CN105985454A - Method for purifying enoxaparin - Google Patents
Method for purifying enoxaparin Download PDFInfo
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- CN105985454A CN105985454A CN201510062140.6A CN201510062140A CN105985454A CN 105985454 A CN105985454 A CN 105985454A CN 201510062140 A CN201510062140 A CN 201510062140A CN 105985454 A CN105985454 A CN 105985454A
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Abstract
The invention discloses a method for purifying enoxaparin. The method comprises the following steps: a) preparing the equipment; b) setting the parameter; c) changing brine, ethanol and water for ultrafiltration; d) completing ultrafiltration; and e) performing detection after freeze-drying of a sample. During the production of enoxaparin, a process of alcohol precipitation of a hydrolysate is required to obtain an enoxaparin crude product. Because that a large amount of an ethanol solvent is consumed during the process, alcohol precipitation time is long, the sample after alcohol precipitation is required to be dried, production disadvantages of high production cost and long production period are brought, such as hidden trouble of solvent volatilization. The provided method employs brine, ethanol and water for liquid change in order during the ultrafiltration process, which replace the alcohol precipitation step in the synthesis production process of enoxaparin, processes of alcohol precipitation and drying of the crude product are removed, operation time is shortened, efficiency is increased, production period of the product is shortened, hidden trouble can be eliminated, and the process is simplified.
Description
Technical field
The present invention relates to the field of Enoxaparin, more particularly it relates to the purification process of Enoxaparin.
Background technology
Heparin sodium (Heparin) is a kind of natural mucopolysaccharide class biologically active drug having last 100 years history in clinical practice, D-glucose aldehydic acid and D-glucose amine are alternately formed by connecting, and mean molecule quantity is
15,000 dalton, are widely present in people and mammalian tissues.Heparin sodium has the strongest anticoagulation, anti-thrombus function, is prevention Post operation thrombosis and the choice drug for the treatment of Acute Venous thrombosis.But life-time service unfractionated heparin sodium, can produce the risk of induced thrombocytopenia, thus cause the increase of thrombosis and mortality rate.
Enoxaparin Sodium (Enoxaparin
Sodium) it is the one of Low molecular heparin class (low molecular weight heparin, be called for short LMWH).Compared with heparin sodium, Enoxaparin not only has the effects such as similar antithrombotic, anticoagulation, treatment acute myocardial infarction and unstable angina pectoris, can also make to cause thrombocytopenic side effect substantially to reduce, hemorrhage complication reduces, and has the plurality of advantages such as subcutaneous injection good absorbing, Half-life in vivo be longer.Compared with unfractionated heparin sodium, Enoxaparin adaptability ratio is wide, has broader market prospect.At present, Enoxaparin produces and mainly includes following flow process: heparin sodium becomes salt and esterification through benzethonium chloride, and carboxylate cracks in the basic conditions, reactant liquor ethanol solution precipitate with ethanol, precipitation dry after dialysis/ultrafiltration, the step such as last lyophilizing obtains pharmaceutical grade Enoxaparin.
In current Enoxaparin Sodium means of purification, after heparin benzyl ester hydrolyzes, hydrolyzed solution needs to carry out precipitate with ethanol, and precipitate with ethanol sample is dried, and then carries out ultrafiltration or dialysis obtains meeting the Enoxaparin product of crude drug standard.The main purpose of precipitate with ethanol is to separate out Enoxaparin crude product from hydrolyzed solution by addition ethanol, removes a small amount of organic molecule such as benzylalcohol etc. produced in hydrolysis simultaneously.During hydrolyzed solution precipitate with ethanol, the general ethanol adding 3-4 times of volume of hydrolyzed solution precipitates, and during this, hydrolyzed solution needs to stand 24-48h or even longer time, and precipitate with ethanol out sample particle is less and sticks at container bottom, uses sucking filtration and the prior art such as to be centrifuged relatively difficult when separating.Sample after precipitate with ethanol, through oven for drying, then carries out ultrafiltration lyophilizing and refines.There are some drawbacks that can not be ignored in existing production technology, such as precipitate with ethanol overlong time causes whole production process the longest, production efficiency is low, the production of precipitate with ethanol is amplified existence and is limited, also bringing the problem such as the huge waste of solvent, solvent volatilization, the use of the most a large amount of ethanol also has hidden danger for security.A large amount of Enoxaparin crude products stick at container bottom, and precipitate with ethanol sample is difficult to be completely removed drying.Owing to hydrolyzed solution volume is relatively big, so causing container very big, bring the biggest inconvenience to producing.Owing to sample still there being part ethanol remain during drying, also bring production safety hidden danger, workshop and equipment be there has also been extra requirement.This invention is directed to the short-cut method of a kind of purification Enoxaparin, by changing saline-alcohol-water in ultra-filtration process, substitute the precipitate with ethanol step in production process, eliminate the operation of precipitate with ethanol and drying, it is thus possible to reduce production cycle, saving production cost, eliminate safe hidden trouble, and whole purge process is simple to operate, it is easy to amplifying, Enoxaparin yield is higher.
