CN103483262A - Stable edaravone trihydrate and pharmaceutical compositions thereof - Google Patents
Stable edaravone trihydrate and pharmaceutical compositions thereof Download PDFInfo
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- CN103483262A CN103483262A CN201310426306.9A CN201310426306A CN103483262A CN 103483262 A CN103483262 A CN 103483262A CN 201310426306 A CN201310426306 A CN 201310426306A CN 103483262 A CN103483262 A CN 103483262A
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- edaravone
- trihydrate
- solution
- injection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
- C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
Abstract
The invention belongs to the technical field of medicine, and provides stable edaravone trihydrate, edaravone trihydrate pharmaceutical compositions for injection, a method for preparing the edaravone trihydrate and a method for preparing the edaravone trihydrate pharmaceutical compositions. Crude edaravone trihydrate is stirred and dissolved in an ethyl alcohol-pure water solution, the pH value is adjusted through hydrochloric acid to range from 3 to 5, and then liquor formed by mixing ethers and ketone according to the volume ratio of 1:(1-4) is added to the solution, and stirring and crystallization are carried out; filtering, collecting, washing and vacuum drying are carried out to obtain the edaravone trihydrate which is high in yield and purity and stable in quality. The edaravone trihydrate pharmaceutical compositions, for injection, prepared according to the preparation formulation and the preparation technology are stable in quality and can be easily employed in an industrialized mode.
Description
Technical field
The present invention relates to field of medicaments, relate to specifically a kind of stable Edaravone trihydrate and pharmaceutical composition thereof.
Background technology
Edaravone
Chemical name: 3-methyl-1-phenyl-2-pyrazolin-5-one (3-Methyl-1-phenyl-2-pyrazolin-5-one);
Molecular formula: C
10h
10n
20;
Molecular weight: 174.20;
Structural formula:
Because the Edaravone main ring is pentacyclic ketone, carbonyl and N are adjacent, the N of No. 2 positions unsaturated link(age) of ining succession, be easy to oxidation, so this molecular structure is very unstable, runs into oxygen and will be oxidized to and do not have activated material, and easily produce macromolecule impurity, human body is damaged.In addition, because there is no the hydrophilic groups such as hydroxyl, carboxyl in structure, and methyl and phenyl are insoluble in water, and long dissolution process can aggravate its oxidation and cause unstable.The research of the domestic and international anti-oxidant aspect to Edaravone Injection is not a lot of at present, there is research to adopt sodium bisulfite as antioxidant, but by test, find only with sodium bisulfite, to be difficult to resolve certainly easy oxidation, the unsettled difficult problem of this product, the sample validity period of preparation is only 1.5 years.
The preparation of listing is aqueous injection at present, and specification is 20ml:30mg, with normal saline dilution posterior vein instillation medication.Because Edaravone is insoluble in water, rare aqueous solution is unstable.Current injection need add more L-cysteine hydrochloride and sodium bisulfite as antioxidant and solubility promoter.Due to the poor stability of the aqueous solution, then the heating for dissolving of preparation process and the more difficult control of high-temperature sterilization, easily to decompose, the stability of finished product is more responsive to condition of storage, and validity period is shorter.
Chinese patent CN201010568820.2 relates to a kind of highly purified edaravone compound, belongs to medical technical field.Edaravone compound provided by the invention, by charcoal absorption, processed by ion-exchange membrane electrodialysis and chromatographic column again, greatly improved purity and the content of Edaravone, improved the quality product of preparation, reduced toxic side effect, ensured the safety of clinical application, present method technique is simple, and cost is low, yield is high, is suitable for suitability for industrialized production.
Chinese patent CN201010128317.5 relates to a kind of Edaravone of variation route, and the method be take phenylhydrazine hydrochloride as starting raw material, and the sodium hydroxide reaction generates phenylhydrazine; Then phenylhydrazine mixes back flow reaction with methyl aceto acetate again, makes the Edaravone crude product; Again the Edaravone crude product is dissolved in to isopropanol-water solution, adds charcoal absorption, filter, make white crystals sprills highly finished product.The inventive method cost is low, and product yield is high, purity is high.
Chinese patent CN200910264437.5 discloses a kind of synthetic method of edaravone metabolite, by the method, can shorten synthetic route on the one hand, also can greatly improve on the other hand yield and the purity of target product.
