CN103204958A - Production process of nadroparin calcium with low ethanol residue - Google Patents
Production process of nadroparin calcium with low ethanol residue Download PDFInfo
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Abstract
The invention discloses a production process of nadroparin calcium with low ethanol residue. The process comprises the following steps of: performing cracking, reduction, ultrafiltration and concentration on heparin sodium which is taken as a raw material to obtain a solution of the nadroparin calcium, and then regulating the concentration of the solution of the nadroparin calcium, the using quantity of anhydrous ethanol during an alcohol precipitation process, the using quantity of the anhydrous ethanol during a pulping process and the temperature during vacuum drying so as to finally obtain a finished product of the nadroparin calcium. According to the production process of the nadroparin calcium with the low ethanol residue, disclosed by the invention, the problem of the ethanol residue during the production process of the nadroparin calcium is solved, the ethanol residue in the nadroparin calcium is not more than 0.5% and in line with the requirements of European Pharmacopoeia EP7.0, the use of freeze-drying equipment is avoided, and the production process has the advantages of low price of the equipment, low operation energy consumption, convenience in maintenance, small floor area, easiness in production amplification, low production cost, stable process and the like.
Description
Technical field
The invention belongs to the production field of Nagqu calciparine, relate in particular to the residual Nagqu calciparine production technique of a kind of low ethanol.
Background technology
Heparin is a kind of Sulfated glycosaminoglycan compounds that extracts from mammalian tissues (as mucous membrane of small intestine, lung, liver).1916, Mclean at first found this material in the liver dog when research blood coagulation problem, and called after " heparin ".Heparin is a kind of mixture of mucopolysaccharide sulfuric ester, and molecular weight does not wait from 3kd～30kd, and molecular structure is extremely complicated, can't synthetic in the long period.The heparin that only derives from present pig intestinal mucosa can be used for clinical treatment.
The heparin medicine series is mainly used in prevention and the treatment of the prevention of acute coronary syndrome and treatment, ischemia cerebral thrombosis, also be used for prevention and the treatment of operation back anti-freezing, anti-bolt, the prevention of other dvts and treatment and dialysis anticoagulant therapy etc. can also be widely used in Obstetric and Gynecologic Department, paediatrics, Pneumology Department, tumour, Department of Burn etc.
Middle 1980s, Low molecular heparin (LMWH) is at first developed in Europe, and it is mainly obtained through physical sepn, chemical cracking, biological enzyme cracking by unfractionated heparin, and molecular-weight average is generally 3kd～6.5kd.Present topmost production method is the chemical cracking method, comprises nitrous acid cracking process, superoxide cracking process, Bian ester cracking process etc.
Low molecular heparin (LMWH) has the higher anti-F II of anti-FXa/ a potency ratio than unfractionated heparin, thereby can significantly reduce the bleeding tendency that causes in the antithrombotic process, is progressively replacing unfractionated heparin at present clinically.Global heparin series products sales volume in 2008 is near 6,000,000,000 dollars, and 2012, the sales volume of global heparin class medicine was about 9,700,000,000 dollars, wherein is low molecule product more than 80%.
The Nagqu calciparine belongs to a kind of of Low molecular heparin, exists with calcium salt forms, and by the exploitation of GlaxoSmithKline PLC pharmaceutical Co. Ltd, the global marketing volume reached 2.29 hundred million pounds in 2009.It is made through the nitrous acid cracking process by heparin sodium, molecular-weight average 3.6kd～5kd, molecular weight accounts for less than 15% of total amount less than the part of 2kd, and the part of molecular weight 2kd～4kd accounts for 35%～55% of total amount, and the part of molecular weight 2kd～8kd accounts for 75%～95% of total amount.
In the production process of Nagqu calciparine, often relate to the wet product that obtain the Nagqu calciparine in the mode of alcohol precipitation, in the Nagqu calciparine that finally obtains, often have the residual of ethanol like this, the conventional vacuum dry technology is difficult to make ethanol residual content≤0.5%.At present the method for business processes organic solvent residual generally is to adopt freeze drying equipment, but this equipment price costliness, running cost height, energy consumption is big, floor space is big and safeguard inconvenience.
