CN102863558A - Process for purifying heparin sodium, production line and device - Google Patents
Process for purifying heparin sodium, production line and device Download PDFInfo
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- CN102863558A CN102863558A CN2012103851995A CN201210385199A CN102863558A CN 102863558 A CN102863558 A CN 102863558A CN 2012103851995 A CN2012103851995 A CN 2012103851995A CN 201210385199 A CN201210385199 A CN 201210385199A CN 102863558 A CN102863558 A CN 102863558A
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Abstract
The invention discloses a process for purifying heparin sodium. The process is characterized by comprising the steps of dissolving a heparin sodium crude product to be purified in water, heating and adjusting the pH value to be within a range of 7-9, and adding sodium chloride; centrifuging a mixed state liquid to separate protide substances; feeding a solvent and substances dissolved in the solvent into a tubular centrifuge for centrifugal separation so as to remove solid impurities; feeding the separated liquid into a reaction still, adding ethanol into the reaction still, adjusting the pH value of the liquid to be within a range of 7.0-8.8 by a sodium hydroxide (NaOH) or hydrogen chloride (HCl) solution, mixing in the revolving speed of 30-65 revolutions per minute, standing, adjusting a still waist liquid draining device of the reaction still after the solution is delaminated or a phenomenon similar to delamination emerges, and draining the dividing layer liquid; and opening a bottom valve of the reaction still to discharge materials until a closed flat centrifuge conducts centrifugation, and drying filter cakes to obtain a purified product. By the aid of the process, protide substances and chondroitin-sulfuric acid or substances similar to the chondroitin-sulfuric acid in the heparin sodium crude product or animal extract crude products similar to the heparin sodium can be removed efficiently, and the maximum total titer yield can exceed 89%.
Description
Technical field
The present invention relates to the purification technique field of animal-origin crude heparin sodium, also relate to streamline and equipment for heparin sodium purification.
Background technology
Heparin class medicine is used very extensive at medical fields such as clinical anticoagulation, antithrombotics, the huge and lasting rising of consumption of the heparin sodium in animal organ such as source, pig farm has proposed more and more higher requirement for the heparin industrial technology.Recently, the correcting that progressively deeply reaches standards of pharmacopoeia along with the quality approach of heparin similar drug, requirement to Impurity removal degree in the heparin product also further promotes, heparin class drug manufacture producer has also proposed than in the past more strict specification of quality heparin sodium supplier, and therefore the upstream enterprise of heparin industry is bearing and former different technological challenge and cost pressure.Wherein, acquisition heparin sodium product how to remove expeditiously protein impurity in the crude heparin sodium and high yield then is the technical barrier that heparin sodium purification factory faces.The enterprise that is engaged in heparin sodium purification adopts the conventional process techniques of repetition heparin sodium crude extraction more, use traditional extraction equipment such as the common vessel of band stirring, the wide aperture filter plant of filtration silica gel resin etc., crude product is carried out again or repeatedly extracts (resin absorption, wash-out, precipitation etc.) to obtain the lower product of protein foreign matter content, adopt again afterwards other technologies (centrifugal such as tubular type) that remaining protein impurity that can't flush away in the product is removed.Increase to a great extent the consumption of supplementary material such as solvent, resin etc. owing to repeat the way of resin absorption, wash-out, increased many production costs; Also owing to the multiple adsorb wash-out loses portioned product, cause the yield of purifying products technique not high.
Summary of the invention
The purification process that the purpose of this invention is to provide a kind of heparin sodium, the present invention also provides streamline and the equipment of the purification process of applicable heparin sodium.
The technical solution used in the present invention is:
The purification process of heparin sodium, with heparin sodium crude to be purified water dissolution with 3-20 times of weight, the rotating speed that turns with per minute 30-65 stirs, intensification 70-90 ℃ and regulate pH value 7-9, the sodium-chlor that adds 0.1-0.6 times of weight, make wherein protein matter sex change and from water free out; Mixed state liquid is carried out centrifugal by disk centrifugal separator with the speed of rotating speed 4500-7500rpm, isolate protein matter; The material of solvent and wherein dissolving enters tubular-bowl centrifuge, through the high speed centrifugation separation of tubular-bowl centrifuge rotating speed 10000-13000rpm rotating speed, removes solid impurity; Separating liquid enters the reactor with still waist pumping device, the mass concentration 90.0%-99.9% ethanol that adds 1/5-4/5 times of separating liquid weight in the reactor, control temperature≤35 ℃, with NaOH or HCl solution regulator solution pH value 7.0-8.8, the rotating speed that per minute 30-65 turns stirs, and is static, when treating the solution layering or the phenomenon of similar layering occurring, conditioned reaction still still waist pumping device is taken out boundary layer liquid; Open the reactor bottom valve and be discharged to a closed dull and stereotyped whizzer and carry out centrifugally with the 800-1200rpm rotating speed, filtration cakes torrefaction namely gets purified product.
