CN101824099B - Method for purifying crude product heparin sodium - Google Patents
Method for purifying crude product heparin sodium Download PDFInfo
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- CN101824099B CN101824099B CN2010101120820A CN201010112082A CN101824099B CN 101824099 B CN101824099 B CN 101824099B CN 2010101120820 A CN2010101120820 A CN 2010101120820A CN 201010112082 A CN201010112082 A CN 201010112082A CN 101824099 B CN101824099 B CN 101824099B
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Abstract
The invention discloses a method for purifying a crude product heparin sodium. The method comprises the following steps of: adjusting the pH value of the heparin sodium solution containing alcohol to remove most impurities; oxidizing the heparin sodium solution containing alcohol by using hydrogen peroxide for decoloring and impurity removing; and performing fractional precipitation of organic solvent to obtain the heparin sodium meeting pharmacopoeia standard. In the method, the heparin sodium solution containing low concentrate alcohol is selected in the steps of pH adjustment, impurity removal, oxidization and the like for operation, so that the method can not only effectively improve the product quality (ensuring impurities can be better separated from the heparin sodium and can be easily flocculated), but also ensure the product yield, the structure of the heparin sodium cannot be changed in the whole process, and the alcohol can be recycled. Therefore, the method has the advantages of low production cost, short production period, stable quality, suitability for mass production, and product quality in accordance with the quality requirement of injection heparin sodium raw material.
Description
Technical field:
The present invention relates to the purification process of heparin sodium, be specifically related to a kind ofly with crude heparin sodium, purifying becomes to meet the method that injection stage heparin sodium raw materials quality requires.
Background technology:
Heparin sodium derives from pig intestinal mucosa, is a kind of acidic mucopolysaccharide that contains sulfate, is typical anticoagulant, can stop the condensing process of blood, the formation of anti-hemostasis suppository.The clinical surgical operation front and back that are widely used as prevent thrombosis and embolism, preclude blood is solidified and as the antithrombotics of preserving fresh blood during blood transfusion, be widely used in prevention thrombus disease, treatment scheming infarction and nephrotic's oozing of blood treatment, can also be used to remove the uremia that children's's ephrosis forms.Heparin ointment is also widespread use in treating for skin disease and make-up and beauty.China is the country of heparin sodium output maximum, the heparin sodium products material of world market more than 70% all from China.Along with the increase of demand, the purification technique of heparin sodium all the more comes into one's own.
At present, the domestic technology that is used for the heparin sodium crude purifying mainly is an ion-exchange-resin process, and the removal of impurity under the different PH condition, oxidation, organic solvent precipitation classification.The ion-exchange-resin process production cycle is long, produces a large amount of waste water, cost height not only, and wasted resource.And deimpurity method under traditional different PH conditions, impurity is not easy flocculation, generally solves separation problem by high speed centrifugation or adding flocculation agent, unstable product quality, and yield is low, and the flocculation agent of adding is easy to generate residual.
Summary of the invention:
The technical problem to be solved in the present invention provides a kind of purification process of crude heparin sodium, separate the impurity in the heparin sodium more efficiently and effectively, simple to operate, with short production cycle, product yield is high, reliable in quality, the purified heparin sodium that obtains reaches and surpasses the pharmacopeia requirement.
The present invention is achieved through the following technical solutions:
A kind of purification process of crude heparin sodium is characterized in that comprising the following steps:
(1) crude heparin sodium is dissolved in the sodium chloride solution that weight concentration is 2-6%, adds alcohol again, making the alcohol weight concentration in the solution is 5%-15%;
(2) solution that step (1) is obtained is warming up to 50-60 ℃, regulates PH to 11-12 with alkali, and insulation was filtered more than 2 hours, discards insolubles (insolubles discards after cleaning with 5% salt solution again, and scavenging solution is recyclable);
(3) the 0.8-1.2 alcohol doubly of adding filtrate weight in gained filtrate, precipitation, supernatant discarded alcohol;
(4) throw out that step (3) is obtained is dissolved in the sodium chloride solution that weight concentration is 2-6%, adds alcohol again, and making the alcohol weight concentration in the solution is 5%-15%;
(5) solution of step (4) is cooled to the freezing point to 5 ℃ of solution, regulates PH to 2.5-3.5, filter, discard insolubles with acid;
(6) the 0.7-0.9 alcohol doubly of adding solution weight in gained solution, precipitation, supernatant discarded alcohol;
(7) throw out that step (6) is obtained is dissolved in the sodium chloride solution that weight concentration is 2-6%, add alcohol again, making the alcohol weight concentration in the solution is 5%-15%, regulate PH to 11-12 with alkali again, intensification also remains on 30-40 ℃, adds the hydrogen peroxide or the potassium permanganate of solution weight 2%, oxidation 23-25 hour, filter, collect filtrate;
(8) filtrate that step (7) obtained is regulated PH to 5-6 with acid, staticly settles after the 0.4-0.6 times of alcohol that adds filtrate weight again mixes, dewaters, dries and obtain heparin sodium.