Chinese patent CN200910234253.4 relates to a kind of crystal formation of Edaravone and preparation method thereof; It is characterized in that its powder x-ray diffraction figure.This crystal formation can significantly improve the water-soluble of Edaravone, more is conducive to the preparation of injection, and related substance is further reduced, and the security of preparation is improved.
The purpose of this invention is to provide a kind of stable edaravone compound and pharmaceutical composition thereof, solve the slow problem of dissolution rate in the preparation process.
Summary of the invention
The first purpose of the present invention is to provide a kind of stable Edaravone trihydrate, and it can overcome the deficiency of prior art, efficiently solve Edaravone in water than problems such as indissoluble solutions.
The second purpose of the present invention is to provide a kind of preparation method of stable Edaravone trihydrate.
The 3rd purpose of the present invention is to provide a kind of pharmaceutical composition of stable Edaravone trihydrate.
The 3rd purpose of the present invention is to provide a kind of preparation method of pharmaceutical composition of stable Edaravone trihydrate.
The object of the invention is to overcome a prior art difficult problem, a kind of simple, method of being easy to produce and effectively prepare the Edaravone trihydrate crystal is provided, products obtained therefrom has the purity of superelevation and ultralow residual solvent.
In order to realize this purpose, the invention provides following technical scheme:
A kind of crystallization method for preparing pure Edaravone trihydrate, comprise the steps:
1) the Edaravone crude product is added to the ethanol pure water solution, 30-50 ℃ of lower stirring and dissolving;
2) be 3-5 by above-mentioned solution with the hydrochloric acid adjust pH under room temperature, then add ethers and ketone volume ratio to be
The mixed solution of 1:1-4, in temperature 10-30 ℃ stirring and crystallizing;
3) filter and collect the Edaravone crystal of separating out, by step 2) middle ether ketone mixed solution washing, vacuum-drying obtains pure Edaravone crystal.
Wherein,
In step 1), the Edaravone crude product: ethanol pure water solution=1g:10-20ml, the volume ratio of ethanol and pure water is 1:3-5, the preferred 40-50 ℃ of whipping temp.
Step 2) in, pH has considerable influence to purifying products, should strictly control the regulation range of pH, is preferably 3-5, and more preferably 4.0 ± 0.2; Wherein ether preferably has the rudimentary ethereal solution of 10 following carbon atoms, and preferred rudimentary ether is one or more the mixed solution in ether, propyl ether, isopropyl ether and n-butyl ether.Ketone preferably has the lower ketones of 10 following carbon atoms, preferably acetone, butanone, pimelinketone or methyl phenyl ketone; Edaravone: ether ketone: mixed solution=1g:100-120ml, recrystallization temperature is preferably 15-25 ℃.The crystallization time between 1-10 hour, is preferably 3-6 hour again.
In step 3), the vacuum-drying temperature is 30-40 ℃, and vacuum tightness is-0.09-0.1MPa, time of drying 20-30 hour.
A kind of Edaravone pharmaceutical composition of injection, is characterized in that, described pharmaceutical composition prepares 1000, following proportioning weight, consists of:
A kind of preparation method of Edaravone pharmaceutical composition of injection, is characterized in that, this preparation method comprises the steps:
1) prepare: Edaravone trihydrate and auxiliary material are got, standby;
2) get recipe quantity water for injection 70%, temperature, at 60 ℃, adds Calcium Disodium Edetate, acetylcysteine, the sodium-chlor of recipe quantity, and after being stirred to dissolving, the Edaravone to adding again recipe quantity in solution, be stirred to dissolve complete;
3) to 2) in add 0.1% Medicinal Charcoal of medicine liquid volume, after stirring fully, place 30 minutes;
4) by 3) adopt plate filter to filter, add water for injection to full dose, mix, record initial pH value, according to initial pH value, with 4% sodium hydroxide solution and 10% phosphoric acid solution, regulate pH value scope at 3.0-4.5;
5) control in: carry out the intermediates check;
6) essence filter: by liquid adopt 0.22 μ m, that 0.45 μ m millipore filtration essence is filtered to visible foreign matters is qualified;
7) filling: filling in ampoule respectively;
8) sterilizing: 121 ℃ of pressure sterilizings 20 minutes;
9) lamp inspection: carry out the visible foreign matters inspection;
10) packing warehouse-in.
