CN103204958B - 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 nadroparin calcium, particularly relate to a kind of nadroparin calcium production technique of low alcohol residue.
Background technology
Heparin is the Sulfated glycosaminoglycan compounds of one extracted from mammalian tissues (as mucous membrane of small intestine, lung, liver).1916, in the liver of Mclean when studying blood coagulation problem dog, first find this material, and called after " heparin ".Heparin is a kind of mixture of mucopolysaccharide sulfuric ester, and from 3kd ~ 30kd not etc., molecular structure is extremely complicated, cannot synthetic in the long period for molecular weight.The heparin only deriving from pig intestinal mucosa at present can be used for clinical treatment.
Heparin medicine series is mainly used in the prevention of acute coronary syndrome and treatment, the prevention of ischemia cerebral thrombosis and treatment, also for the Prevention and Curation of Post operation anti-freezing, anti-bolt, the prevention of other dvts and treatment and anticoagulant therapy etc. of dialysing, 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 developed in Europe first, and it obtains through physical sepn, chemical cracking, biological enzyme cracking primarily of unfractionated heparin, and molecular-weight average is generally 3kd ~ 6.5kd.Current topmost production method is chemical cleavage method, comprises nitrous acid cleavage method, hydroperoxide cleavage method, Bian ester cracking process etc.
Low molecular heparin (LMWH) has higher anti-FXa/ anti-F II a potency ratio than unfractionated heparin, thus can greatly reduce the bleeding tendency caused in antithrombotic process, progressively replace unfractionated heparin clinically at present.Within 2008, global heparin series products sales volume is close to 6,000,000,000 dollars, 2012, and the sales volume of global heparin class medicine is about 9,700,000,000 dollars, and wherein more than 80% is low molecule product.
Nadroparin calcium belongs to the one of Low molecular heparin, and exist with calcium salt forms, by GlaxoSmithKline PLC, pharmaceutical Co. Ltd develops, and within 2009, global marketing volume reaches 2.29 hundred million pounds.It is obtained through nitrous acid cleavage method by heparin sodium, molecular-weight average 3.6kd ~ 5kd, the part that molecular weight is less than 2kd accounts for less than total amount 15%, 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 nadroparin calcium, often relate in the mode of alcohol precipitation to obtain the wet product of nadroparin calcium, in the nadroparin calcium finally obtained, often have the residual of ethanol like this, conventional vacuum dry technology is difficult to make alcohol residue content≤0.5%.The method of current business processes organic solvent residual is generally adopt freeze drying equipment, but this equipment price is expensive, running cost is high, energy consumption is large, floor space is large and it is inconvenient to safeguard.
Summary of the invention
For the alcohol residue problem in nadroparin calcium production process, the object of the present invention is to provide a kind of nadroparin calcium production technique of low alcohol residue, to make ethanol content≤0.5% in nadroparin calcium, thus the quality of nadroparin calcium is made to meet the requirement of European Pharmacopoeia EP7.0.
In order to achieve the above object, present invention employs following technical scheme:
A nadroparin calcium production technique for low alcohol residue take heparin sodium as raw material, through cracking, reduction, ultrafiltration, concentrated after obtain the solution of nadroparin calcium, also comprise following 5 steps:
S1, by add water or the concentrated solution quality of nadroparin calcium that regulates is 3.5 ~ 8.2 times of heparin sodium quality;
S2, in Alcohol-settling tank, add dehydrated alcohol, adding the volume of dehydrated alcohol with the ratio range of the volume of the nadroparin calcium solution after S1 step process is 3 ~ 7, then nadroparin calcium solution is all instilled Alcohol-settling tank, stir 0.5 ~ 5 hour afterwards, leave standstill 1 ~ 60 hour, form precipitation and leave standstill liquid;
S3, leave standstill sucking-off supernatant liquor liquid from precipitation, then in residue feed liquid, add dehydrated alcohol and pull an oar, and the volume of the dehydrated alcohol added is 0.1 ~ 3 times of residue material liquid volume, beating time is 0.2 ~ 10 hour;
S4, centrifugal treating is carried out to the feed liquid after S3 step process, and with 70 ~ 99% ethanol rinse, and then centrifuge dripping obtains nadroparin calcium wet product, and the volume of ethanol used accounts for 1 ~ 10L/Kg of heparin sodium quality;
S5, nadroparin calcium wet product is placed in vacuum drying oven drying, vacuum tightness is not less than-0.09MPa, first Air drying 1 ~ 15 hour, then under 30 ° of C, 45 ° of C, 60 ° of C each dry 0.5 ~ 10 hour successively, finally under 80 ° of C dry 1 ~ 20 hour.
