CN104448043B - The production of a kind of Enoxaparin Sodium and purification process - Google Patents
The production of a kind of Enoxaparin Sodium and purification process Download PDFInfo
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Abstract
The present invention relates to production and the purification process of a kind of Enoxaparin Sodium, Enoxaparin Sodium crude product is performing centrifugal separation on alcohol precipitation removal of impurities after, the Enoxaparin Sodium finished product of standards of pharmacopoeia can be met.Yield of the present invention is high, easy and simple to handle, and product clarity is good, can meet the needs of pharmaceuticals industry.
Description
Technical field
The present invention relates to production and the purification process of a kind of Enoxaparin Sodium, belong to pharmaceutical field.
Background technology
Heparin always prevented and the choice drug for the treatment of thrombus class medicine since the eighties in last century.LMWHs is made up by specific chemical cleavage and purifies and separates of unfractionated heparin, and due to its determined curative effect, side effect is little and the advantage such as measurable, progressively instead of the market position of traditional heparin.
Enoxaparin Sodium (Enoxaparin
Sodium) belong to LMWHs, be mainly characterized by molecule having a 4-alkene pyranose aldehydic acid structure.This product anti thrombotic action is strong, hemorrhage risk is little, is one of current anticoagulation, antithrombotic primary treatment medicine.
Enoxaparin Sodium obtains by the benzyl ester derivative of chitling mucous membrane heparin carries out alkaline hydrolysis poly-, its basic step is: with pig mucous membrane heparin as initiation material, prepare through heparin quaternary ammonium salt, prepared by heparin benzyl ester, heparin benzyl ester carries out alkaline hydrolysis poly-, with acid neutralization, alcohol precipitation, refined, decolouring, dehydrate, obtain Enoxaparin Sodium finished product.Wherein, the Enoxaparin Sodium intermediate that obtains after acid neutralization, alcohol precipitation, its clarity is the most very poor, if the most in addition polishing purification, is just unable to reach the requirement of clarity in pharmacopeia.
Existing purification process is broadly divided into following several: (1) is by Enoxaparin Sodium activated carbon decolorizing, filter through macroreticular resin, lyophilized the obtaining of filtrate purifies Enoxaparin Sodium, the method decolorizing effect is preferable, but shortcoming is to have substantial amounts of product to adsorb in activated carbon and resin, and yield is only capable of reaching about 60%；(2) Enoxaparin Sodium NaOH is adjusted pH, by hydrogen peroxide for decoloration, it is lyophilized after sodium chloride and ethanol wash, obtain purifying Enoxaparin Sodium, the method needs to use the hydrogen peroxide that oxidisability is extremely strong, while removing pigment, it is easily caused the generation of other accessory substances, and environmental pollution is relatively big, is extremely difficult to environmental impact assessment requirement；(3) Enoxaparin Sodium passing sequentially through hydrophobic chromatography post and anion exchange resin, after nanofiltration desalination, precipitate, be dried the Enoxaparin Sodium obtaining purifying, the method needs too much time chromatographic column, and product loss is the biggest；(4) Enoxaparin Sodium passing sequentially through filtration, micro-filtration and ultrafiltration apparatus, obtain purifying Enoxaparin Sodium after being lyophilized, the loss of the method product is less, but the operation pressure of this classification ultrafiltration is relatively big, is not suitable for industrially applying；(5) Enoxaparin Sodium sodium chloride solution and methyl alcohol repeatedly being processed, the Enoxaparin Sodium that final acquisition clarity is up to standard, the method is easy and simple to handle, easily industrially realize, but its purification effect is poor, and the number of times every time repeatedly processed is difficult to accurately determine, is unfavorable for the foundation of production standard.
There is many drawbacks in the market prospects wide due to Enoxaparin Sodium and existing purification technique, developing a kind of method that can be suitable for that industrial production uses, fast and convenient purifying Enoxaparin Sodium just becomes problem demanding prompt solution.
Summary of the invention
It is an object of the invention to provide a kind of method improving Enoxaparin Sodium clarity that yield is high, easy and simple to handle.
A kind of preparation method improving Enoxaparin Sodium clarity, it is characterised in that comprise the following steps:
(1) by Enoxaparin Sodium crude product, put in sodium chloride solution and dissolve, obtain Enoxaparin Sodium crude product solution, filter；
(2) step (1) gained filtrate is performing centrifugal separation on, obtains supernatant and sediment；
(3) ethanol or methyl alcohol are joined in the supernatant obtained in step (2), after stirring and standing, be precipitated thing；
(4) sediment purified water is dissolved into the solution of 10wt ~ 15wt%, after 0.1 μm membrane filtration, is spray-dried to obtain Enoxaparin Sodium finished product.
In step (1), the concentration of sodium chloride solution is 5-15%, and Enoxaparin Sodium crude product is 1:5-10 with the weight/volume of sodium chloride solution.
In step (2), the rotating speed of centrifugation is 1000 ~ 3000 r/min, and centrifugation time is 10min ~ 60min.
In step (3), the volume ratio of ethanol or methyl alcohol and supernatant is 1-5:1, and mixing time is 1 ~ 3h, and time of repose is 3-10h.