Compared with prior art, the present invention has following advantage
1) stable Yi Dala trihydrate provided by the present invention is given the thorough more insoluble problem in water that has solved Edaravone.
2) stable Edaravone trihydrate provided by the present invention improves the yield of this product greatly.
3) stable Edaravone trihydrate provided by the present invention, through industrialized production and study on the stability, proves constant product quality.
4) preparation method of stable Edaravone trihydrate provided by the present invention, the method is simple, prepared Edaravone good stability.
5) injection Edaravone trihydrate pharmaceutical composition provided by the present invention, steady quality, related substance is less controlled, and to thermally-stabilised, product normal temperature is preserved, steady quality.
6) preparation method of injection Edaravone trihydrate pharmaceutical composition provided by the present invention, technique is simple, is applicable to industrialized implementation, and yield rate is high.
Figure of description:
Fig. 1, the X-ray diffractogram of Edaravone trihydrate;
Embodiment
Below in conjunction with embodiment, the invention will be further described, and all ingredients used in embodiment is commercially available purchase if no special instructions.
Embodiment 1
1) Edaravone crude product 5.0g is put into to the single port bottle, add 80ml ethanol pure water solution (ethanol: pure water=1:3), under the condition of 45 ℃, stirring and dissolving;
2) then under room temperature, Edaravone solution is regulated to pH=4.0 with hydrochloric acid, (ether: acetone=1:2.5), temperature was 20 ℃ of stirring and crystallizing 3 hours to add 600ml ether, acetone mixed solution;
3) filter the Edaravone crystal of collecting precipitation, with dry in the above-mentioned ether of 100ml, the washing of acetone mixed solution the baking oven under 30 ℃ of conditions, obtain 4.5g Edaravone trihydrate, yield 90%, purity 99.7%.
Embodiment 2
1) Edaravone crude product 5.0g is put into to the single port bottle, add 100ml ethanol pure water solution (ethanol: pure water=1:3), under the condition of 48 ℃, stirring and dissolving;
2) then under room temperature, Edaravone solution is regulated to pH=4.2 with hydrochloric acid, (isopropyl ether: acetone=1:3), temperature was 30 ℃ of stirring and crystallizing 5 hours to add 500ml isopropyl ether, acetone mixed solution;
3) filter the Edaravone crystal of collecting precipitation, with dry in the above-mentioned isopropyl ether of 100ml, the washing of acetone mixed solution the baking oven under 30 ℃ of conditions, obtain 4.55g Edaravone trihydrate, yield 91%, purity 99.6%.
Prepare Edaravone trihydrate pharmaceutical composition and prepare 1000, formed by following proportioning weight:
Comprise the steps:
1) prepare: Edaravone trihydrate and auxiliary material are got, standby;
2) get recipe quantity water for injection 70%, temperature, at 60 ℃, adds Calcium Disodium Edetate, acetylcysteine, the sodium-chlor of recipe quantity, and after being stirred to dissolving, the Edaravone to adding again recipe quantity in solution, be stirred to dissolve complete;
3) to 2) in add 0.1% Medicinal Charcoal of medicine liquid volume, after stirring fully, place 30 minutes;
4) by 3) adopt plate filter to filter, add water for injection to full dose, mix, record initial pH value, according to initial pH value, with 4% sodium hydroxide solution and 10% phosphoric acid solution, regulate pH value scope at 3.0-4.5;
5) control in: carry out the intermediates check;
6) essence filter: by liquid adopt 0.22 μ m, that 0.45 μ m millipore filtration essence is filtered to visible foreign matters is qualified;
7) filling: filling in ampoule respectively;
8) sterilizing: 121 ℃ of pressure sterilizings 30 minutes;
9) lamp inspection: carry out the visible foreign matters inspection;
10) packing warehouse-in.
Test example 1
Long-term stable experiment
Above test-results shows: embodiment 1 places 12 months in the test of long duration condition, and each indices of investigating project, without considerable change, has stability preferably.
Test example 2
Accelerated test
Above test-results shows: embodiment 1 places 6 months in accelerated test, and each indices of investigating project, without considerable change, has stability preferably.
Test example 3
Get embodiment 1, adopt D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value are as follows, see Fig. 1.
In the present invention, the mensuration of 2 θ values is used light source, and precision is ± 0.2 °, therefore represents that above-mentioned got value has allowed certain reasonably limit of error, and its limit of error is ± 0.2 °.
