CN104592421A - Refining method of enoxaparin sodium - Google Patents
Refining method of enoxaparin sodium Download PDFInfo
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- CN104592421A CN104592421A CN201310527771.1A CN201310527771A CN104592421A CN 104592421 A CN104592421 A CN 104592421A CN 201310527771 A CN201310527771 A CN 201310527771A CN 104592421 A CN104592421 A CN 104592421A
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- enoxaparin sodium
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Abstract
The invention belongs to the technical field of medicine and relates to a refining method of enoxaparin sodium. The refining method solves the problems of the prior art, utilizes an enoxaparin sodium crude product as a raw material, realizes combination of hydrogen peroxide oxidation decoloring and methanol grading alcohol precipitation, and adopts a two-step decoloring and methanol grading alcohol precipitation method. The decolored agent obtained by the refining method is basically colorless, colored impurities can be effectively removed and an enoxaparin sodium finished product is obtained by spray drying. The refining method realizes synthesis of the enoxaparin sodium finished product satisfying the requirement EP 7.0. The refining method has product collection easiness and is suitable for industrial expanded production. Through integral cooperation of decoloring, grading alcohol precipitation and spray drying, product clarity is less than or equal to that of a turbidimetric liquid 0.5, European pharmacopoeia EP 7.0 requirements are satisfied, production processes are simple, product collection is easy and the refining method is provided for industrial production.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of process for purification of Enoxaparin Sodium.
Background technology
Its English name of Enoxaparin Sodium: enoxaparin sodium, trade(brand)name: Ke Sai, its structural formula is:
Enoxaparin Sodium, within 1987, in France's first time approval, first time in 1993, this medicine existing was used the treatment whole world 1.08 hundred million patient's DVT with low molecular weight heparin by America & Canada approval listing.About the production technique of Enoxaparin Sodium, the existing report having had many sections of documents both at home and abroad, such as: US5389618, CN100436483, CN101165071A etc.But one of them important production technique, namely Enoxaparin Sodium is refining, being but not quite similar of domestic and international pertinent literature report.(1) the decolouring problem of Enoxaparin Sodium crude product, has in pertinent literature and uses macroporous adsorbent resin, charcoal absorption decolouring, hydrogen peroxide oxidation decolouring etc.Enoxaparin Sodium crude product molecular weight and molecular weight distribution as a Low molecular heparin of paramount importance index and EP7.0 requires and a gram match exists bigger difference, and pertinent literature report is less, and mainly concentrates on and use the method for ultrafiltration to carry out regulation and control.(3) Enoxaparin Sodium finished product prepares link, and have methods such as using alcohol precipitation, lyophilize in pertinent literature report, above method not can solve Enoxaparin Sodium finished product clarity problem.
Summary of the invention
For above-mentioned prior art Problems existing, the present invention with Enoxaparin Sodium crude product for raw material, hydrogen peroxide oxidation decolouring is combined with methyl alcohol classification alcohol precipitation, and take twice decolouring and methyl alcohol classification alcohol precipitating method, be close in colourless through the method decolouring liquid, foreign pigment is able to effective removal, take spraying dry as Enoxaparin Sodium finished product preparation method, successfully synthesize and meet EP7.0 requirement Enoxaparin Sodium finished product, the method of the invention is easy to carry out product-collecting, is applicable to industrialization expanding production.
The present invention solves the problems of the technologies described above taked technical scheme: a kind of process for purification of Enoxaparin Sodium, with Enoxaparin Sodium crude product for raw material, adopts hydrogen peroxide oxidation decolouring, methyl alcohol classification alcohol precipitation, synthesis Enoxaparin Sodium finished product.
The process for purification of described Enoxaparin Sodium, specifically comprises the steps:
(1) Enoxaparin Sodium crude product is joined in purified water, at 10 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 5% ~ 20% concentration, regulate pH to 6.8 ~ 8.8, the concentration adding 0.3% ~ 3% medicine liquid volume is the hydrogen peroxide of 30%, Keep agitation 8 ~ 20 hours, in liquid, progressively add sodium-chlor be stirred to and dissolve completely, then in liquid, add the methyl alcohol of medicine liquid volume 2 ~ 5 times, precipitation, filter to obtain the middle product of Enoxaparin Sodium; By this step repetitive operation once;
(2) product in the middle of Enoxaparin Sodium are joined in purified water, at 10 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 20% ~ 40% concentration, liquid filters through 0.1 micron membrane filter, spraying dry, wherein spraying dry liquid temperature in is 140 DEG C ~ 180 DEG C, and temperature out is 70 DEG C ~ 90 DEG C, medicine liquid spray speed is that 500 ml ~ 1000 ml are per hour, obtains Enoxaparin Sodium highly finished product after spraying dry.