Research finds, affect high molecular weight protein and the oligosaccharides of little molecule that the impurity of Enoxaparin Sodium clarity is mainly derived from liquaemin, and these impurity are in the preparation process of Enoxaparin Sodium, and aldehyde radical warp " Maillard reaction " in its molecule can produce coloring matter.The present invention first uses high-speed low temperature to be centrifuged off the albumen of big molecule, then is removed the small molecular weight impurities such as oligosaccharides by alcohol deposition method, thus has reached to purify the purpose of Enoxaparin Sodium.
Compared with existing purification process, the method for the invention yield is up to more than 90%, and product clarity is good, and purification process is easy, is especially suitable for pharmaceuticals industry and produces.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
Embodiment 1: the preparation of Enoxaparin Sodium crude product
Step (1): the preparation of heparin benzethonium chloride salt
In retort, put into liquaemin 1kg and purified water 20L, stir about 20 minutes, after dissolving completely, transfer to eliminate in tank.In retort, put into benzethonium chloride 2.5kg and purified water 20L, stir about 20 minutes, after dissolving completely, benzethonium chloride solution suction is eliminated in tank, stirring reaction 30 minutes.Supplementary purified water 60L being added eliminates in tank, continues stirring 10 minutes, stands 30 minutes.Reaction mixture is filtered, filter cake purified water 3 times (50kg, 50kg, 60kg) of making beating.Collect filter cake, be vacuum dried 10 hours under 60 DEG C ± 2 DEG C hot water, vacuum are more than 0.08MPa, obtain heparin benzethonium chloride salt 2.1kg.
Step (2): the preparation of heparin benzyl ester
The esterification tank of clean dried puts under heparin benzethonium chloride salt 2.1kg and dichloromethane 20L, stirring and be warming up to 35 DEG C ± 1 DEG C, insulation reaction 1 hour.Put into benzyl chloride 9kg, continue insulation reaction 25 hours.Reaction is finished, and adds sodium acetate-methanol solution, finishes continuation reaction 30 minutes.Reacting liquid filtering, filter cake methyl alcohol is pulled an oar 2 times, then be washed once.Collecting filter cake, at room temperature vacuum drying 10 hours, obtain heparin benzyl ester 1.3kg.
Step (3): the degraded of heparin benzyl ester
Degraded tank puts under heparin benzyl ester 1.3kg and purified water 10L, stirring and be warming up to 60 DEG C ± 2 DEG C.NaOH 150g and purified water 1L, stirring and dissolving, temperature control to 60 DEG C ± 2 DEG C are put in alkali-prepared tank.Sodium hydroxide solution suction in alkali-prepared tank is degraded in tank, insulation reaction 2 hours.Reaction is finished, and is cooled to room temperature, dropping 2N hydrochloric acid acidifying, regulates reactant liquor pH to 6 ~ 7, continue stirring 5 minutes, filter.Filtrate adds sodium chloride 0.5kg, stirs 30 minutes, transfer in settling tank after dissolving completely, add 5L methyl alcohol, finish, continue stirring 5 minutes, filter, collect filter cake, be dried to obtain Enoxaparin Sodium crude product 1.1kg.
The purifying of embodiment 2 Enoxaparin Sodium
Enoxaparin Sodium crude product 1.1kg embodiment 1 prepared puts into stirring and dissolving in the sodium chloride solution of 5L 10%, obtains Enoxaparin Sodium crude product solution, is filtrated to get filtrate.By filtrate 30min in the centrifuge of 2000 r/min, obtain supernatant and sediment.10L ethanol is joined in supernatant, stands 3h after stirring 1h, obtain sediment.Sediment purified water is dissolved into the solution of 10wt ~ 15wt%, after 0.1 μm membrane filtration, is spray-dried to obtain Enoxaparin Sodium finished product 1.02kg, purifies yield 92.7%.
The purifying of embodiment 3 Enoxaparin Sodium
Enoxaparin Sodium crude product 1.1kg embodiment 1 prepared puts into stirring and dissolving in the sodium chloride solution of 10L 5%, obtains Enoxaparin Sodium crude product solution, is filtrated to get filtrate.By filtrate 30min in the centrifuge of 2000 r/min, obtain supernatant and sediment.10L methyl alcohol is joined in supernatant, stands 5h after stirring 1.5h, obtain sediment.Sediment purified water is dissolved into the solution of 10wt ~ 15wt%, after 0.1 μm membrane filtration, is spray-dried to obtain Enoxaparin Sodium finished product 1.01 kg, purifies yield 91.8%.
Embodiment 4 product inspection
According to European Pharmacopoeia 8.0(EP 8.0) method the recorded Enoxaparin Sodium finished product for preparing the present invention detected: weight average molecular weight: 4350-4500
Molecular weight less than 2000: 14%-18%
2000-8000 molecular weight: 72%-77%
Anti-Xa titer: 106-120 IU/mg
Anti-IIa titer: 25-29 IU/mg
The anti-IIa:3.5-4.0 of anti-Xa/
PH:6.5-7.0
231nm absorbance: 17-18
Phenmethylol remains: < 0.05%
Sodium content: 11.5%-12.5%
Clarity: be shallower than No. 1 turbidity standard
Above index has all reached the standard of EP 8.0, especially clarity one, far above the requirement of not higher than No. 6 turbidity standards described in EP 8.0.