Be used for carrying out the streamline of heparin sodium purification, comprise reactor, it is characterized in that also comprising butterfly centrifugal machine, tubular-bowl centrifuge, have reactor and the closed dull and stereotyped whizzer of still waist pumping device, described reactor bottom is connected with the butterfly centrifugal machine by pipeline, described butterfly centrifugal machine is connected with tubular-bowl centrifuge by pipeline, described tubular-bowl centrifuge is connected with the reactor with still waist pumping device by pipeline, and described reactor bottom with still waist pumping device is connected with closed dull and stereotyped whizzer by pipeline.
In the reactor with still waist pumping device, its still waist pumping device is fixed in the side of reactor, described still waist pumping device comprises visor, handle, hand lever and pumping pipe, described visor is located at the reactor side, described handle is individually fixed in top and the middle and lower part of hand lever, and described hand lever is flexibly connected with the conical gear that is fixed on the pumping pipe by the conical gear of its bottom.
The present invention can high-level efficiency removes in the animal extracts crude product of crude heparin sodium or similar heparin sodium protein matter and chondroitin sulfate or is similar to the chondroitin sulfate material.The total titer yield of purifying products technique reaches as high as more than 89%.
Description of drawings
Fig. 1 is the streamline synoptic diagram that the present invention is used to carry out heparin sodium purification.
Fig. 2 is the reactor structural representation with still waist pumping device.
Wherein: 1, reactor, 2, the butterfly centrifugal machine, 3, tubular-bowl centrifuge, 4, have a reactor of still waist pumping device, 5, closed dull and stereotyped whizzer, 6, handle, 7, hand lever, 8, pumping pipe, 9, conical gear, 10, to visor.
Embodiment
Just to the elaboration of the inventive method and equipment, protection scope of the present invention is not limited to following embodiment to following embodiment, and all method and apparatus and streamlines that have with same idea of the present invention all belong to protection scope of the present invention.
Embodiment 1
In reactor, add about 650kg process water, the rotating speed that about per minute 32 turns stirs, the heparin sodium crude of 45.243 hundred million units (is total to 62.84kg, 72 U/mg tire, sulfur acid chrondroitin 27.2%) drops into reactor, add about 19kg sodium-chlor, be warming up to about 75 ± 2 ℃, insulation is also regulated about pH value to 7.5, centrifugal (rotating speed is about 5300rpm by disk centrifugal separator, the discharge nozzle mouth pressure is controlled at about 0.1MPa), filtrate is again by tubular-bowl centrifuge centrifugal (rotating speed is about 10200rpm), and centrifugal when shared about 3 hours of butterfly centrifugal and tubular type and are compared (same treatment amount with the centrifugal case of tubular-bowl centrifuge merely before, use 8-18 hour), wherein the centrifugally operated time spent of corresponding steps has lacked a lot.The tubular type centrifugal filtrate enters aforementioned specially designed reactor, adds about 900kg ethanol, and rotating speed that per minute about 63 turns stirred 20 minutes, regulates pH value to 7.5, continues stir about 30 minutes, stops stirring, staticly treats the solution layering.Adjustment reactor waist is taken out the bend pipe direction in the materials device, makes its mouth of pipe be in the middle boundary layer of solution or similar minute stratum place in the still, and this layer liquid is extracted out.Then opening the reactor bottom valve, to be discharged to a closed dull and stereotyped whizzer centrifugal, and filtration cakes torrefaction gets the product (altogether about 36.16kg, tiring is 106 U/mg, chondroitin sulfate 10.3%) of 38.326 hundred million unit purifying, and the total titer yield is about 84.71%.
Embodiment 2:
123.733 the heparin sodium crude of hundred million units (169.50kg tires as 63-87 U/mg does not wait altogether, and chondroitin sulfate cellulose content 15-35% does not wait) is pulverized with pulverizer, mixes with mixing machine again.In reactor, add about 1.7 tons of process waters, the rotating speed that turns with per minute about 63 stirs, heparin sodium crude after being pulverized and mixed is dropped into reactor, add about 26kg sodium-chlor, be warming up to about 82 ± 2 ℃, insulation is also regulated about pH value to 7.5, and centrifugal (rotating speed is about 5300rpm by disk centrifugal separator, the discharge nozzle mouth pressure is controlled at about 0.1MPa), filtrate is again by tubular-bowl centrifuge centrifugal (rotating speed is about 10200rpm).The tubular type centrifugal filtrate enters aforementioned specially designed reactor, adds about 2 ton 98% ethanol, and the rotating speed that turns with per minute about 32 stirred 40 minutes, regulates pH value to 7.8, continues stir about 30 minutes, stops stirring, staticly treats the solution layering.Adjustment reactor waist is taken out the bend pipe direction in the materials device, makes its mouth of pipe be in the middle boundary layer of solution or similar minute stratum place in the still, and this layer liquid is extracted out.Then opening the reactor bottom valve, to be discharged to a closed dull and stereotyped whizzer centrifugal, and filtration cakes torrefaction gets the product (about 96.35kg altogether, tiring is 113 U/mg, chondroitin sulfate is 8.3%) of 108.875 hundred million unit purifying, and the total titer yield is about 87.99%.
