethane 1.7 ~ 2.5 weight part, 30 ~ 50 DEG C of stirring reactions 18 ~ 23 hours, filter, obtain hydroxyethylamyle.
The preparation method of hydroxyethylamyle of the present invention is preferably following steps:
A, prepare basic activated starch
In reactor, add the aqueous solution 40 parts by volume, stir lower input starch 10 weight part, filter after 40 DEG C of Water Unders are washed; Get 30 parts by volume water and add reactor, then add the starch after washing, add sodium hydroxide or sodium carbonate 0.10 weight part under stirring, filter after 90 minutes at 40 DEG C of condition stirring reactions, obtain basic activated starch;
B, prepare hydroxyethylamyle
Add 90% ethanolic soln 30 parts by volume in the reactor, stir after dropping into basic activated starch 10 weight part, reactor is airtight, vacuumize, add oxyethane 2.1 weight part, 40 DEG C of stirring reactions 21 hours, filter, obtain hydroxyethylamyle.
The preparation method of hydroxyethylamyle of the present invention can also be preferably following steps:
A, prepare basic activated starch
In reactor, add the aqueous solution 35 parts by volume, stir lower input starch 12 weight part, filter after 45 DEG C of Water Unders are washed; Add 27 parts by volume water and add reactor, then the starch after washing is added, sodium hydroxide or sodium carbonate 0.05 weight part is added under stirring, filter after 30 minutes at 40 DEG C of condition stirring reactions, get the starch after above-mentioned washing, add sodium hydroxide or sodium carbonate 0.10 weight part under stirring, filter after 120 minutes at 40 DEG C of condition stirring reactions, obtain basic activated starch;
B, prepare hydroxyethylamyle
Add in the reactor, 85% ethanolic soln 25 parts by volume, stirs after dropping into the sodium hydroxide of basic activated starch 10 weight part and 0.05 weight part, reactor is airtight, vacuumize, add oxyethane 1.8 weight part, 45 DEG C of stirring reactions 18 hours, filter, obtain hydroxyethylamyle.
The preparation method of hydroxyethylamyle of the present invention can also be preferably following steps:
A, prepare basic activated starch
In reactor, add the aqueous solution 45 parts by volume, stir lower input starch 8 weight part, filter after 35 DEG C of Water Unders are washed; Get 35 parts by volume water and add reactor, then add the starch after washing, add sodium hydroxide or sodium carbonate 0.12 weight part under stirring, filter after 110 minutes at 45 DEG C of condition stirring reactions, obtain basic activated starch;
B, prepare hydroxyethylamyle
Add 87% ethanolic soln 35 parts by volume in the reactor, stir after dropping into the sodium hydroxide of basic activated starch 15 weight part and 0.10 weight part, reactor is airtight, vacuumize, add oxyethane 3.4 weight part, 35 DEG C of stirring reactions 23 hours, filter, obtain hydroxyethylamyle.
Weight part in the invention described above pharmaceutical composition preparation method and the pass of parts by volume are the relation of g/ml.
The hydroxyethylamyle prepared of the inventive method can by being hydrolyzed to obtain the hydroxyethylamyle of different molecular weight; In preparation method's step B of hydroxyethylamyle of the present invention, ethanol is substituted by methyl alcohol or propyl alcohol; Every inventive concept instruct under do any flexible behavior, as added salt inhibitor in this step, or change some parameter, all within scope.
Hydroxyethylamyle preparation method of the present invention can reduce the charging capacity of the alkali when hydroxyethylation, does not even drop into alkali, greatly reduces the severe degree of reaction and the generation of side reaction like this, makes condition very gentle, and better quality controls.Experimental example and embodiment are used for further illustrating but are not limited to the present invention below.
Experimental example one: contrast experiment
*the inventive method, is shown in embodiment one.
*direct feeding method: 1. put into by 30g starch and be added with in 200ml water, then add 0.3g sodium hydroxide, stirs and is warming up to 95 DEG C, make gelation, be then cooled to less than 10 DEG C, add oxyethane 6.8g.Stirring is warming up to 40 DEG C, keeps 21 hours.2. regulate pH1.0 with hydrochloric acid, 80 DEG C of hydrolysis after 4 hours, then with sodium hydroxide neutralization, filter and get final product.
* *first hydroxyethylation method after hydrolysis: 1. put into by 30g starch and be added with in 150ml water, regulate pH1.0 with hydrochloric acid, 80 DEG C of hydrolysis after 4 hours, again with sodium hydroxide neutralization, 2. then add 0.5g sodium hydroxide, stirring and dissolving, be cooled to less than 10 DEG C, add oxyethane 6.8g.Stirring is warming up to 40 DEG C, keeps 23 hours.Filter and get final product.
Table one: contrast and experiment (feeding intake calculating by 30g starch)
Conclusion: hydroxyethylamyle preparation method reaction conditions of the present invention is gentle, and side reaction is low, better quality controls.
Following embodiment all can realize the effect of above-mentioned experimental example.