Further, described in our preferred steps (1), the pH value of solution is adjusted to 6.8 ~ 7.2.
Further, the concentration adding 0.3% ~ 1% medicine liquid volume in our preferred steps (1) is the hydrogen peroxide of 30%.。
Further, the add-on that we also disclosed methyl alcohol described in step (1) is 2 ~ 3 times of medicine liquid volume.
The invention has the beneficial effects as follows: by the macrogamy of the technology such as decolouring, classification alcohol precipitation and spraying dry, its clarity of the product obtained is not deeper than No. 0.5 than turbid liquid, meet the requirement of European Pharmacopoeia EP7.0, simultaneously production technique simple, be easy to carry out product-collecting, for industrial carrying out provides method.
Embodiment
Unless stated otherwise, the reagent selected in following examples is commercially available general reagent.
Embodiment 1
Enoxaparin Sodium crude product 20 g, purified water 400 ml is added in the 1L reaction flask of drying, at 10 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 5% concentration, 1mol/L sodium hydroxide adjust ph 7.8, the hydrogen peroxide of 1% times is added by medicine liquid volume, the concentration of hydrogen peroxide is 30%, here concentration is the mass body volume concentrations on ordinary meaning, Keep agitation 12 hours, 40 g sodium-chlor stirring and dissolving are progressively added in liquid, add medicine liquid volume 2.5 times of methyl alcohol, precipitation, filter to obtain the middle product of Enoxaparin Sodium.By this step repetitive operation once.
Add in middle product 15 g of Enoxaparin Sodium, purified water 75 ml in 250 ml reaction flasks of drying, at 20 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 20% concentration, liquid filters through 0.1 micron membrane filter, spraying dry, wherein spraying dry liquid temperature in is 180 DEG C, and temperature out is 90 DEG C, medicine liquid spray speed is that 800 ml are per hour, namely obtains Enoxaparin Sodium highly finished product after spraying dry.
Embodiment 2
Enoxaparin Sodium crude product 20 g, Purified Water 400 ml is added in the 1L reaction flask of drying, at 10 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 5% concentration, and 1mol/L sodium hydroxide adjust ph 8.8, adds the hydrogen peroxide of 0.5% times by medicine liquid volume, the concentration of hydrogen peroxide is 30%, Keep agitation 20 hours, progressively adds 40 g sodium-chlor stirring and dissolving in liquid, adds medicine liquid volume 2.5 times of methyl alcohol, precipitation, filter in the middle of Enoxaparin Sodium.By this step repetitive operation once.
Add in 250 ml reaction flasks of drying in Enoxaparin Sodium crude product 15 g, Purified Water 50 ml, at 20 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 30% concentration, liquid filters through 0.1 micron membrane filter, spraying dry, wherein spraying dry liquid temperature in is 140 DEG C, and temperature out is 70 DEG C, medicine liquid spray speed is that 1000 ml are per hour, namely obtains Enoxaparin Sodium highly finished product after spraying dry.
Embodiment 3
Enoxaparin Sodium crude product 20 g, Purified Water 400 ml is added in the 1L reaction flask of drying, at 10 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 5% concentration, and 1mol/L sodium hydroxide adjust ph 6.8, adds the hydrogen peroxide of 0.3% times by medicine liquid volume, the concentration of hydrogen peroxide is 30%, Keep agitation 18 hours, progressively adds 40 g sodium-chlor stirring and dissolving in liquid, adds medicine liquid volume 5 times of methyl alcohol, precipitation, filters to obtain the middle product of Enoxaparin Sodium.By this step repetitive operation once.