Found by research, before alcohol precipitation during concentration, the alcohol precipitation of nadroparin calcium dehydrated alcohol consumption, making beating time dehydrated alcohol consumption and dry time temperature four factors must consider, indispensable, and each parameter is not changeless, when there is larger variation in a factor, another three factors also change possibly thereupon, otherwise probably cause alcohol residue to exceed standard.Corresponding reason infer have following some:
(1), control the concentration of nadroparin calcium before alcohol precipitation, when can make alcohol precipitation, product particle form is better, if concentration is too low, then particle is meticulous, and centrifugal rear product is more sticky, and weight in wet base is large, and the ethanol carried and moisture increase greatly, are unfavorable for drying.If excessive concentration, then deposit seeds is comparatively large, is unfavorable for that ethanol is to external diffusion in drying process.
(2), control alcohol precipitation time dehydrated alcohol consumption, possess good particle form when being equally and product is precipitated.
(3), control making beating time dehydrated alcohol consumption, be then the ratio in order to regulate the second alcohol and water carried in product.Application conventional vacuum drying plant, is dried to the later stage, and the weight loss on drying of product is tending towards constant (this part water possible and ethanol combine with hydrogen bond formation and nadroparin calcium molecule, are difficult to dry) about 4 ~ 6%.Regulate the ratio of suitable second alcohol and water during making beating, the later stage of drying remaining 4 ~ 6% mainly moisture can be made, 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 ethanol, exceed standard certainly; If proportion of ethanol is too low, then easily occur in drying process that a large amount of caking even melts, and embeds ethanol in product, is difficult to diffusion, alcohol residue also can be made to exceed standard.
(4), drying temperature is controlled.Initial stage Air drying, can remove the ethanol of product surface as far as possible, and makes the ethanol of granule interior to external diffusion, and now the evaporation rate of ethanol is 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 is gradually close; Later stage 80 DEG C, time dry, along with the reduction of ethanol content, moisture evaporation speed finally exceeded ethanol evaporation rate, and the loft drier later stage has more water of condensation.The later stage of drying remaining 4 ~ 6% mainly moisture, ethanol then≤0.5%.
Namely, during consumption, making beating by dehydrated alcohol when the concentration, the alcohol precipitation that control nadroparin calcium before alcohol precipitation dehydrated alcohol consumption and dry time temperature four factors, reduce the alcohol residue in nadroparin calcium, make Residual ethanol meet the requirement of European Pharmacopoeia EP7.0.
Preferably, the mass percentage of the nadroparin calcium solution after S1 step process is 8.5 ~ 20%.
Preferably, the solution quality of the nadroparin calcium after S1 step process is 3.9 ~ 7.0 times of heparin sodium quality, and the mass percentage of this nadroparin calcium solution is 10 ~ 18%.
Preferably, adding the volume of dehydrated alcohol in S2 step with the ratio range of the volume of the nadroparin calcium solution after S1 step process is 3.5 ~ 6.5.
Preferably, in S2 step after nadroparin calcium solution instillation Alcohol-settling tank, churning time is 1 ~ 3 hour, and time of repose is 3 ~ 20 hours.
Preferably, the volume of the dehydrated alcohol added in S3 step is 0.3 ~ 1 times of residue material liquid volume, and in S3 step, beating time is 0.5 ~ 5 hour.
Preferably, in S4 step, the volume of ethanol used accounts for 2 ~ 5L/Kg of heparin sodium quality.
Preferably, ethanol used in S4 step is 80 ~ 95% ethanol.
Preferably, first Air drying 2 ~ 10 hours in S5 step, then under 30 ° of C, 45 ° of C, 60 ° of C each dry 1 ~ 6 hour successively, finally under 80 ° of C dry 5 ~ 15 hours.