Summary of the invention
At the ethanol residue problem in the calciparine production process of Nagqu, the object of the present invention is to provide the residual Nagqu calciparine production technique of a kind of low ethanol, so that ethanol content≤0.5% in the calciparine of Nagqu, thereby make the quality of Nagqu calciparine meet the requirement of European Pharmacopoeia EP7.0.
In order to achieve the above object, the present invention has adopted following technical scheme:
The Nagqu calciparine production technique that a kind of low ethanol is residual is raw material with the heparin sodium, obtains the solution of Nagqu calciparine through cracking, reduction, ultrafiltration, after concentrating, and also comprises following 5 steps:
S1, be 3.5～8.2 times of heparin sodium quality by the solution quality that adds water or concentrate to regulate the Nagqu calciparine;
S2, in Alcohol-settling tank, add dehydrated alcohol, the ratio range that adds the volume of the volume of dehydrated alcohol and the Nagqu calciparine solution after the S1 step process is 3～7, then Nagqu calciparine solution is all splashed into Alcohol-settling tank, stirred afterwards 0.5～5 hour, left standstill 1～60 hour, and formed precipitation and leave standstill liquid;
S3, leaves standstill sucking-off supernatant liquor the liquid from precipitation, add dehydrated alcohol in the residue feed liquid then and pull an oar, and the volume of the dehydrated alcohol that adds is 0.1～3 times of the residue material liquid volume that beating time is 0.2～10 hour;
S4, the feed liquid after the S3 step process is carried out centrifugal treating, and with 70～99% ethanol drip washing, and then centrifuge dripping obtains the wet product of Nagqu calciparine, the volume of used ethanol accounts for 1～10L/Kg of heparin sodium quality;
S5, calciparine wet product in Nagqu are placed the vacuum drying oven drying, vacuum tightness is not less than-0.09MPa, first Air drying 1～15 hour, each drying 0.5～10 hour under 30 ° of C, 45 ° of C, 60 ° of C successively again, drying 1～20 hour under 80 ° of C at last.
By discovering, the consumption of dehydrated alcohol and four factors of temperature when dry must be taken all factors into consideration when the consumption of dehydrated alcohol when the concentration of the preceding Nagqu of alcohol precipitation calciparine, alcohol precipitation, making beating, indispensable, and each parameter is not changeless, when a factor occurs than cataclysm, three factors also change possibly thereupon in addition, and ethanol is residual to exceed standard otherwise cause probably.Corresponding reason infer have following some:
(1), the concentration of control alcohol precipitation preceding Nagqu calciparine, the product particle form is better in the time of making alcohol precipitation, if concentration is low excessively, then particle is meticulous, centrifugal back product is more sticking, weight in wet base is big, the ethanol and the moisture that carry increase greatly, are unfavorable for drying.If excessive concentration, then deposit seeds is bigger, is unfavorable in the drying process that ethanol is to external diffusion.
(2), the consumption of control dehydrated alcohol during alcohol precipitation, be to possess particle form preferably when making the product precipitation equally.
(3), when making beating control dehydrated alcohol consumption, then be in order to regulate the ratio of the second alcohol and water that carries in the product.Use the conventional vacuum drying plant, be dried to the later stage, the weight loss on drying of product is tending towards about 4～6% constant (possible this part water and ethanol are difficult to dry with hydrogen bond form and Nagqu calciparine molecule combination).Regulate the ratio of suitable second alcohol and water during making beating, can make the later stage of drying remaining 4～6% mainly is moisture, and ethanol then≤0.5%.If proportion of ethanol is too high, then the later stage of drying is on the contrary, and remaining 4～6% mainly is ethanol, exceeds standard certainly; If proportion of ethanol is low excessively, then occur a large amount of cakings in the drying process easily even melt, embedding ethanol in the product is difficult to diffusion, can make also that ethanol is residual to exceed standard.