Embodiment 3:
In reactor, add about 730kg process water, the rotating speed that turns with per minute about 63 stirs, with the heparin sodium crude of 62.144 hundred million units that are pulverized and mixed (73.11kg altogether, tiring is 85 U/mg, chondroitin sulfate is 32.2%) the input reactor, add about 35kg sodium-chlor, be warming up to about 90 ± 2 ℃, insulation is also regulated about pH value to 6.8, centrifugal (rotating speed is about 6700rpm by disk centrifugal separator, the discharge nozzle mouth pressure is controlled at about 0.35MPa), filtrate is again by tubular-bowl centrifuge centrifugal (rotating speed is about 11300rpm).The tubular type centrifugal filtrate enters aforementioned specially designed reactor, adds 97.8% the about 550kg of ethanol, and the rotating speed that per minute about 63 turns stirred 30 minutes, regulates pH value to 8.0, and continuation stir about 30 minutes stops stirring, staticly treats the solution layering.Adjustment reactor waist is taken out the bend pipe direction in the materials device, makes its mouth of pipe be in the middle boundary layer of solution or similar minute stratum place in the still, and this layer liquid is extracted out.Then opening the reactor bottom valve, to be discharged to a closed dull and stereotyped whizzer centrifugal, and filtration cakes torrefaction gets the product (about 42.27kg altogether, tiring is 131 U/mg, chondroitin sulfate is 12.2%) of 55.379 hundred million unit purifying, and the total titer yield is about 89.11%.
Embodiment 4
As shown in Figure 1, be used for carrying out the streamline of heparin sodium purification, comprise reactor 1, also comprise butterfly centrifugal machine 2, tubular-bowl centrifuge 3, have reactor 4 and the closed dull and stereotyped whizzer 5 of still waist pumping device, reactor 1 bottom is connected with butterfly centrifugal machine 2 by pipeline, butterfly centrifugal machine 2 is connected with tubular-bowl centrifuge 3 by pipeline, tubular-bowl centrifuge 3 is connected with the reactor 4 with still waist pumping device by pipeline, and reactor 4 bottoms with still waist pumping device are connected with closed dull and stereotyped whizzer 5 by pipeline.
Embodiment 5
As shown in Figure 2, in the reactor 4 with still waist pumping device, its still waist pumping device is fixed in the side of reactor, still waist pumping device comprises visor 10, handle 6, hand lever 7 and pumping pipe 8, visor 10 is located at the reactor side, handle 6 is individually fixed in top and the middle and lower part of hand lever 7, and hand lever 7 is flexibly connected with the conical gear 9 that is fixed on the pumping pipe 8 by the conical gear 9 of its bottom.When needs carry out drawing liquid, rotate the handle 6 on the hand lever 7, hand lever 7 bottoms by and pumping pipe 8 between conical gear 9 combination drive pumping pipes 8 and rotate, pumping pipe 8 is slowly taken out boundary layer liquid under to the observation of visor 10, then heparin sodium aqua enters next flow process.
Claims (4)
1. the purification process of heparin sodium, it is characterized in that: with heparin sodium crude to be purified water dissolution with 3-20 times of weight, the rotating speed that turns with per minute 30-65 stirs, intensification 70-90 ℃ and regulate pH value 7-9, the sodium-chlor that adds 0.1-0.6 times of weight, make wherein protein matter sex change and from water free out; Mixed state liquid is carried out centrifugal by disk centrifugal separator with the speed of rotating speed 4500-7500rpm, isolate protein matter; The material of solvent and wherein dissolving enters tubular-bowl centrifuge, through the high speed centrifugation separation of tubular-bowl centrifuge rotating speed 10000-13000rpm rotating speed, removes solid impurity; Separating liquid enters the reactor with still waist pumping device, the mass concentration 90.0%-99.9% ethanol that adds 1/5-4/5 times of separating liquid weight in the reactor, control temperature≤35 ℃, with NaOH or HCl solution regulator solution pH value 7.0-8.8, the rotating speed that per minute 30-65 turns stirs, and is static, when treating the solution layering or the phenomenon of similar layering occurring, conditioned reaction still still waist pumping device is taken out boundary layer liquid; Open the reactor bottom valve and be discharged to a closed dull and stereotyped whizzer and carry out centrifugally with the 800-1200rpm rotating speed, filtration cakes torrefaction namely gets purified product.