The invention discloses a kind of nadroparin calcium production technique of low alcohol residue, this technique is by the concentration of nadroparin calcium solution before control alcohol precipitation, the consumption of dehydrated alcohol during alcohol precipitation, the consumption of dehydrated alcohol and temperature four factors time dry during making beating, the problem of alcohol residue in nadroparin calcium production process is solved by simple vacuum-drying, make alcohol residue≤0.5%, meet the requirement of European Pharmacopoeia EP7.0, avoid the use of freeze drying equipment, there is equipment price cheap, operation energy consumption is low, easy to maintenance, floor space is little, be easy to produce and amplify, the 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 made further clear and complete instructions.
Embodiment one
Embodiment one discloses a kind of nadroparin calcium production technique of low alcohol residue, and concrete technology is as follows:
After taking 1kg heparin sodium nitrous acid cleavage, reduction, ultrafiltration and concentration, be wherein about 0.7kg containing nadroparin calcium;
Above-mentioned concentrated solution quality is about 3kg, adds 4.2 times that purified water to solution quality reaches 4.2kg(heparin sodium charging capacity), now the concentration of nadroparin calcium solution is about 16.6%, and volume is about 4L;
Add 14L dehydrated alcohol (3.5 times of volumes are in above-mentioned nadroparin calcium solution) in Alcohol-settling tank, stir the above-mentioned feed liquid of lower dropping, finish stirring 3 hours, leave standstill 10 hours;
Sucking-off supernatant liquor 9.5L, residue material liquid volume is about 8.5L, adds the dehydrated alcohol 6.8L of residue feed liquid 0.8 times of volume, pull an oar 0.5 hour under stirring;
By centrifugal for the feed liquid after making beating, with 5L, 95% ethanol rinse, dry, obtain nadroparin calcium wet product 1.15kg;
Vacuum-drying, vacuum tightness is not less than-0.09MPa, first Air drying 3 hours, then 30 DEG C of dryings, 1 hour, 45 DEG C dryings, 2 hours, 60 DEG C dryings 3 hours successively, last 80 DEG C of dryings 10 hours;
Obtain nadroparin calcium finished product 706g, after testing alcohol residue 0.21%, meet the requirement of European Pharmacopoeia EP7.0.
Embodiment two
Embodiment two discloses a kind of nadroparin calcium production technique of low alcohol residue, and concrete technology is as follows:
After taking 1kg heparin sodium nitrous acid cleavage, reduction, ultrafiltration and concentration, be wherein about 0.7kg containing nadroparin calcium;
Above-mentioned concentrated solution quality is about 3kg, adds 6.6 times that purified water to solution quality reaches 6.6kg(heparin sodium charging capacity), now the concentration of nadroparin calcium solution is about 10.6%, and volume is about 6.2L;
Add 24.8L dehydrated alcohol (4 times of volumes are in above-mentioned nadroparin calcium solution) in Alcohol-settling tank, stir the above-mentioned feed liquid of lower dropping, finish stirring 2 hours, leave standstill 15 hours;
Sucking-off supernatant liquor 12.7L, residue material liquid volume is about 18.3L, adds the dehydrated alcohol 7.3L of residue feed liquid 0.4 times of volume, pull an oar 1 hour under stirring;
By centrifugal for the feed liquid after making beating, with 3L, 85% ethanol rinse, drying, obtain nadroparin calcium wet product 1.68kg;
Vacuum-drying, vacuum tightness is not less than-0.09MPa, first Air drying 5 hours, then 30 DEG C of dryings, 3 hours, 45 DEG C dryings, 2 hours, 60 DEG C dryings 2 hours successively, last 80 DEG C of dryings 12 hours;
Obtain nadroparin calcium finished product 692g, after testing alcohol residue 0.38%, meet the requirement of European Pharmacopoeia EP7.0.