Summary of the invention
It is contemplated that the method changing ethanol in employing ultrafiltration, it is provided that a kind of technique using ultrafiltration purification Enoxaparin, thus overcome the deficiency of existing production technology, avoiding this operation of precipitate with ethanol, a step realizes remove impurity desalination and concentration, quickly, the gentleest, shorten the production time, reduce cost.
Time-consuming and the solvent consumption problem for solution precipitate with ethanol, the technical scheme that the present invention uses there is provided a kind of method using ultrafiltration purification Enoxaparin, comprises the following steps:
A, pre-preparation: by heparin benzyl ester hydrolyzed solution, being filled to port and process in container, and connect buffer container after neutral filter paper and filtering with microporous membrane, osmotic balance is placed liquid header, osmotic balance makes zero；
B, parameter are arranged: pressure monitor and peristaltic pump, by the external computer of USB interface data wire, connect ultrafiltration software and carry out parameter setting；The flow velocity of peristaltic pump is set: open peristaltic pump, from porthandler, Enoxaparin solution is extracted by peristaltic pump, hollow fiber film assembly is entered by the pipeline of film upper liquid outlet, pressure transducer by data feedback to pressure monitor, Enoxaparin solution enters the pipeline backflow of film fluid port last time, flows back into port by automatic backpressure valve and processes in container；Date and filter assemblies Part No. etc. are set.Then arrange and step up TMP, changing the flow velocity of penetrating fluid in the pipeline of infiltration mouth.
C, change saline, ethanol, water ultra-filtration stage: in buffer container, add saline, owing to tubing is inner sealing state, when buffer container penetrates liquid, port processes container and is internally formed vacuum, saline in buffer container is sucked, Enoxaparin solution enters and changes the saline stage, carries out the most successively changing ethanol and changing pure water, it is achieved low molecule impurity and the removing of salt.
D, complete ultrafiltration: by measuring salt content in penetrating fluid, determine and change water multiple, when changing water and reaching 4-8 times, Enoxaparin solution completes ultrafiltration, concentrates the half of Enoxaparin extremely original volume, and computer terminates data collection, preserve data, close peristaltic pump, terminate the experiment of Enoxaparin ultrafiltration, cleaning equipment；
E, Indexs measure: by Enoxaparin heparin sample lyophilizing, weigh quality, calculated yield, product G PC Indexs measure.
In a preferred embodiment of the present invention, described hydrolyzed solution is that heparin benzyl ester hydrolyzes in the basic conditions, adjusts pH after hydrolysis
6-7, adds NaCl stirring and dissolving, obtains through neutral filter paper and 0.45 μm water film filtering.
In a preferred embodiment of the present invention, described heparin benzyl ester is that heparin benzyl rope chlorine amine salt obtains with benzyl chloride generation esterification.
In a preferred embodiment of the present invention, described heparin benzethonium chloride salt is that heparin obtains with benzethonium chloride generation salt-forming reaction.
In a preferred embodiment of the present invention, whole ultra-filtration process includes changing saline, changes ethanol, changes water and enriching stage.