2. be used for carrying out the streamline of claim 1 heparin sodium purification, comprise reactor, it is characterized in that also comprising butterfly centrifugal machine, tubular-bowl centrifuge, have reactor and the closed dull and stereotyped whizzer of still waist pumping device, described reactor bottom is connected with the butterfly centrifugal machine by pipeline, described butterfly centrifugal machine is connected with tubular-bowl centrifuge by pipeline, described tubular-bowl centrifuge is connected with the reactor with still waist pumping device by pipeline, and described reactor bottom with still waist pumping device is connected with closed dull and stereotyped whizzer by pipeline.
3. the purification process of heparin sodium according to claim 1, it is characterized in that: in the reactor with still waist pumping device, its still waist pumping device is fixed in the side of reactor, described still waist pumping device comprises visor, handle, hand lever and pumping pipe, described visor is located at the reactor side, described handle is individually fixed in top and the middle and lower part of hand lever, and described hand lever is flexibly connected with the conical gear that is fixed on the pumping pipe by the conical gear of its bottom.
4. described streamline be used to carrying out heparin sodium purification according to claim 2, it is characterized in that: in the reactor with still waist pumping device, its still waist pumping device is fixed in the side of reactor, described still waist pumping device comprises visor, handle, hand lever and pumping pipe, described visor is located at the reactor side, described handle is individually fixed in top and the middle and lower part of hand lever, and described hand lever is flexibly connected with the conical gear that is fixed on the pumping pipe by the conical gear of its bottom.
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| CN201210385199.5A CN102863558B (en) | 2012-10-12 | 2012-10-12 | Process for purifying heparin sodium, production line and device |
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| CN201210385199.5A CN102863558B (en) | 2012-10-12 | 2012-10-12 | Process for purifying heparin sodium, production line and device |
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| CN102863558B CN102863558B (en) | 2014-08-13 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (6)
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|---|---|---|---|---|
| US3016331A (en) * | 1960-01-28 | 1962-01-09 | Ormonoterapia Richter Spa | Purification of heparin |
| JP3252595B2 (en) * | 1994-03-31 | 2002-02-04 | 三菱ウェルファーマ株式会社 | Method for purifying antithrombin-III |
| CN101824099A (en) * | 2010-02-12 | 2010-09-08 | 淮安麦德森化学有限公司 | Method for purifying crude product heparin sodium |
| CN102093491A (en) * | 2010-12-22 | 2011-06-15 | 烟台东诚生化股份有限公司 | Production process for lowering 400-nanometer light absorption of liquaemin by using active carbon filter element |
| CN202157037U (en) * | 2011-06-28 | 2012-03-07 | 四川茂森生物科技有限公司 | Heparin separating and settling device |
| CN102633909A (en) * | 2012-05-03 | 2012-08-15 | 白银富瑞康生物制品有限公司 | Method for extracting heparin sodium from cattle lungs |
-
2012
- 2012-10-12 CN CN201210385199.5A patent/CN102863558B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3016331A (en) * | 1960-01-28 | 1962-01-09 | Ormonoterapia Richter Spa | Purification of heparin |
| JP3252595B2 (en) * | 1994-03-31 | 2002-02-04 | 三菱ウェルファーマ株式会社 | Method for purifying antithrombin-III |
| CN101824099A (en) * | 2010-02-12 | 2010-09-08 | 淮安麦德森化学有限公司 | Method for purifying crude product heparin sodium |
| CN102093491A (en) * | 2010-12-22 | 2011-06-15 | 烟台东诚生化股份有限公司 | Production process for lowering 400-nanometer light absorption of liquaemin by using active carbon filter element |
| CN202157037U (en) * | 2011-06-28 | 2012-03-07 | 四川茂森生物科技有限公司 | Heparin separating and settling device |
| CN102633909A (en) * | 2012-05-03 | 2012-08-15 | 白银富瑞康生物制品有限公司 | Method for extracting heparin sodium from cattle lungs |
Non-Patent Citations (1)
| Title |
|---|
| 徐俊涛等: "粗品肝素钠精制工艺优化研究", 《食品与机械》, vol. 28, no. 4, 18 July 2012 (2012-07-18), pages 206 - 208 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| CN102863558B (en) | 2014-08-13 |
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