Claims (3)
1. a stable Edaravone trihydrate, is characterized in that, its structural formula is:
Its preparation method comprises the following steps:
1) the Edaravone crude product is added to ethanol pure water solution=1g:10-20ml, 40-50 ℃ of lower stirring and dissolving;
2) be 3-5 by above-mentioned solution with the hydrochloric acid adjust pH under room temperature, then add the mixed solution that ethers and ketone volume ratio are 1:1-4, in temperature 10-30 ℃ stirring and crystallizing;
3) filter and collect the Edaravone crystal of separating out, by step 2) middle ether ketone mixed solution washing, vacuum-drying obtains pure Edaravone crystal.
2. the Edaravone trihydrate pharmaceutical composition of an injection, is characterized in that, described pharmaceutical composition prepares 1000, following proportioning weight, consists of:
3. the preparation method of the Edaravone trihydrate pharmaceutical composition of an injection, is characterized in that, this preparation method comprises the steps:
1) prepare: Edaravone trihydrate and auxiliary material are got, standby;
2) get recipe quantity water for injection 70%, temperature, at 60 ℃, adds Calcium Disodium Edetate, acetylcysteine, the sodium-chlor of recipe quantity, and after being stirred to dissolving, the Edaravone to adding again recipe quantity in solution, be stirred to dissolve complete;
3) to 2) in add 0.1% Medicinal Charcoal of medicine liquid volume, after stirring fully, place 30 minutes;
4) by 3) adopt plate filter to filter, add water for injection to full dose, mix, record initial pH value, according to initial pH value, with 4% sodium hydroxide solution and 10% phosphoric acid solution, regulate pH value scope at 3.0-4.5;
5) control in: carry out the intermediates check;
6) essence filter: by liquid adopt 0.22 μ m, that 0.45 μ m millipore filtration essence is filtered to visible foreign matters is qualified;
7) filling: filling in ampoule respectively;
8) sterilizing: 121 ℃ of pressure sterilizings 30 minutes;
9) lamp inspection: carry out the visible foreign matters inspection;
10) packing warehouse-in.
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| CN201310426306.9A CN103483262A (en) | 2013-09-17 | 2013-09-17 | Stable edaravone trihydrate and pharmaceutical compositions thereof |
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| CN201310426306.9A CN103483262A (en) | 2013-09-17 | 2013-09-17 | Stable edaravone trihydrate and pharmaceutical compositions thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198823A (en) * | 2015-11-06 | 2015-12-30 | 西安近代化学研究所 | 4,6-dinitrobenzene triazole-1-oxide guanylurea salt compound |
| CN111465597A (en) * | 2017-10-13 | 2020-07-28 | 萃微Tw001公司 | Edaravone salt |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351795A (en) * | 2011-08-02 | 2012-02-15 | 天津市嵩锐医药科技有限公司 | Edaravone compound with stable crystal form |
-
2013
- 2013-09-17 CN CN201310426306.9A patent/CN103483262A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351795A (en) * | 2011-08-02 | 2012-02-15 | 天津市嵩锐医药科技有限公司 | Edaravone compound with stable crystal form |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198823A (en) * | 2015-11-06 | 2015-12-30 | 西安近代化学研究所 | 4,6-dinitrobenzene triazole-1-oxide guanylurea salt compound |
| CN105198823B (en) * | 2015-11-06 | 2017-11-24 | 西安近代化学研究所 | 4,6 dinitro benzos connect the oxide dicyandiamidines salt compound of triazole 1 |
| CN111465597A (en) * | 2017-10-13 | 2020-07-28 | 萃微Tw001公司 | Edaravone salt |
| JP2020536940A (en) * | 2017-10-13 | 2020-12-17 | ツリーウェイ ティーダブリュー００１ ビー．ブイ．Ｔｒｅｅｗａｙ ＴＷ００１ Ｂ．Ｖ． | Edaravone salt |
| JP7152122B2 (en) | 2017-10-13 | 2022-10-12 | ツリーウェイ ティーダブリュー００１ ビー．ブイ． | edaravone salt |
| CN111465597B (en) * | 2017-10-13 | 2023-08-25 | 萃微Tw001公司 | Edaravone Salt |
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Application publication date: 20140101 |