In a preferred embodiment of the present invention, described ultrafiltration apparatus is KR2i cross-flow ultrafiltration system.Including hollow fiber membrane filter, osmotic balance, pressure detector, pressure transducer, peristaltic pump, buffer container.
In a preferred embodiment of the present invention, three interfaces it are provided with on described hollow fiber membrane filter, including infiltration mouth, film upper liquid outlet and film fluid port last time, described infiltration mouth is arranged on a middle side part of hollow fiber membrane filter and is connected with infiltration pincers, and described film fluid port last time and film upper liquid outlet are separately mounted to top and the bottom of hollow fiber membrane filter.
In a preferred embodiment of the present invention, described hollow fiber membrane filter assembly is connected with automatic backpressure valve and pressure monitor respectively, described port processes container and is connected between automatic backpressure valve and pressure monitor, described buffer container processes container with port and is connected, described computer is external with pressure monitor, described liquid header is placed on above osmotic balance, and described pressure monitor is arranged on peristaltic pump.
In a preferred embodiment of the present invention, the flow velocity 600-700mL/min of described peristaltic pump.
In a preferred embodiment of the present invention, described hollow fiber film assembly includes hollow fiber membrane filter and at the 790cm within hollow fiber membrane filter2Ultrafilter membrane.
In a preferred embodiment of the present invention, described ultrafilter membrane is polyether sulfone Modified Membrane, molecular cut off 1kD.
In a preferred embodiment of the present invention, in a preferred embodiment of the present invention, described pressure transducer includes pp pressure transducer, pr pressure transducer and pf pressure transducer, described pp pressure transducer and pf pressure transducer are separately mounted to film upper liquid outlet and the position of film fluid port last time, and described pr pressure transducer is arranged on the position of infiltration mouth.
The invention has the beneficial effects as follows: the present invention proposes the method for a kind of saline-alcohol-water ultrafiltration purification Enoxaparin, ethanol precipitate with ethanol is eliminated in Enoxaparin purge process, crude product needs the step dried, production cycle reduces, and reduces energy consumption, reduces production cost, a step can realize remove impurity desalination and concentration, quickly, efficiently gentle, shorten operating time and operability.
Accompanying drawing explanation
For the technical scheme being illustrated more clearly that in the embodiment of the present invention, in describing embodiment below, the required accompanying drawing used is briefly described, apparently, accompanying drawing in describing below is only some embodiments of the present invention, for those of ordinary skill in the art, on the premise of not paying creative work, it is also possible to obtain other similar enforcement legend according to these accompanying drawings, wherein:
Fig. 1 is the flow chart of method one preferred embodiment of purification Enoxaparin of the present invention；
Fig. 2 is the structured flowchart that purification Enoxaparin of the present invention uses equipment.
Detailed description of the invention
Below by a part of embodiment of the present invention, the technical scheme in embodiment is clearly and completely described, but described embodiment is not all, of embodiment.Based on the embodiment in the present invention, all other embodiments that those of ordinary skill in the art are obtained under not making creative work premise, broadly fall into the scope of protection of the invention.
Referring to Fig. 1, the embodiment of the present invention includes:
A, pre-preparation: by heparin benzyl ester hydrolyzed solution, being filled to port and process in container, and connect buffer container after neutral filter paper and 0.45 μm water film filtering, osmotic balance is placed liquid header, osmotic balance makes zero；
B, parameter are arranged: pressure monitor and peristaltic pump, by the external computer of USB interface data wire, connect ultrafiltration software and carry out parameter setting；The flow velocity of peristaltic pump is set: open peristaltic pump, from porthandler, Enoxaparin solution is extracted by peristaltic pump, hollow fiber film assembly is entered by the pipeline of film upper liquid outlet, pressure transducer by data feedback to pressure monitor, Enoxaparin solution enters the pipeline backflow of film fluid port last time, flows back into port by automatic backpressure valve and processes in container；Arrange and step up TMP, changing the flow velocity of penetrating fluid in the pipeline of infiltration mouth.
C, change saline, ethanol, water ultra-filtration stage: in buffer container, add saline, owing to tubing is inner sealing state, when buffer container penetrates liquid, port processes container and is internally formed vacuum, saline in buffer container is sucked, Enoxaparin solution enters and changes the saline stage, carries out the most successively changing ethanol and changing pure water, it is achieved low molecule impurity and the removing of salt.