Embodiment
Embodiment one:
A, prepare basic activated starch
Aqueous solution 40ml is added in reactor, stir lower input starch 10g, under 40 DEG C of conditions, filter after washing starch, get 30ml water in reactor, add the starch after washing, under stirring, add sodium hydroxide 0.10g, filter after 90 minutes at 40 DEG C of condition stirring reactions, obtain basic activated starch;
B, prepare hydroxyethylamyle
Add 90% ethanolic soln 30ml in the reactor, stir after dropping into basic activated starch 10g, reactor is airtight, vacuumize, add oxyethane 2.1g, 40 DEG C of stirring reactions 21 hours, filter, obtain hydroxyethylamyle.
Embodiment two:
A, prepare basic activated starch
Aqueous solution 35ml is added in reactor, stir lower input starch 12g, under 45 DEG C of conditions, filter after washing starch, add 27ml water in reactor, add the starch after washing, under stirring, add sodium carbonate 0.05g, filter after 30 minutes at 40 DEG C of condition stirring reactions, add above-mentioned starch again, add sodium carbonate 0.10g under stirring, filter after 120 minutes at 40 DEG C of condition stirring reactions, obtain basic activated starch;
B, prepare hydroxyethylamyle
Add in the reactor, 85% methanol solution 25ml, stir after dropping into the sodium hydroxide of basic activated starch 10g and 0.05g, reactor is airtight, vacuumize, add oxyethane 1.8g, 45 DEG C of stirring reactions 18 hours, filter, obtain hydroxyethylamyle;
Obtained hydroxyethylamyle is made into the concentration of 20%, regulates PH to 1.5, react 5 hours under 60 DEG C of conditions, the hydroxyethylamyle of obtained molecular weight 200KD.
Embodiment three:
A, prepare basic activated starch
Aqueous solution 45ml is added in reactor, stir lower input starch 8g, under 35 DEG C of conditions, filter after washing starch, get 35ml water in reactor, add the starch after washing, under stirring, add sodium hydroxide 0.12g, filter after 110 minutes at 45 DEG C of condition stirring reactions, obtain basic activated starch;
B, prepare hydroxyethylamyle
Add 87% ethanolic soln 35ml in the reactor, stir after dropping into the sodium hydroxide of basic activated starch 15g and 0.10g, reactor is airtight, vacuumize, add oxyethane 3.4g, 35 DEG C of stirring reactions 23 hours, filter, obtain hydroxyethylamyle;
Obtained hydroxyethylamyle is made into the concentration of 25%, regulates PH to 1.0, react 4 hours under 60 DEG C of conditions, the hydroxyethylamyle of obtained molecular weight 130KD.
Embodiment four:
A, prepare basic activated starch
In reactor, add aqueous solution 40ml, stir lower input starch 8g, under 42 DEG C of conditions, filter after washing starch, then add the above-mentioned starch of 30ml, under stirring, add sodium hydroxide 0.15g, under 50 DEG C of conditions, stirring reaction filtered after 100 minutes, obtained basic activated starch;
B, prepare hydroxyethylamyle
Add ethanolic soln 25ml in the reactor, stir, after adding the sodium hydroxide solution containing 0.1g after dropping into the basic activated starch of 14g, reactor is airtight, vacuumize, add oxyethane 2.0g, 40 DEG C of stirring reactions 19 hours, filter, obtain hydroxyethylamyle.
Obtained hydroxyethylamyle is made into the concentration of 10%, regulates PH to 1.0, react 2 hours under 60 DEG C of conditions, the hydroxyethylamyle of obtained molecular weight 110KD.
Embodiment five:
A, prepare basic activated starch
In reactor, add aqueous solution 28ml, stir lower input starch 11g, under 38 DEG C of conditions, filter after washing starch, get 22ml water in reactor, add the starch after washing, add sodium carbonate 0.14g under stirring, filter after 120 minutes at 48 DEG C of condition stirring reactions, obtain basic activated starch;
B, prepare hydroxyethylamyle
Add 90% acetone soln 36ml in the reactor, stir after dropping into basic activated starch 12g, reactor is airtight, vacuumize, add oxyethane 2.0g, 40 DEG C of stirring reactions 22 hours, filter, obtain hydroxyethylamyle; Obtained hydroxyethylamyle is made into the concentration of 20%, regulates PH to 1.0, react 3 hours under 70 DEG C of conditions, the hydroxyethylamyle of obtained molecular weight 480KD.
Claims (4)
1. a preparation method for hydroxyethylamyle, is characterized in that this hydroxyethylamyle preparation method comprises the steps:
A, prepare basic activated starch
In reactor, add the aqueous solution 30 ~ 50 parts by volume, stir lower input starch 5 ~ 15 weight part, filter after 30 ~ 50 DEG C of Water Unders are washed; Add 20 ~ 40 parts by volume water in the reactor, then add the starch after washing, add sodium hydroxide or sodium carbonate 0.05 ~ 0.15 weight part under stirring, filter after 60 ~ 150 minutes at 30 ~ 50 DEG C of condition stirring reactions, obtain basic activated starch;
B, prepare hydroxyethylamyle
Add 85% ~ 95% ethanolic soln 20 ~ 40 parts by volume in the reactor, stir after dropping into basic activated starch 10 ~ 15 weight part, reactor is airtight, vacuumize, add oxyethane 1.7 ~ 2.5 weight part, 30 ~ 50 DEG C of stirring reactions 18 ~ 23 hours, filter, obtain hydroxyethylamyle; The pass of wherein said weight part/parts by volume is g/ml.