Add in 250 ml reaction flasks of drying in Enoxaparin Sodium crude product 15 g, Purified Water 50 ml, at 20 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 30% concentration, liquid filters through 0.1 micron membrane filter, spraying dry, wherein spraying dry liquid temperature in is 120 DEG C, and temperature out is 60 DEG C, medicine liquid spray speed is that 800 ml are per hour, namely obtains Enoxaparin Sodium highly finished product after spraying dry.
Comparative example 1
By the Enoxaparin Sodium dissolving crude product of 1 weight part in the deionized water of 8 ~ 11 weight parts of 40 ~ 60 DEG C, pH value to 9 ~ 11 of mixed solution are regulated with sodium hydroxide, filter, add the hydrogen peroxide of 1% ~ 3% of water-soluble liquid measure, regulate pH value to 9 ~ 11 of mixed solution, insulation reaction 1 ~ 3 hour, add 10% sodium-chlor, regulate pH value to 6 ~ 8, filter, reaction solution is joined in the methanol solvate of 1.6-1.8 weight part, separate out precipitation, centrifugal, product spraying dry, obtains fine work Enoxaparin Sodium.(wherein spraying dry adopts conventional spray drying process)
Comparative example 2
By the Enoxaparin Sodium dissolving crude product of 1 weight part in the deionized water of 8 ~ 11 weight parts of 10 ~ 30 DEG C, pH value to 9 ~ 11 of mixed solution are regulated with sodium hydroxide, filter, add the hydrogen peroxide of 1% ~ 3% of water-soluble liquid measure, regulate pH value to 9 ~ 11 of mixed solution, insulation reaction 1 ~ 3 hour, add 10% sodium-chlor, regulate pH value to 6 ~ 8, filter, reaction solution is joined in the methanol solvate of 1.6-1.8 weight part, separate out precipitation, centrifugal, product spraying dry, obtains fine work Enoxaparin Sodium.(wherein spraying dry adopts conventional spray drying process)
Comparative example 3
By the Enoxaparin Sodium dissolving crude product of 1 weight part in the deionized water of 8 ~ 11 weight parts of 40 ~ 60 DEG C, regulate pH value to 9 ~ 11 of mixed solution with sodium hydroxide, filter, add the hydrogen peroxide of 1% ~ 3% of water-soluble liquid measure, regulate pH value to 6 ~ 8 of mixed solution, insulation reaction 1 ~ 3 hour, adds 10% sodium-chlor, filter, reaction solution is joined in the methanol solvate of 1.6-1.8 weight part, separate out precipitation, centrifugal, product spraying dry, obtains fine work Enoxaparin Sodium.(wherein spraying dry adopts conventional spray drying process)
Embodiment 4
By the Enoxaparin Sodium dissolving crude product of 1 weight part in the deionized water of 8 ~ 11 weight parts of 40 ~ 60 DEG C, pH value to 9 ~ 11 of mixed solution are regulated with sodium hydroxide, filter, add the hydrogen peroxide of 1% ~ 3% of water-soluble liquid measure, regulate pH value to 9 ~ 11 of mixed solution, insulation reaction 1 ~ 3 hour, add 10% sodium-chlor, regulate pH value to 6 ~ 8, filter, reaction solution is joined in the methanol solvate of 1.6-1.8 weight part, separate out precipitation, centrifugal, product spraying dry, obtains fine work Enoxaparin Sodium.
Spray dried form is with reference to the spray dried form in the present invention
Embodiment 5
According to the mensuration mode in EP7.0 pharmacopeia, respectively the product of the product obtained in embodiment in the present invention 1 ~ 3 and comparative example 1 ~ 3 is compared, the results are shown in Table 1.
| project | the product obtained in embodiment 1 ~ 3 | imported product standard | the product of comparative example 1 ~ 3 | product advantage of the present invention |
| molecular weight and molecular weight distribution | weight-average molecular weight: 4619; Less than 2000 content are 13.57; 2000 ~ 8000 content are 73.81. | weight-average molecular weight: 4552; Less than 2000 content are 14.44; 2000 ~ 8000 content are 73.63. | weight-average molecular weight: 3800 ~ 5000; Less than 2000 content are 12 ~ 20; 2000 ~ 8000 content are 68 ~ 82. | molecular weight and molecular weight distribution and import standard substance more close, be better than the domestic drug standard. |
| clarity | ≤ No. 0.5 standard is than turbid liquid | ≤ No. 1 standard is than turbid liquid | ≤ No. 1 standard is than turbid liquid | clarity is all better than import and domestic standard. |
| color | ≤ yellow No. 1 standard color solution | ≤ yellow No. 2 standard color solutions | ≤ yellow No. 2 standard color solutions | foreign pigment is removed more thorough. |
Embodiment 6
Respectively by embodiment 1 ~ 4, and the product in comparative example 1 ~ 3, carry out product qualitative observation, result is as table 2.