D, complete ultrafiltration: by measuring salt content in penetrating fluid, determine and change water multiple, when changing water and reaching 4-8 times, Enoxaparin solution completes ultrafiltration, concentrates the half of Enoxaparin extremely original volume, and computer terminates data collection, preserve data, close peristaltic pump, terminate the experiment of Enoxaparin ultrafiltration, cleaning equipment；
E, Indexs measure: by Enoxaparin heparin sample lyophilizing, weigh quality, calculated yield, product G PC Indexs measure.
In above-mentioned, the parameter in step b arranges and includes:
1. the date；
2. filter assemblies Part No., after Part No. is filtered in input, the filtration information including surface area, approximation fibre count, fibre length, shear rate guide and film type can automatically enter；
3. sequence number；
4. by pump head and the line size of pipeline correction, such as: tubing size:18.
5.
The assembly form date.
After completing ultrafiltration, needing external 10ml pure water rinse ultrafiltration pipeline and collect, then 50mL pure water rinses ultrafiltration system, finally uses 0.4% sodium hydroxide solution to clean ultrafilter membrane, and moistening preservation.
Further, the flow velocity of described peristaltic pump is 600-700mL/min.
As shown in Figure 2, described osmotic balance is connected with hollow fiber film assembly by infiltration pincers, described hollow fiber film assembly is connected with automatic backpressure valve and pressure monitor respectively, described port processes container and is connected between automatic backpressure valve and pressure monitor, described buffer container processes container with port and is connected, described computer is external with pressure monitor, and described liquid header is placed on above osmotic balance, and described pressure monitor is arranged on peristaltic pump.
In the present invention, described hollow fiber film assembly includes that hollow fiber membrane filter and ultrafilter membrane, described ultrafilter membrane are arranged on inside hollow fiber membrane filter.Wherein, described ultrafilter membrane is polyether sulfone Modified Membrane, molecular cut off 1kD.
In above-mentioned, three interfaces it are provided with on described hollow fiber membrane filter, including infiltration mouth, film upper liquid outlet and film fluid port last time, described infiltration mouth is arranged on a middle side part of hollow fiber membrane filter and is connected with infiltration pincers, and described film fluid port last time and film upper liquid outlet are separately mounted to top and the bottom of hollow fiber membrane filter.
Further, described pressure transducer includes pp pressure transducer, pr pressure transducer and pf pressure transducer, described pp pressure transducer and pf pressure transducer are separately mounted to film upper liquid outlet and the position of film fluid port last time, and described pr pressure transducer is arranged on the position of infiltration mouth.
In the present invention, the fine work Enoxaparin GPC that described ultrafiltration obtains is as shown in table 1.
Example one:
A, 4g heparin benzyl ester hydrolyzes, reconcile pH 7, salt adding obtains hydrolysis liquid after dissolving, after double-deck neutral filter paper and 0.45 μm moisture film filter respectively, add the water dilution of three times, it is placed in port and processes in container, and connect buffer container, and osmotic balance is placed liquid header, osmotic balance makes zero；
B, pressure monitor and peristaltic pump pass through the external computer of USB interface data wire, carry out parameter setting by software in computer, and selection ultrafilter membrane is 1kD, 790cm2；
C, the flow velocity 630mL/min of setting peristaltic pump, open peristaltic pump, and Enoxaparin solution enters reflux pipeline on film and is back in port process container；
D, by the regulation of automatic backpressure valve to the most manual, carry out TMP pressure setting, progressively rise to 20psi；
E, in buffer container, add 10% saline (amount of hydrolyzed solution in 0.5 volume port processor), Enoxaparin solution is entered and changes saline, ethanol, water ultra-filtration stage.Computer is used to start to gather data, record.Peristaltic pump processes from port and extracts the small amount of liquids in Enoxaparin solution container, can infiltrate in liquid header by the pipeline of infiltration mouth, major part liquid flows to inbound port by the back of pipeline of film fluid port last time and processes in container, and infiltration flow rate is 22L/m2/h；
F, after saline has changed, think highly of the dehydrated alcohol adding equivalent brine volume in buffering, membrane flux starts slowly to decline, until TMP is stable, infiltration flow rate is 15.5 L/m2/h；
G, after in buffer, ethanol is thought highly of completely into port, buffer container adds pure water, Enoxaparin solution is changed water desalination remove impurity, membrane flux begins to ramp up, and stable.When TMP is 20psi, infiltration flow rate is 26L/m2/h；
H, when changing water and reaching 3 times, Enoxaparin solution penetrating fluid measures salt-free, disconnects buffer container, concentrates Enoxaparin and terminates data collection to the half of original volume, computer, preserves data, close peristaltic pump, terminate the experiment of Enoxaparin ultrafiltration.Lyophilizing Enoxaparin product obtains 3.22g, numbering INK001-4141201-a, and product meets pharmacopoeial requirements, and GPC the results are shown in Table 1.