(4), control drying temperature.The initial stage Air drying can be removed the ethanol of product surface as far as possible, and the ethanol that makes granule interior is to external diffusion, and this moment, the evaporation rate of ethanol was far longer than moisture; When heating up gradually, the evaporation rate of ethanol, moisture is accelerated simultaneously, and the volatilization of ethanol is still faster than moisture, but the two approaches gradually; When 80 ℃ of later stages were dry, along with the reduction of ethanol content, moisture evaporation speed surpassed the ethanol evaporation rate at last, and the loft drier later stage has more water of condensation.The later stage of drying remaining 4～6% mainly is moisture, and ethanol then≤0.5%.
Namely, the consumption of dehydrated alcohol and four factors of temperature when dry when the consumption of dehydrated alcohol, making beating when the concentration by control alcohol precipitation preceding Nagqu calciparine, alcohol precipitation, the ethanol that reduces in the calciparine of Nagqu is residual, makes the ethanol residual quantity meet the requirement of European Pharmacopoeia EP7.0.
Preferably, the quality percentage composition of the Nagqu calciparine solution after the S1 step process is 8.5～20%.
Preferably, the solution quality of the Nagqu calciparine after the S1 step process is 3.9～7.0 times of heparin sodium quality, and the quality percentage composition of this Nagqu calciparine solution is 10～18%.
Preferably, the ratio range of the volume of the volume of adding dehydrated alcohol and the Nagqu calciparine solution after the S1 step process is 3.5～6.5 in the S2 step.
Preferably, after Nagqu calciparine solution splashed into Alcohol-settling tank in the S2 step, churning time was 1～3 hour, and time of repose is 3～20 hours.
Preferably, the volume of the dehydrated alcohol that adds in the S3 step is 0.3～1 times of residue material liquid volume, and beating time is 0.5～5 hour in the S3 step.
Preferably, the volume of used ethanol accounts for 2～5L/Kg of heparin sodium quality in the S4 step.
Preferably, used ethanol is 80～95% ethanol in the S4 step.
Preferably, first Air drying is 2～10 hours in the S5 step, each drying 1～6 hour under 30 ° of C, 45 ° of C, 60 ° of C successively again, under 80 ° of C dry 5～15 hours at last.
The invention discloses the residual Nagqu calciparine production technique of a kind of low ethanol, this technology is by the concentration of the preceding Nagqu of control alcohol precipitation calciparine solution, the consumption of dehydrated alcohol during alcohol precipitation, four factors of temperature when the consumption of dehydrated alcohol is with drying during making beating, solved the residual problem of ethanol in the calciparine production process of Nagqu by simple vacuum-drying, make ethanol residual≤0.5%, meet the requirement of European Pharmacopoeia EP7.0, avoided the use of freeze drying equipment, it is cheap to have an equipment price, operation energy consumption is low, easy to maintenance, floor space is little, be easy to produce and amplify, advantages such as the low and process stabilizing of production cost.
Embodiment
Below in conjunction with specific embodiment technical scheme of the present invention is done further explanation clearly and completely.
Embodiment one
Embodiment one discloses the residual Nagqu calciparine production technique of a kind of low ethanol, and concrete technology is as follows:
After taking by weighing the cracking of 1kg heparin sodium usefulness nitrous acid, reduction, ultrafiltration and concentration wherein contain the about 0.7kg of Nagqu calciparine;
The about 3kg of above-mentioned concentrated solution quality, adding purified water to solution quality reaches 4.2 times of 4.2kg(heparin sodium charging capacity), this moment, the concentration of Nagqu calciparine solution was about 16.6%, and volume is about 4L;
Add 14L dehydrated alcohol (3.5 times of volumes are in above-mentioned Nagqu calciparine solution) in Alcohol-settling tank, stir down and drip above-mentioned feed liquid, finish and stirred 3 hours, left standstill 10 hours;
Sucking-off supernatant liquor 9.5L, the about 8.5L of residue material liquid volume stirs the dehydrated alcohol 6.8L that adds 0.8 times of volume of residue feed liquid down, pulls an oar 0.5 hour;
Feed liquid after the making beating is centrifugal, with 5L, 95% ethanol drip washing, dry, get the wet product 1.15kg of Nagqu calciparine;
Vacuum-drying, vacuum tightness are not less than-0.09MPa, first Air drying 3 hours, 2 hours, 60 ℃ dryings of 1 hour, 45 ℃ dryings of 30 ℃ of dryings 3 hours successively again, last 80 ℃ of dryings 10 hours;
Obtain Nagqu calciparine finished product 706g, ethanol is residual 0.21% after testing, meets the requirement of European Pharmacopoeia EP7.0.