Table 2
| sample source | enoxaparin Sodium product property |
| embodiment 1 | white solid powder, sample good water solubility, sample clarity meets Chinese Pharmacopoeia standard. |
| embodiment 2 | white solid powder, sample good water solubility, sample clarity meets Chinese Pharmacopoeia standard |
| embodiment 3 | thick solid, more difficult collection. |
| embodiment 4 | off-white powder, product has moisture absorption phenomenon. |
| comparative example 1 | off-white color pressed powder, sample clarity close to foreign standard, lower than Chinese Pharmacopoeia requirement |
| comparative example 2 | off-white color pressed powder, product has moisture absorption phenomenon, and clarity is lower than Chinese Pharmacopoeia standard. |
| comparative example 3 | off-white color pressed powder, product has moisture absorption phenomenon, and clarity is lower than Chinese Pharmacopoeia standard. |
Claims (4)
1. the process for purification of Enoxaparin Sodium, is characterized in that: the process for purification of described Enoxaparin Sodium, specifically comprises the steps:
(1) Enoxaparin Sodium crude product is joined in purified water, at 10 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 5% ~ 20% concentration, regulate pH to 6.8 ~ 8.8, the concentration adding 0.3% ~ 3% medicine liquid volume is the hydrogen peroxide of 30%, Keep agitation 8 ~ 20 hours, in liquid, progressively add sodium-chlor be stirred to and dissolve completely, then in liquid, add the methyl alcohol of medicine liquid volume 2 ~ 5 times, precipitation, filter to obtain the middle product of Enoxaparin Sodium; By this step repetitive operation once;
(2) Enoxaparin Sodium is joined in purified water, at 10 DEG C ~ 30 DEG C, stirring and dissolving forms the liquid of 20% ~ 40% concentration, liquid filters through 0.1 micron membrane filter, spraying dry, wherein spraying dry liquid temperature in is 140 DEG C ~ 180 DEG C, and temperature out is 70 DEG C ~ 90 DEG C, medicine liquid spray speed is that 500 ml ~ 1000 ml are per hour, Enoxaparin Sodium highly finished product.
2. the process for purification of Enoxaparin Sodium according to claim 1, is characterized in that: described in step (1), the pH value of solution is adjusted to 6.8 ~ 7.2.
3. the process for purification of Enoxaparin Sodium according to claim 1, is characterized in that: the concentration adding 0.3% ~ 1% medicine liquid volume in step (1) is the hydrogen peroxide of 30%.
4. the process for purification of Enoxaparin Sodium according to claim 1, is characterized in that: the add-on of methyl alcohol described in step (1) is 2 ~ 3 times of medicine liquid volume.
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| CN201310527771.1A CN104592421A (en) | 2013-10-31 | 2013-10-31 | Refining method of enoxaparin sodium |
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| CN201310527771.1A CN104592421A (en) | 2013-10-31 | 2013-10-31 | Refining method of enoxaparin sodium |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108219031A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of process for purification of Enoxaparin Sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102585037A (en) * | 2012-02-10 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Enoxaparin sodium and production purification method thereof |
| CN102603925A (en) * | 2012-03-21 | 2012-07-25 | 东营天东生化工业有限公司 | Method for directly producing enoxaparin sodium from crude product heparin sodium |
-
2013
- 2013-10-31 CN CN201310527771.1A patent/CN104592421A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102585037A (en) * | 2012-02-10 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Enoxaparin sodium and production purification method thereof |
| CN102603925A (en) * | 2012-03-21 | 2012-07-25 | 东营天东生化工业有限公司 | Method for directly producing enoxaparin sodium from crude product heparin sodium |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108219031A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of process for purification of Enoxaparin Sodium |
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