Claims (2)
1. a preparation method for Enoxaparin Sodium, it comprises the steps:
(1) being put into by Enoxaparin Sodium crude product in sodium chloride solution and dissolve, obtain Enoxaparin Sodium crude product solution, filter, wherein the concentration of sodium chloride solution is 5-15%, and Enoxaparin Sodium crude product is 1:5-10 with the weight/volume of sodium chloride solution
kg/l；
(2) step (1) gained filtrate being performing centrifugal separation on, obtain supernatant and sediment, the rotating speed of centrifugation is 1000 ~ 3000
R/min, centrifugation time is 10min ~ 60min；
(3) ethanol or methyl alcohol being joined in the supernatant obtained in step (2), the volume ratio of ethanol or methyl alcohol and supernatant is 1-5:1, is precipitated thing after stirring and standing, and mixing time is 1 ~ 3h, and time of repose is 3-10h；
(4) the sediment purified water that step (3) obtains is dissolved into the solution of 10wt ~ 15wt%, after 0.1 μm membrane filtration, is spray-dried to obtain Enoxaparin Sodium finished product；
The Enoxaparin Sodium finished product prepared is detected by the method recorded according to European Pharmacopoeia 8.0:
Weight average molecular weight: 4350-4500
Molecular weight less than 2000: 14%-18%
2000-8000 molecular weight: 72%-77%
Anti-Xa titer: 106-120
IU/mg
Anti-IIa titer: 25-29 IU/mg
The anti-IIa:3.5-4.0 of anti-Xa/
PH:6.5-7.0
231nm absorbance: 17-18
Phenmethylol remains: < 0.05%
Sodium content: 11.5%-12.5%
Clarity: be shallower than I turbidity standard.
2. the preparation method of Enoxaparin Sodium as claimed in claim 1, Enoxaparin Sodium crude product preparation method therein is:
Step (1): the preparation of heparin benzethonium chloride salt
In retort, put into liquaemin 1kg and purified water 20L, stir 20 minutes, after dissolving completely, transfer to eliminate in tank；In retort, put into benzethonium chloride 2.5kg and purified water 20L, stir 20 minutes, after dissolving completely, benzethonium chloride solution suction is eliminated in tank, stirring reaction 30 minutes；Supplementary purified water 60L being added eliminates in tank, continues stirring 10 minutes, stands 30 minutes；Being filtered by reaction mixture, filter cake purified water is pulled an oar 3 times, collects filter cake, is vacuum dried 10 hours, obtains heparin benzethonium chloride salt 2.1kg under 60 DEG C ± 2 DEG C hot water, vacuum are more than 0.08MPa；
Step (2): the preparation of heparin benzyl ester
Heparin benzethonium chloride salt 2.1kg and dichloromethane is put in the esterification tank of clean dried
20L, is warming up to 35 DEG C ± 1 DEG C, insulation reaction 1 hour under stirring, putting into benzyl chloride 9kg, continue insulation reaction 25 hours, reaction is finished, add sodium acetate-methanol solution, finishing continuation reaction 30 minutes, reacting liquid filtering, filter cake methyl alcohol is pulled an oar 2 times, washed once again, collecting filter cake, at room temperature vacuum drying 10 hours, obtain heparin benzyl ester 1.3kg；
Step (3): the degraded of heparin benzyl ester
Degraded tank puts under heparin benzyl ester 1.3kg and purified water 10L, stirring and be warming up to 60 DEG C ± 2 DEG C；NaOH 150g and purified water 1L, stirring and dissolving, temperature control to 60 DEG C ± 2 DEG C are put in alkali-prepared tank；Sodium hydroxide solution suction in alkali-prepared tank is degraded in tank, insulation reaction 2 hours, reaction is finished, it is cooled to room temperature, dropping 2N hydrochloric acid acidifying, regulates reactant liquor pH to 6 ~ 7, continue stirring 5 minutes, filter, filtrate adds sodium chloride 0.5kg, stir 30 minutes, transfer in settling tank after dissolving completely, add 5L methyl alcohol, finish, continue stirring 5 minutes, filter, collect filter cake, be dried to obtain Enoxaparin Sodium crude product 1.1kg.
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| CN106699928A (en) * | 2015-08-13 | 2017-05-24 | 烟台东诚药业集团股份有限公司 | Drying method of nadroparin calcium |
| CN108219031B (en) * | 2016-12-21 | 2020-07-03 | 鲁南制药集团股份有限公司 | Refining method of enoxaparin sodium |
| CN106977627A (en) * | 2017-05-16 | 2017-07-25 | 苏州二叶制药有限公司 | A kind of Enoxaparin production method of sodium |
| CN109467621A (en) * | 2017-09-08 | 2019-03-15 | 山阳县恒瑞肉制品有限公司 | A kind of production of Enoxaparin Sodium and purification process |
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