Embodiment two
Embodiment two discloses the residual Nagqu calciparine production technique of a kind of low ethanol, and concrete technology is as follows:
After taking by weighing the cracking of 1kg heparin sodium usefulness nitrous acid, reduction, ultrafiltration and concentration wherein contain the about 0.7kg of Nagqu calciparine;
The about 3kg of above-mentioned concentrated solution quality, adding purified water to solution quality reaches 6.6 times of 6.6kg(heparin sodium charging capacity), this moment, the concentration of Nagqu calciparine solution was about 10.6%, and volume is about 6.2L;
Add 24.8L dehydrated alcohol (4 times of volumes are in above-mentioned Nagqu calciparine solution) in Alcohol-settling tank, stir down and drip above-mentioned feed liquid, finish and stirred 2 hours, left standstill 15 hours;
Sucking-off supernatant liquor 12.7L, the about 18.3L of residue material liquid volume stirs the dehydrated alcohol 7.3L that adds 0.4 times of volume of residue feed liquid down, pulls an oar 1 hour;
Feed liquid after the making beating is centrifugal, with 3L, 85% ethanol drip washing, drying, obtain the wet product 1.68kg of Nagqu calciparine;
Vacuum-drying, vacuum tightness are not less than-0.09MPa, first Air drying 5 hours, 2 hours, 60 ℃ dryings of 3 hours, 45 ℃ dryings of 30 ℃ of dryings 2 hours successively again, last 80 ℃ of dryings 12 hours;
Obtain Nagqu calciparine finished product 692g, ethanol is residual 0.38% after testing, meets the requirement of European Pharmacopoeia EP7.0.
In other embodiments, the ratio range of regulating Nagqu calciparine solution quality and heparin sodium quality before the alcohol precipitation is 3.5～8.2, is preferably 3.9～7; The ratio range of dehydrated alcohol and Nagqu calciparine liquor capacity is 3～7 in the alcohol precipitation process, is preferably 3.5～6.5; Churning time is 0.5～5 hour in the alcohol precipitation process, is preferably 1～3 hour, and time of repose is 1～60 hour, is preferably 3～20 hours; The volume of dehydrated alcohol is preferably 0.3～1 times for 0.1～3 times of the residue material liquid volume in the pulping process; Beating time is 0.2～10 hour in the pulping process, is preferably 0.5～5 hour; Used ethanol is 70～99% ethanol in the lessivation, is preferably 80～95% ethanol, and used ethanol volume accounts for 1～10L/Kg of heparin sodium quality, is preferably 2～5L/Kg; In the process of vacuum drying, vacuum tightness is not less than-0.09MPa, elder generation's Air drying 1～15 hour, again successively 30 ℃, 45 ℃, 60 ℃ dry 0.5～10 hour respectively, last 80 ℃ of dryings 1～20 hour, be preferably first Air drying 2～10 hours, more successively 30 ℃, 45 ℃, 60 ℃ dry 1～6 hour respectively, last 80 ℃ of dryings 5～15 hours.
Below by with the contrast experiment 1 of embodiment one, when contrast experiment 2 illustrates alcohol precipitation dehydrated alcohol consumption and when making beating dehydrated alcohol the vital role in reducing the ethanol residual process, brought into play of these two factors of consumption, the vital role that these two factors of temperature when by contrast experiment 1, contrast experiment 2 with embodiment two concentration of the preceding Nagqu of alcohol precipitation calciparine solution and vacuum-drying being described are brought into play in reducing the ethanol residual process.