Example two:
A, 4g heparin benzyl ester hydrolyzes, reconcile pH 7, salt adding obtains hydrolysis liquid after dissolving, after double-deck neutral filter paper and 0.45 μm moisture film filter respectively, add the water dilution of three times, it is placed in port and processes in container, and connect buffer container, and osmotic balance is placed liquid header, osmotic balance makes zero；
B, pressure monitor and peristaltic pump pass through the external computer of USB interface data wire, carry out parameter setting by software in computer, and selection ultrafilter membrane is 1kD, 790cm2；
C, the flow velocity 630mL/min of setting peristaltic pump, open peristaltic pump, and Enoxaparin solution enters reflux pipeline on film and is back in port process container；
D, by the regulation of automatic backpressure valve to the most manual, carry out TMP pressure setting, progressively rise to 20psi；
E, in buffer container, add 10% saline (amount of hydrolyzed solution in 1 volume port processor), Enoxaparin solution is entered and changes saline, ethanol, water ultra-filtration stage.Computer is used to start to gather data, record.Peristaltic pump processes from port and extracts the small amount of liquids in Enoxaparin solution container, can infiltrate in liquid header by the pipeline of infiltration mouth, major part liquid flows to inbound port by the back of pipeline of film fluid port last time and processes in container, and infiltration flow rate is 23L/m2/h；
F, after saline has changed, think highly of the dehydrated alcohol adding equivalent brine volume in buffering, membrane flux starts slowly to decline, until TMP is stable, infiltration flow rate is 9.5 L/m2/h；
G, after in buffer, ethanol is thought highly of completely into port, buffer container adds pure water, Enoxaparin solution is changed water desalination remove impurity, membrane flux begins to ramp up, and stable.When TMP is 20psi, infiltration flow rate is 26.5 L/m2/h；
H, when changing water and reaching 4 times, Enoxaparin solution penetrating fluid measures salt-free, disconnects buffer container, concentrates Enoxaparin and terminates data collection to the half of original volume, computer, preserves data, close peristaltic pump, terminate the experiment of Enoxaparin ultrafiltration.Lyophilizing Enoxaparin product obtains 3.02g, numbering INK001-4141201-b, and product meets pharmacopoeial requirements, and GPC the results are shown in Table 1.