2. the preparation method of hydroxyethylamyle as claimed in claim 1, is characterized in that this hydroxyethylamyle preparation method comprises the steps:
A, prepare basic activated starch
The aqueous solution 40 parts by volume is added in reactor, stir lower input starch 10 weight part, filter after 40 DEG C of Water Unders are washed, add 30 parts by volume water in the reactor, then the starch after washing is added, add sodium hydroxide or sodium carbonate 0.10 weight part under stirring, filter after 90 minutes at 40 DEG C of condition stirring reactions, obtain basic activated starch;
B, prepare hydroxyethylamyle
Add 90% ethanolic soln 30 parts by volume in the reactor, stir after dropping into basic activated starch 10 weight part, reactor is airtight, vacuumize, add oxyethane 2.1 weight part, 40 DEG C of stirring reactions 21 hours, filter, obtain hydroxyethylamyle; The pass of wherein said weight part/parts by volume is g/ml.
3. the preparation method of the hydroxyethylamyle as described in as arbitrary in claim 1-2, is characterized in that in preparation method's step B, ethanol is substituted by methyl alcohol or propyl alcohol.
4. the preparation method of the hydroxyethylamyle as described in as arbitrary in claim 1-2, is characterized in that hydroxyethylamyle passes through to be hydrolyzed obtaining the hydroxyethylamyle of different molecular weight.
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| CN201110202084.3A CN102887958B (en) | 2011-07-19 | 2011-07-19 | Preparation method of hydroxyethyl starch |
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| CN201110202084.3A CN102887958B (en) | 2011-07-19 | 2011-07-19 | Preparation method of hydroxyethyl starch |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105777920A (en) * | 2016-05-19 | 2016-07-20 | 郑桂富 | Method for preparing hydroxyethyl starch 200/0.5 |
| CN109810199B (en) * | 2018-12-28 | 2021-04-06 | 东莞建泰生物科技有限公司 | Pretreatment method and system of starch slurry |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4016354A (en) * | 1974-10-07 | 1977-04-05 | The United States Of America As Represented By The Secretary Of The Navy | Preparation of pharmacologically active hydroxyalkyl starch |
| DE2700011A1 (en) * | 1977-01-03 | 1978-07-06 | Hideo Omoto | Prodn. of hydroxyethyl starch for use as plasma substitute - from waxy starch by reaction with ethylene oxide then controlled acid hydrolysis |
| US6015700A (en) * | 1997-06-13 | 2000-01-18 | Mayo Foundation For Medical Education And Research | Cdc2 protein kinase from pneumocystis carinii |
| CN1926155A (en) * | 2004-03-01 | 2007-03-07 | B·布朗·梅尔松根有限公司 | Hydroxyethyl starch |
| CN101402690A (en) * | 2008-09-27 | 2009-04-08 | 杭州民生药业集团有限公司 | Method for preparation of hydroxyethyl starch |
| CN101775076A (en) * | 2010-02-25 | 2010-07-14 | 成都青山利康药业有限公司 | Method for preparing hydroxyethyl starch |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5941441B2 (en) * | 1977-11-14 | 1984-10-06 | 杏林製薬株式会社 | Method for producing hydroxyethyl starch |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4016354A (en) * | 1974-10-07 | 1977-04-05 | The United States Of America As Represented By The Secretary Of The Navy | Preparation of pharmacologically active hydroxyalkyl starch |
| DE2700011A1 (en) * | 1977-01-03 | 1978-07-06 | Hideo Omoto | Prodn. of hydroxyethyl starch for use as plasma substitute - from waxy starch by reaction with ethylene oxide then controlled acid hydrolysis |
| US6015700A (en) * | 1997-06-13 | 2000-01-18 | Mayo Foundation For Medical Education And Research | Cdc2 protein kinase from pneumocystis carinii |
| CN1926155A (en) * | 2004-03-01 | 2007-03-07 | B·布朗·梅尔松根有限公司 | Hydroxyethyl starch |
| CN101402690A (en) * | 2008-09-27 | 2009-04-08 | 杭州民生药业集团有限公司 | Method for preparation of hydroxyethyl starch |
| CN101775076A (en) * | 2010-02-25 | 2010-07-14 | 成都青山利康药业有限公司 | Method for preparing hydroxyethyl starch |
Non-Patent Citations (1)
| Title |
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| JP特开昭54-69193A 1979.06.02 * |
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Address after: 611138 Sichuan science and Technology Development Zone, Wenjiang District, Chengdu City, Xinhua Road, the central section of the two paragraph Patentee after: SICHUAN KELUN DRUG RESEARCH INSTITUTE CO., LTD. Address before: 611138 south two road, Satellite City Industrial Development Zone, Xindu District, Chengdu, Sichuan Patentee before: SICHUAN KELUN DRUG RESEARCH INSTITUTE CO., LTD. |