The contrast experiment 1 of embodiment one: the consumption of dehydrated alcohol changes during alcohol precipitation
After taking by weighing the cracking of 1kg heparin sodium usefulness nitrous acid, reduction, ultrafiltration and concentration wherein contain the about 0.7kg of Nagqu calciparine;
The about 3kg of above-mentioned concentrated solution quality, adding purified water to solution quality reaches 4.2 times of 4.2kg(heparin sodium charging capacity), this moment, the concentration of Nagqu calciparine solution was about 16.6%, and volume is about 4L;
Add 30L dehydrated alcohol (7.5 times of volumes are in above-mentioned Nagqu calciparine solution) in Alcohol-settling tank, stir down and drip above-mentioned feed liquid, finish and stirred 3 hours, left standstill 10 hours;
Sucking-off supernatant liquor 19.8L, the about 14.2L of residue material liquid volume stirs the dehydrated alcohol 11.4L that adds 0.8 times of volume of residue feed liquid down, pulls an oar 0.5 hour;
Feed liquid after the making beating is centrifugal, with 5L, 95% ethanol drip washing, dry, get the wet product 1.32kg of Nagqu calciparine;
Vacuum-drying, vacuum tightness are not less than-0.09MPa, first Air drying 3 hours, 2 hours, 60 ℃ dryings of 1 hour, 45 ℃ dryings of 30 ℃ of dryings 3 hours successively again, last 80 ℃ of dryings 10 hours;
Obtain Nagqu calciparine finished product 710g, ethanol is residual 3.24% after testing, does not meet the requirement of European Pharmacopoeia EP7.0.
The contrast experiment 2 of embodiment one: the consumption of dehydrated alcohol changes during making beating
After taking by weighing the cracking of 1kg heparin sodium usefulness nitrous acid, reduction, ultrafiltration and concentration wherein contain the about 0.7kg of Nagqu calciparine;
The about 3kg of above-mentioned concentrated solution quality, adding purified water to solution quality reaches 4.2 times of 4.2kg(heparin sodium charging capacity), this moment, the concentration of Nagqu calciparine solution was about 16.6%, and volume is about 4L;
Add 14L dehydrated alcohol (3.5 times of volumes are in above-mentioned Nagqu calciparine solution) in Alcohol-settling tank, stir down and drip above-mentioned feed liquid, finish and stirred 3 hours, left standstill 10 hours;
Sucking-off supernatant liquor 9.6L, the about 8.4L of residue material liquid volume stirs adding dehydrated alcohol 29.4L (3.5 times to the residue feed liquid) down, pulls an oar 0.5 hour;
Feed liquid after the making beating is centrifugal, with 5L, 95% ethanol drip washing, drying, get the wet product 1.29kg of Nagqu calciparine;
Vacuum-drying, vacuum tightness are not less than-0.09MPa, first Air drying 3 hours, 2 hours, 60 ℃ dryings of 1 hour, 45 ℃ dryings of 30 ℃ of dryings 3 hours successively again, last 80 ℃ of dryings 10 hours;
Obtain Nagqu calciparine finished product 701g, ethanol is residual 4.20% after testing, does not meet the requirement of European Pharmacopoeia EP7.0.