Example three:
A, 4g heparin benzyl ester hydrolyzes, and obtains hydrolysis liquid after reconciling pH 7, salt adding dissolving, after double-deck neutral filter paper and 0.45 μm moisture film filter respectively, it is placed in port and processes in container, and connect buffer container, and osmotic balance is placed liquid header, osmotic balance makes zero；
B, pressure monitor and peristaltic pump pass through the external computer of USB interface data wire, carry out parameter setting by software in computer, and selection ultrafilter membrane is 1kD, 790cm2；
C, the flow velocity 650mL/min of setting peristaltic pump, open peristaltic pump, and Enoxaparin solution enters reflux pipeline on film and is back in port process container；
D, by the regulation of automatic backpressure valve to the most manual, carry out TMP pressure setting, progressively rise to 20psi；
E, in buffer container, add 10% saline (amount of hydrolyzed solution in 1.5 volume port processors), Enoxaparin solution is entered and changes saline, ethanol, water ultra-filtration stage.Computer is used to start to gather data, record.Peristaltic pump processes from port and extracts the small amount of liquids in Enoxaparin solution container, can infiltrate in liquid header by the pipeline of infiltration mouth, and major part liquid flows to inbound port by the back of pipeline of film fluid port last time and processes in container, and infiltration flow rate is 24.3
L/m2/h；
F, after saline has changed, think highly of the dehydrated alcohol adding 2 times of hydrolyzed solution volumes in buffering, membrane flux starts slowly to decline, until TMP is stable, infiltration flow rate is 9.1 L/m2/h；
G, after in buffer, ethanol is completely into port device, buffer container adds pure water, Enoxaparin solution is changed water desalination remove impurity, membrane flux begins to ramp up, and stable.When TMP is 20psi, infiltration flow rate is 25 L/m2/h。
H, when changing water and reaching 5 times, Enoxaparin solution penetrating fluid measures salt-free, disconnects buffer container, is concentrated into the half of original volume, and computer terminates data collection, preserves data, closes peristaltic pump, terminates the experiment of Enoxaparin ultrafiltration.Lyophilizing Enoxaparin product obtains 2.88g, numbered INK001-4141201-c, and product meets pharmacopoeial requirements, and GPC the results are shown in Table 1.
Example four:
A, 4g heparin benzyl ester hydrolyzes, reconcile pH 7, salt adding obtains hydrolysis liquid after dissolving, after double-deck neutral filter paper and 0.45 μm moisture film filter respectively, add the water dilution of three times, it is placed in port and processes in container, and connect buffer container, and osmotic balance is placed liquid header, osmotic balance makes zero；
B, pressure monitor and peristaltic pump pass through the external computer of USB interface data wire, carry out parameter setting by software in computer, and selection ultrafilter membrane is 1kD, 790cm2；
C, the flow velocity 630mL/min of setting peristaltic pump, open peristaltic pump, and Enoxaparin solution enters reflux pipeline on film and is back in port process container；
D, by the regulation of automatic backpressure valve to the most manual, carry out TMP pressure setting, progressively rise to 20psi；
E, in buffer container, add 10% saline (amount of hydrolyzed solution in 3 volume port processors), Enoxaparin solution is entered and changes saline, ethanol, water ultra-filtration stage.Computer is used to start to gather data, record.Peristaltic pump processes from port and extracts the small amount of liquids in Enoxaparin solution container, can infiltrate in liquid header by the pipeline of infiltration mouth, major part liquid flows to inbound port by the back of pipeline of film fluid port last time and processes in container, and infiltration flow rate is 28L/m2/h；
F, after saline has changed, think highly of the dehydrated alcohol adding equivalent brine volume in buffering, membrane flux starts slowly to decline, until TMP is stable, infiltration flow rate is 8.5 L/m2/h；
G, after in buffer, ethanol is thought highly of completely into port, buffer container adds pure water, Enoxaparin solution is changed water desalination remove impurity, membrane flux begins to ramp up, and stable.When TMP is 20psi, infiltration flow rate is 22.5 L/m2/h；
H, when changing water and reaching 8 times, Enoxaparin solution penetrating fluid measures salt-free, disconnects buffer container, concentrates Enoxaparin and terminates data collection to the half of original volume, computer, preserves data, close peristaltic pump, terminate the experiment of Enoxaparin ultrafiltration.Lyophilizing Enoxaparin product obtains 2.38g, numbering INK001-4141201-d, and product meets pharmacopoeial requirements, and GPC the results are shown in Table 1.
The invention provides the short-cut method of a kind of purification Enoxaparin, it is intended to improve production efficiency, reduce production cost and reduce the potential safety hazard in producing.By use in ultra-filtration process with saline-alcohol-water change liquid substitute Enoxaparin synthetically produced during the new technology of precipitate with ethanol step, be successfully used to improve ethanol in original commercial production and precipitated some drawbacks that this operating procedure is brought.Such as, need to consume a large amount of ethanol during precipitate with ethanol, but use the hyperfiltration process changing saline-alcohol-water, be greatly saved solvent, reduce production cost.Meanwhile, use the method changing saline-alcohol-water, the operating time is shortened to YYY from XXX, decreases life cycle of the product, thus improve production efficiency.