In other embodiments, the ratio range regulating nadroparin calcium solution quality and heparin sodium quality before alcohol precipitation is 3.5 ~ 8.2, is preferably 3.9 ~ 7; In alcohol precipitation process, the ratio range of dehydrated alcohol and nadroparin calcium liquor capacity is 3 ~ 7, is preferably 3.5 ~ 6.5; In alcohol precipitation process, churning time is 0.5 ~ 5 hour, and be preferably 1 ~ 3 hour, time of repose is 1 ~ 60 hour, is preferably 3 ~ 20 hours; In pulping process, the volume of dehydrated alcohol is 0.1 ~ 3 times of residue material liquid volume, is preferably 0.3 ~ 1 times; In pulping process, beating time is 0.2 ~ 10 hour, is preferably 0.5 ~ 5 hour; In lessivation, ethanol used is 70 ~ 99% ethanol, and be preferably 80 ~ 95% ethanol, ethanol contend used accounts for 1 ~ 10L/Kg of heparin sodium quality, is preferably 2 ~ 5L/Kg; In process of vacuum drying, vacuum tightness is not less than-0.09MPa, first Air drying 1 ~ 15 hour, again successively 30 DEG C, 45 DEG C, 60 DEG C dry 0.5 ~ 10 hour respectively, last 80 DEG C of dryings 1 ~ 20 hour, be preferably first Air drying 2 ~ 10 hours, then 30 DEG C successively, 45 DEG C, 60 DEG C dry 1 ~ 6 hour respectively, last 80 DEG C of dryings 5 ~ 15 hours.
Below by the consumption of dehydrated alcohol when with the contrast experiment 1 of embodiment one, contrast experiment 2 alcohol precipitation being described and when pulling an oar these two factors of consumption of dehydrated alcohol reducing the vital role played in alcohol residue technique, these two factors of temperature during concentration and vacuum-drying by nadroparin calcium solution before alcohol precipitation being described with the contrast experiment 1 of embodiment two, contrast experiment 2 are reducing the vital role played in alcohol residue technique.
The contrast experiment 1 of embodiment one: during alcohol precipitation, the consumption of dehydrated alcohol changes
After taking 1kg heparin sodium nitrous acid cleavage, reduction, ultrafiltration and concentration, be wherein about 0.7kg containing nadroparin calcium;
Above-mentioned concentrated solution quality is about 3kg, adds 4.2 times that purified water to solution quality reaches 4.2kg(heparin sodium charging capacity), now the concentration of nadroparin calcium solution is about 16.6%, and volume is about 4L;
Add 30L dehydrated alcohol (7.5 times of volumes are in above-mentioned nadroparin calcium solution) in Alcohol-settling tank, stir the above-mentioned feed liquid of lower dropping, finish stirring 3 hours, leave standstill 10 hours;
Sucking-off supernatant liquor 19.8L, residue material liquid volume is about 14.2L, adds the dehydrated alcohol 11.4L of residue feed liquid 0.8 times of volume, pull an oar 0.5 hour under stirring;
By centrifugal for the feed liquid after making beating, with 5L, 95% ethanol rinse, dry, obtain nadroparin calcium wet product 1.32kg;
Vacuum-drying, vacuum tightness is not less than-0.09MPa, first Air drying 3 hours, then 30 DEG C of dryings, 1 hour, 45 DEG C dryings, 2 hours, 60 DEG C dryings 3 hours successively, last 80 DEG C of dryings 10 hours;
Obtain nadroparin calcium finished product 710g, after testing alcohol residue 3.24%, do not meet the requirement of European Pharmacopoeia EP7.0.
The contrast experiment 2 of embodiment one: during making beating, the consumption of dehydrated alcohol changes
After taking 1kg heparin sodium nitrous acid cleavage, reduction, ultrafiltration and concentration, be wherein about 0.7kg containing nadroparin calcium;
Above-mentioned concentrated solution quality is about 3kg, adds 4.2 times that purified water to solution quality reaches 4.2kg(heparin sodium charging capacity), now the concentration of nadroparin calcium solution is about 16.6%, and volume is about 4L;
Add 14L dehydrated alcohol (3.5 times of volumes are in above-mentioned nadroparin calcium solution) in Alcohol-settling tank, stir the above-mentioned feed liquid of lower dropping, finish stirring 3 hours, leave standstill 10 hours;
Sucking-off supernatant liquor 9.6L, residue material liquid volume is about 8.4L, adds dehydrated alcohol 29.4L (3.5 times to residue feed liquid), pull an oar 0.5 hour under stirring;
By centrifugal for the feed liquid after making beating, with 5L, 95% ethanol rinse, drying, obtain nadroparin calcium wet product 1.29kg;
Vacuum-drying, vacuum tightness is not less than-0.09MPa, first Air drying 3 hours, then 30 DEG C of dryings, 1 hour, 45 DEG C dryings, 2 hours, 60 DEG C dryings 3 hours successively, last 80 DEG C of dryings 10 hours;
Obtain nadroparin calcium finished product 701g, after testing alcohol residue 4.20%, do not meet the requirement of European Pharmacopoeia EP7.0.