The contrast experiment 1 of embodiment two: the concentration of the preceding Nagqu of alcohol precipitation calciparine solution changes
After taking by weighing the cracking of 1kg heparin sodium usefulness nitrous acid, reduction, ultrafiltration and concentration wherein contain the about 0.7kg of Nagqu calciparine;
The about 3kg of above-mentioned concentrated solution quality, adding purified water to solution quality reaches 8.5 times of 8.5kg(heparin sodium charging capacity), this moment, the concentration of Nagqu calciparine solution was about 8.23%, and volume is about 8.2L;
Add 32.8L dehydrated alcohol (4 times of volumes are in above-mentioned Nagqu calciparine solution) in Alcohol-settling tank, stir down and drip above-mentioned feed liquid, finish and stirred 2 hours, left standstill 15 hours;
Sucking-off supernatant liquor 19.1L, the about 21.9L of residue material liquid volume stirs the dehydrated alcohol 8.8L that adds 0.4 times of volume of residue feed liquid down, pulls an oar 1 hour;
Feed liquid after the making beating is centrifugal, with 3L, 85% ethanol drip washing, dry, get the wet product 1.81kg of Nagqu calciparine;
Vacuum-drying, vacuum tightness are not less than-0.09MPa, first Air drying 5 hours, 2 hours, 60 ℃ dryings of 3 hours, 45 ℃ dryings of 30 ℃ of dryings 2 hours successively again, last 80 ℃ of dryings 12 hours;
Obtain Nagqu calciparine finished product 703g, ethanol is residual 2.88% after testing, does not meet the requirement of European Pharmacopoeia EP7.0.
The contrast experiment 2 of embodiment two: temperature control break during vacuum-drying
After taking by weighing the cracking of 1kg heparin sodium usefulness nitrous acid, reduction, ultrafiltration and concentration wherein contain the about 0.7kg of Nagqu calciparine;
The about 3kg of above-mentioned concentrated solution quality, adding purified water to solution quality reaches 6.6 times of 6.6kg(heparin sodium charging capacity), this moment, the concentration of Nagqu calciparine solution was about 10.6%, and volume is about 6.2L;
Add 24.8L dehydrated alcohol (4 times of volumes are in above-mentioned Nagqu calciparine solution) in Alcohol-settling tank, stir down and drip above-mentioned feed liquid, finish and stirred 2 hours, left standstill 15 hours;
Sucking-off supernatant liquor 12.5L, the about 18.5L of residue material liquid volume stirs the dehydrated alcohol 7.4L that adds 0.4 times of volume of residue feed liquid down, pulls an oar 1 hour;
Feed liquid after the making beating is centrifugal, with 3L, 85% ethanol drip washing, dry, obtain the wet product 1.70kg of Nagqu calciparine;
Vacuum-drying, vacuum tightness are not less than-0.09MPa, direct 80 ℃, drying product in mid-term caking is very serious, pulverizes the back and continues drying, amounts to dry 20 hours, obtain Nagqu calciparine finished product 696g, ethanol is residual 2.70% after testing, does not meet the requirement of European Pharmacopoeia EP7.0.
By above-described embodiment and contrast experiment as can be known, the invention discloses the residual Nagqu calciparine production technique of a kind of low ethanol, the consumption of dehydrated alcohol and four factors of temperature when dry when the consumption of dehydrated alcohol, making beating when the concentration by control alcohol precipitation preceding Nagqu calciparine solution, alcohol precipitation, solved the residual problem of ethanol in the calciparine production process of Nagqu by simple vacuum-drying, illustrated that by the comparative example these four factors are bringing into play important effect in reducing the ethanol residual process; This technology makes the residual requirement that meets European Pharmacopoeia EP7.0 of ethanol in the calciparine of Nagqu, avoided the use of freeze drying equipment, have that equipment price is cheap, operation energy consumption is low, easy to maintenance, floor space is little, be easy to produce amplify, production cost is low and advantage such as process stabilizing.
It should be noted that above-described embodiment only is to the specifying of technical scheme of the present invention, and be not used in restriction the present invention, everyly the present invention is done being equal to of same design replace or conversion, all belong to protection scope of the present invention.