Tiring of described crude heparin sodium is about 100.
Liquid in the above-mentioned steps and liquid mixing, liquid-solidly mix and regulate the liquid potential of hydrogen, all under whipped state, carry out.
The weight ratio of crude heparin sodium and sodium chloride solution is 1: 9-20.
The alcohol that adds in step (1), (3), (4), (6), (7), (8), its weight concentration is more than 95%.
The present invention is earlier by regulating the potential of hydrogen of alcoholic heparin sodium aqua, remove most of impurity, then by the alcoholic heparin sodium aqua of hydrogen peroxide oxidation, the removal of impurity of decolouring, by the fractionation precipitation of organic solvent, obtain to meet the heparin sodium of standards of pharmacopoeia at last.The heparin sodium aqua that present method is selected to contain low-concentration ethanol in transferring the PH removal of impurity and each step of oxidation is operated, the quality that can either effectively improve product (guarantees that impurity better separates with heparin sodium, the easier flocculation of impurity), can guarantee product yield again, and in whole process, can not change the structure of heparin sodium, alcohol again can recycling.To sum up, the present invention has that production cost is low, with short production cycle, and steady quality and products obtained therefrom quality meet the requirement of injection stage heparin sodium raw materials quality, are suitable for the advantage of scale production.
Embodiment:
(1) is that 7,000,000,000 heparin sodium crudes (100 tire/milligram) are dissolved in 1000 kilogram 5% the sodium chloride solution with total titer, adds weight concentration again and be 95% alcohol, make the solution ethanol concn reach 10%;
(2) solution is warming up to 50-60 ℃, is that 20% sodium hydroxide is regulated PH11-12 with weight concentration, be incubated 2 hours, filters, and insolubles discards after with the cleaning of 5% salt solution;
(3) 1 times of alcohol of adding filtrate weight in gained filtrate, precipitation is more than 8 hours, and supernatant discarded alcohol obtains throw out;
(4) throw out is dissolved in 800 liter 5% the sodium chloride solution, adds weight concentration again and be 95% alcohol, make the solution ethanol concn reach 10%;
(5) solution with step (4) is cooled to 0 ℃, regulates PH to 3.0 with hydrochloric acid, treats that post precipitation filters, and discards insolubles, collects filtrate;
(6) 0.8 times alcohol of adding solution weight in gained solution precipitates 12 hours, supernatant discarded alcohol;
(7) to be dissolved in weight concentration be in 800 liters of sodium chloride solutions of 3% to the throw out that step (6) is obtained, add weight concentration again and be 95% alcohol, making the alcohol weight concentration in the solution is 10%, regulate PH to 11-12 with sodium hydroxide again, be warming up to 30-40 ℃ and keep under this temperature, add the hydrogen peroxide (the hydrogen peroxide weight concentration is 20%) of solution weight 2%, oxidation 24 hours, use Plate Filtration, collect filtrate;
(8) filtrate that step (7) is obtained is regulated PH to 5.5 with hydrochloric acid, staticly settles, dewaters, dry, pulverizes, packs after the 0.5 times of alcohol that adds filtrate weight again mixes, and promptly obtains meeting the heparin sodium product of pharmacopeia requirement.Obtain 39.6 kilograms of heparin sodiums, yield is 92.7%.
It is as follows that product detects leading indicator:
Tire: 164USP/mg.
Other index all meets American Pharmacopeia, European Pharmacopoeia standard.
Claims (3)
1. the purification process of a crude heparin sodium is characterized in that comprising the following steps:
(1) crude heparin sodium is dissolved in the sodium chloride solution that weight concentration is 2-6%, adds alcohol again, making the alcohol weight concentration in the solution is 5%-15%;
(2) solution that step (1) is obtained is warming up to 50-60 ℃, regulates PH to 11-12 with alkali, and insulation was filtered more than 2 hours, discarded insolubles;
(3) the 0.8-1.2 alcohol doubly of adding filtrate weight in gained filtrate, precipitation, supernatant discarded alcohol;
(4) throw out that step (3) is obtained is dissolved in the sodium chloride solution that weight concentration is 2-6%, adds alcohol again, and making the alcohol weight concentration in the solution is 5%-15%;
(5) solution of step (4) is cooled to the freezing point to 5 ℃ of solution, regulates PH to 2.5-3.5, filter, discard insolubles with acid;
(6) the 0.7-0.9 alcohol doubly of adding solution weight in gained solution, precipitation, supernatant discarded alcohol;
(7) throw out that step (6) is obtained is dissolved in the sodium chloride solution that weight concentration is 2-6%, add alcohol again, making the alcohol weight concentration in the solution is 5%-15%, regulate PH to 11-12 with alkali again, intensification also remains on 30-40 ℃, adds the hydrogen peroxide or the potassium permanganate of solution weight 2%, oxidation 23-25 hour, filter, collect filtrate;
(8) filtrate that step (7) obtained is regulated PH to 5-6 with acid, staticly settles after the 0.4-0.6 times of alcohol that adds filtrate weight again mixes, dewaters, dries and obtain heparin sodium.