The contrast experiment 1 of embodiment two: before alcohol precipitation, the concentration of nadroparin calcium solution changes
After taking 1kg heparin sodium nitrous acid cleavage, reduction, ultrafiltration and concentration, be wherein about 0.7kg containing nadroparin calcium;
Above-mentioned concentrated solution quality is about 3kg, adds 8.5 times that purified water to solution quality reaches 8.5kg(heparin sodium charging capacity), now the concentration of nadroparin calcium solution is about 8.23%, and volume is about 8.2L;
Add 32.8L dehydrated alcohol (4 times of volumes are in above-mentioned nadroparin calcium solution) in Alcohol-settling tank, stir the above-mentioned feed liquid of lower dropping, finish stirring 2 hours, leave standstill 15 hours;
Sucking-off supernatant liquor 19.1L, residue material liquid volume is about 21.9L, adds the dehydrated alcohol 8.8L of residue feed liquid 0.4 times of volume, pull an oar 1 hour under stirring;
By centrifugal for the feed liquid after making beating, with 3L, 85% ethanol rinse, dry, obtain nadroparin calcium wet product 1.81kg;
Vacuum-drying, vacuum tightness is not less than-0.09MPa, first Air drying 5 hours, then 30 DEG C of dryings, 3 hours, 45 DEG C dryings, 2 hours, 60 DEG C dryings 2 hours successively, last 80 DEG C of dryings 12 hours;
Obtain nadroparin calcium finished product 703g, after testing alcohol residue 2.88%, do not meet the requirement of European Pharmacopoeia EP7.0.
The contrast experiment 2 of embodiment two: temperature control break during vacuum-drying
After taking 1kg heparin sodium nitrous acid cleavage, reduction, ultrafiltration and concentration, be wherein about 0.7kg containing nadroparin calcium;
Above-mentioned concentrated solution quality is about 3kg, adds 6.6 times that purified water to solution quality reaches 6.6kg(heparin sodium charging capacity), now the concentration of nadroparin calcium solution is about 10.6%, and volume is about 6.2L;
Add 24.8L dehydrated alcohol (4 times of volumes are in above-mentioned nadroparin calcium solution) in Alcohol-settling tank, stir the above-mentioned feed liquid of lower dropping, finish stirring 2 hours, leave standstill 15 hours;
Sucking-off supernatant liquor 12.5L, residue material liquid volume is about 18.5L, adds the dehydrated alcohol 7.4L of residue feed liquid 0.4 times of volume, pull an oar 1 hour under stirring;
By centrifugal for the feed liquid after making beating, with 3L, 85% ethanol rinse, dry, obtain nadroparin calcium wet product 1.70kg;
Vacuum-drying, vacuum tightness is not less than-0.09MPa, direct 80 DEG C, drying product in mid-term caking is very serious, continues drying, amount to dry 20 hours after pulverizing, obtain nadroparin calcium finished product 696g, after testing alcohol residue 2.70%, do not meet the requirement of European Pharmacopoeia EP7.0.
From above-described embodiment and contrast experiment, the invention discloses a kind of nadroparin calcium production technique of low alcohol residue, during consumption, making beating by dehydrated alcohol when the concentration, the alcohol precipitation that control nadroparin calcium solution before alcohol precipitation dehydrated alcohol consumption and dry time temperature four factors, solved the problem of alcohol residue in nadroparin calcium production process by simple vacuum-drying, describe these four factors by comparative example and play an important role in reduction alcohol residue technique; This technique makes the alcohol residue in nadroparin calcium meet the requirement of European Pharmacopoeia EP7.0, avoid 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, the advantage such as the low and process stabilizing of production cost.