Claims (9)
1. the Nagqu calciparine production technique that low ethanol is residual is raw material with the heparin sodium, obtains the solution of Nagqu calciparine through cracking, reduction, ultrafiltration, after concentrating, and it is characterized in that: also comprise following 5 steps:
S1, be 3.5～8.2 times of described heparin sodium quality by the solution quality that adds water or concentrate to regulate described Nagqu calciparine;
S2, in Alcohol-settling tank, add dehydrated alcohol, the ratio range that adds the volume of the volume of described dehydrated alcohol and the Nagqu calciparine solution after described S1 step process is 3～7, then Nagqu calciparine solution is all splashed into Alcohol-settling tank, stirred afterwards 0.5～5 hour, left standstill 1～60 hour, and formed precipitation and leave standstill liquid;
S3, leaves standstill sucking-off supernatant liquor the liquid from precipitation, add dehydrated alcohol in the residue feed liquid then and pull an oar, and the volume of the described dehydrated alcohol that adds is 0.1～3 times of the residue material liquid volume that beating time is 0.2～10 hour;
S4, the feed liquid after the S3 step process is carried out centrifugal treating, and with 70～99% ethanol drip washing, and then centrifuge dripping obtains the wet product of Nagqu calciparine, the volume of used ethanol accounts for 1～10L/Kg of described heparin sodium quality;
S5, calciparine wet product in described Nagqu are placed the vacuum drying oven drying, vacuum tightness is not less than-0.09MPa, first Air drying 1～15 hour, each drying 0.5～10 hour under 30 ° of C, 45 ° of C, 60 ° of C successively again, drying 1～20 hour under 80 ° of C at last.
2. the residual Nagqu calciparine production technique of low ethanol according to claim 1, it is characterized in that: the quality percentage composition of the Nagqu calciparine solution after described S1 step process is 8.5～20%.
3. the residual Nagqu calciparine production technique of low ethanol according to claim 1, it is characterized in that: the solution quality of the Nagqu calciparine after described S1 step process is 3.9～7.0 times of described heparin sodium quality, and the quality percentage composition of this Nagqu calciparine solution is 10～18%.
4. the residual Nagqu calciparine production technique of low ethanol according to claim 1 is characterized in that: the ratio range that adds the volume of dehydrated alcohol and the volume of Nagqu calciparine solution after described S1 step process in the described S2 step is 3.5～6.5.
5. the residual Nagqu calciparine production technique of low ethanol according to claim 1, it is characterized in that: after Nagqu calciparine solution splashed into Alcohol-settling tank in the described S2 step, churning time was 1～3 hour, and time of repose is 3～20 hours.
6. the residual Nagqu calciparine production technique of low ethanol according to claim 1 is characterized in that: the volume of the dehydrated alcohol that adds in the described S3 step is 0.3～1 times of residue material liquid volume, and beating time is 0.5～5 hour in the described S3 step.
7. the residual Nagqu calciparine production technique of low ethanol according to claim 1, it is characterized in that: the volume of used ethanol accounts for 2～5L/Kg of described heparin sodium quality in the described S4 step.
8. the residual Nagqu calciparine production technique of low ethanol according to claim 1, it is characterized in that: used ethanol is 80～95% ethanol in the described S4 step.
9. the residual Nagqu calciparine production technique of low ethanol according to claim 1, it is characterized in that: first Air drying is 2～10 hours in the described S5 step, each drying 1～6 hour under 30 ° of C, 45 ° of C, 60 ° of C successively again, under 80 ° of C dry 5～15 hours at last.
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| CN104072639A (en) * | 2014-07-16 | 2014-10-01 | 南京健友生化制药股份有限公司 | Production method for nadroparin calcium |
| CN104448052A (en) * | 2014-12-29 | 2015-03-25 | 青岛九龙生物医药有限公司 | Method for reducing organic residue in heparin sodium by using vacuum drying method |
| CN104804110A (en) * | 2015-05-08 | 2015-07-29 | 深圳赛保尔生物药业有限公司 | High-purity nadroparin calcium |
| CN106074400A (en) * | 2016-06-23 | 2016-11-09 | 湖北亿诺瑞生物制药有限公司 | A kind of nadroparin calcium lyophilizing technique of low ethanol residual |
| CN107328763A (en) * | 2017-06-27 | 2017-11-07 | 常州千红生化制药股份有限公司 | N NO system and method in a kind of chemical extraction heat energy analytic approach detection Nadroparin Calcium |
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