The foregoing is only embodiments of the invention; not thereby the scope of the claims of the present invention is limited; every equivalent structure utilizing description of the invention content to be made or equivalence flow process conversion; or directly or indirectly it is used in other relevant technical field, the most in like manner it is included in the scope of patent protection of the present invention.
Table 1: ultrafiltration obtains Enoxaparin fine work GPC result table.
Note: Eno-USP is Enoxaparin standard substance.
Claims (9)
1. the purification process of an Enoxaparin, it is characterised in that comprise the following steps:
A, pre-preparation: by heparin benzyl ester hydrolyzed solution, being filled to port and process in container, and connect buffer container after neutral filter paper and filtering with microporous membrane, osmotic balance is placed liquid header, osmotic balance makes zero；
B, parameter are arranged: pressure monitor and peristaltic pump, by the external computer of USB interface data wire, connect ultrafiltration software and carry out parameter setting；The flow velocity of peristaltic pump is set: open peristaltic pump, from porthandler, Enoxaparin solution is extracted by peristaltic pump, hollow fiber film assembly is entered by the pipeline of film upper liquid outlet, pressure transducer by data feedback to pressure monitor, Enoxaparin solution enters the pipeline backflow of film fluid port last time, flows back into port by automatic backpressure valve and processes in container；Arrange and step up TMP, changing the flow velocity of penetrating fluid in the pipeline of infiltration mouth；
C, change saline, ethanol, water ultra-filtration stage: in buffer container, add saline, owing to tubing is inner sealing state, when buffer container penetrates liquid, port processes container and is internally formed vacuum, saline in buffer container is sucked, Enoxaparin solution enters and changes the saline stage, carries out the most successively changing ethanol and changing pure water, it is achieved low molecule impurity and the removing of salt；
D, complete ultrafiltration: by measuring salt content in penetrating fluid, determine and change water multiple, when changing water and reaching 4-8 times, Enoxaparin solution completes ultrafiltration, concentrates the half of Enoxaparin extremely original volume, and computer terminates data collection, preserve data, close peristaltic pump, terminate the experiment of Enoxaparin ultrafiltration, cleaning equipment；
E, Indexs measure: by Enoxaparin heparin sample lyophilizing, weigh the Indexs measure such as quality, calculated yield, product G PC.
Hyperfiltration process the most according to claim 1, it is characterised in that ultrafiltration apparatus used is cross-flow ultrafiltration system.
Hyperfiltration process the most according to claim 1, it is characterised in that ultrafilter membrane used is the polyether sulfone Modified Membrane of molecular cut off 1kD, described membrane area is 100-10000cm2。
Hyperfiltration process the most according to claim 1, it is characterised in that the flow velocity 100-1000mL/min of described ultrafiltration peristaltic pump.
Hyperfiltration process the most according to claim 1, it is characterised in that described hydrolyzed solution is that heparin benzyl ester hydrolyzes in the basic conditions, adjusts pH 6-7, adds NaCl stirring and dissolving after hydrolysis, obtain through neutral filter paper and filtering with microporous membrane.
Hyperfiltration process the most according to claim 1, it is characterised in that described ultra-filtration process includes changing saline, changes ethanol, changes water and enriching stage.
Hyperfiltration process the most according to claim 1, it is characterised in that described brine strength is 4%-10%, volume is the volume of 0.5-3 times of hydrolyzed solution.
Hyperfiltration process the most according to claim 1, it is characterised in that described ethanol is AG dehydrated alcohol, volume is the volume of 0.5-3 times of hydrolyzed solution.
Hyperfiltration process the most according to claim 1, it is characterised in that described water is high purity water, volume is the volume of 3-8 times of hydrolyzed solution.
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| CN112159487A (en) * | 2020-11-05 | 2021-01-01 | 山东万邦赛诺康生化制药股份有限公司 | Preparation method of high-purity enoxaparin sodium |
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