It should be noted that above-described embodiment is only illustrating technical scheme of the present invention, be not intended to limit the present invention, every equivalent replacement or conversion doing same design to the present invention, all belongs to protection scope of the present invention.
Claims (8)
1. a nadroparin calcium production technique for low alcohol residue take heparin sodium as raw material, through cracking, reduction, ultrafiltration, concentrated after obtain the solution of nadroparin calcium, it is characterized in that, also comprise following 5 steps:
S1, by add water or the concentrated solution quality of described nadroparin calcium that regulates is 3.5 ~ 8.2 times of described heparin sodium quality; The mass percentage of the nadroparin calcium solution through adding water or after concentrated adjustment is 8.5 ~ 20%;
S2, in Alcohol-settling tank, add dehydrated alcohol, adding the volume of described dehydrated alcohol with the ratio range of the volume of the nadroparin calcium solution after described S1 step process is 3 ~ 7, then nadroparin calcium solution is all instilled Alcohol-settling tank, stir 0.5 ~ 5 hour afterwards, leave standstill 1 ~ 60 hour, form precipitation and leave standstill liquid;
S3, leave standstill sucking-off supernatant liquor liquid from precipitation, then in residue feed liquid, add dehydrated alcohol and pull an oar, and the volume of the described dehydrated alcohol added is 0.1 ~ 3 times of residue material liquid volume, beating time is 0.2 ~ 10 hour;
S4, centrifugal treating is carried out to the feed liquid after S3 step process, and with 70 ~ 99% ethanol rinse, and then centrifuge dripping obtains nadroparin calcium wet product, and the volume of ethanol used accounts for 1 ~ 10L/Kg of described heparin sodium quality;
S5, described nadroparin calcium wet product is placed in vacuum drying oven drying, vacuum tightness is not less than-0.09MPa, first Air drying 1 ~ 15 hour, then at 30 DEG C, 45 DEG C, 60 DEG C each dry 0.5 ~ 10 hour successively, finally at 80 DEG C dry 1 ~ 20 hour.
2. the nadroparin calcium production technique of low alcohol residue according to claim 1, it is characterized in that: the solution quality of the nadroparin calcium after described S1 step process is 3.9 ~ 7.0 times of described heparin sodium quality, the mass percentage of this nadroparin calcium solution is 10 ~ 18%.
3. the nadroparin calcium production technique of low alcohol residue according to claim 1, is characterized in that: adding the volume of dehydrated alcohol in described S2 step with the ratio range of the volume of the nadroparin calcium solution after described S1 step process is 3.5 ~ 6.5.
4. the nadroparin calcium production technique of low alcohol residue according to claim 1, is characterized in that: in described S2 step after nadroparin calcium solution instillation Alcohol-settling tank, churning time is 1 ~ 3 hour, and time of repose is 3 ~ 20 hours.
5. the nadroparin calcium production technique of low alcohol residue according to claim 1, is characterized in that: the volume of the dehydrated alcohol added in described S3 step is 0.3 ~ 1 times of residue material liquid volume, and in described S3 step, beating time is 0.5 ~ 5 hour.
6. the nadroparin calcium production technique of low alcohol residue according to claim 1, is characterized in that: in described S4 step, the volume of ethanol used accounts for 2 ~ 5L/Kg of described heparin sodium quality.
7. the nadroparin calcium production technique of low alcohol residue according to claim 1, is characterized in that: in described S4 step, ethanol used is 80 ~ 95% ethanol.
8. the nadroparin calcium production technique of low alcohol residue according to claim 1, it is characterized in that: first Air drying 2 ~ 10 hours in described S5 step, successively at 30 DEG C, 45 DEG C, 60 DEG C each dry 1 ~ 6 hour again, finally at 80 DEG C dry 5 ~ 15 hours.
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| CN104072639B (en) * | 2014-07-16 | 2015-04-22 | 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 |
| CN104804110B (en) * | 2015-05-08 | 2017-04-12 | 深圳赛保尔生物药业有限公司 | High-purity nadroparin calcium |
| CN106074400B (en) * | 2016-06-23 | 2019-08-30 | 湖北亿诺瑞生物制药有限公司 | A kind of remaining nadroparin calcium lyophilized technique of low ethanol |
| 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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