2. the purification process of a kind of crude heparin sodium as claimed in claim 1, it is characterized in that: the weight ratio of crude heparin sodium and sodium chloride solution is 1: 9-20.
3. the purification process of a kind of crude heparin sodium as claimed in claim 1 is characterized in that: the alcohol that adds in step (1), (3), (4), (6), (7), (8), its weight concentration is more than 95%.
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| CN2010101120820A CN101824099B (en) | 2010-02-12 | 2010-02-12 | Method for purifying crude product heparin sodium |
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| CN2010101120820A CN101824099B (en) | 2010-02-12 | 2010-02-12 | Method for purifying crude product heparin sodium |
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| CN101824099B true CN101824099B (en) | 2011-11-30 |
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Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101974107B (en) * | 2010-09-16 | 2012-07-04 | 山东海科化工集团有限公司 | Method for separating ester |
| CN102153676B (en) * | 2011-03-04 | 2012-07-04 | 南京健友生化制药股份有限公司 | Method for removing organic residue in heparin sodium through vacuum drying |
| CN102863558B (en) * | 2012-10-12 | 2014-08-13 | 江苏天慧生物科技有限公司 | Process for purifying heparin sodium, production line and device |
| CN103145877B (en) * | 2012-12-08 | 2016-01-27 | 青岛九龙生物医药有限公司 | N-propyl alcohol extraction process reduces the method for the GalN content in heparin sodium |
| CN103923230A (en) * | 2013-01-11 | 2014-07-16 | 青岛亚博生物科技有限公司 | Heparin sodium refinement method |
| CN103214597B (en) * | 2013-05-14 | 2015-11-11 | 枣庄赛诺康生化股份有限公司 | Decoloration method for enoxaparin sodium intermediate |
| CN103804521A (en) * | 2013-11-22 | 2014-05-21 | 青岛九龙生物医药有限公司 | Method for purifying heparin sodium through rapid temperature rise |
| CN104479049A (en) * | 2014-12-24 | 2015-04-01 | 青岛九龙生物医药有限公司 | Pretreatment method for analysis of impurities in heparin sodium crude products |
| CN104479048A (en) * | 2014-12-24 | 2015-04-01 | 青岛九龙生物医药有限公司 | Method for removing heparinoid impurities such as DS (dermatan sulfate) and the like in heparin sodium |
| CN105037585A (en) * | 2015-08-31 | 2015-11-11 | 南通天龙畜产品有限公司 | Classification alcohol precipitation technology for crude heparin sodium |
| CN111560087A (en) * | 2020-06-28 | 2020-08-21 | 揭阳市润达肠衣有限公司 | Purification method of high-quality heparin sodium |
| CN114805638A (en) * | 2021-01-22 | 2022-07-29 | 烟台东诚药业集团股份有限公司 | Method for purifying heparin sodium crude product |
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| CN1447820A (en) * | 2000-07-21 | 2003-10-08 | 阿文蒂斯药物股份有限公司 | Heparin-derived polysaccharide mixtures, prepn. method and pharmaceutical compsns. contg. same |
| CN1566162A (en) * | 2003-07-07 | 2005-01-19 | 张国良 | Heparin sodium and its preparing process |
| CN1844165A (en) * | 2006-03-22 | 2006-10-11 | 南京健友生物化学制药有限公司 | Process for preparing high purity sodium heparin by purification of crude sodium heparin |
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- 2010-02-12 CN CN2010101120820A patent/CN101824099B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1447820A (en) * | 2000-07-21 | 2003-10-08 | 阿文蒂斯药物股份有限公司 | Heparin-derived polysaccharide mixtures, prepn. method and pharmaceutical compsns. contg. same |
| CN1566162A (en) * | 2003-07-07 | 2005-01-19 | 张国良 | Heparin sodium and its preparing process |
| CN1844165A (en) * | 2006-03-22 | 2006-10-11 | 南京健友生物化学制药有限公司 | Process for preparing high purity sodium heparin by purification of crude sodium heparin |
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Address after: 223005 Hefei North Road, Huaian economic and Technological Development Zone, Jiangsu 58 Patentee after: HUAIAN MAIDESEN PHARMACEUTICAL Co.,Ltd. Address before: 223001 Hefei North Road, Huaian Economic Development Zone, Jiangsu 58 Patentee before: HUAIAN MDC CHEMICAL Co.,Ltd. |
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Denomination of invention: Purification method of crude heparin sodium Effective date of registration: 20211226 Granted publication date: 20111130 Pledgee: Huaian Qingjiang puyintai financing Company limited by guarantee Pledgor: HUAIAN MAIDESEN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021320000412 |
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Date of cancellation: 20230116 Granted publication date: 20111130 Pledgee: Huaian Qingjiang puyintai financing Company limited by guarantee Pledgor: HUAIAN MAIDESEN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021320000412 |