CN102766097A - Edaravone A-type crystal and preparation method thereof - Google Patents
Edaravone A-type crystal and preparation method thereof Download PDFInfo
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- CN102766097A CN102766097A CN2012102163733A CN201210216373A CN102766097A CN 102766097 A CN102766097 A CN 102766097A CN 2012102163733 A CN2012102163733 A CN 2012102163733A CN 201210216373 A CN201210216373 A CN 201210216373A CN 102766097 A CN102766097 A CN 102766097A
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Abstract
The invention discloses an edaravone A-type crystal and a preparation method thereof. The X-ray diffraction pattern of the crystal is basically shown in the figure 1. According to the crystal and the method thereof, related substance of the product can be effectively reduced, the purity is improved, and the reaction yield is increased. The crystal has strengthened stability, and is suitable for storing particularly in high-temperature high-humidity conditions. The crystal has excellent solubility due to its better chemical property and stable crystal distribution. When medicine is prepared, satisfactory dosage accuracy can be achieved, so as to improve the safety of the product and reduce the patient's risk. Therefore, the crystal provided by the invention is suitable for preparing stable medicinal preparation.
Description
Technical field
The invention belongs to pharmaceutical field, be specifically related to a kind of Edaravone, new crystal of chemical name 1-phenyl-3-methyl-5-pyrazolone and preparation method thereof.
Background technology
Edaravone pharmaceutically is being a kind of cerebral protective agent (free-radical scavengers), is used to treat the DPN that cerebral infarction causes.Its chemical structural formula is as follows:
Edaravone (Edaravone, 1-phenyl-3-methyl-5-pyrazolone) is a kind of strong effect free-radical scavengers and inhibitor, and these article belong to the lipophilic compounds, is prone to see through hemato encephalic barrier and is absorbed.Edaravone is the cerebral protective agent that Mitsubishi chemical company develops, and goes on the market in Japan June 1 calendar year 2001.Its mechanism of action is to remove the radical that increases behind the ischemic, suppresses peroxidatic reaction of lipid, and tissue is played a protective role.Clinically, these article can be used for improving symptoms such as acute period of cerebral infarction patient's nerve, daily life behavior, and its spinoff is slight, and is evident in efficacy, and good prognosis effect is arranged.
In U.S. Pat 4857542, be described to Edaravone first.US 4857542 discloses the Edaravone structure, demonstrates that disorder has effective prevention and treatment to the recycle system, has good effect as lipid peroxidation inhibitor and disordered brain function treatment especially.WO2006/71730 discloses phenylhydrazine and methyl aceto acetate 50 ℃ of reactions in acetic acid, prepares Edaravone.But yield is lower among the preparation technology, pollution is bigger.
Domestic patent about Edaravone mainly concentrates on prepared, preparation and indication aspect, and relevant crystal formation patent report seldom.The preparation of a kind of crystal formation of Edaravone is disclosed among the Chinese patent CN 102060771A.
Summary of the invention
The objective of the invention is on the basis of existing technology, provide a kind of and be more suitable in the Edaravone crystal of preparation stabilised pharmaceutical preparation.
Another object of the present invention provides a kind of above-mentioned Edaravone crystalline preparation method.
The object of the invention can reach through following measure:
A kind of Edaravone A N-type waferN, this crystalline X-ray diffracting spectrum are that 11.2 ± 0.2,13.5 ± 0.2,14.7 ± 0.2,19.1 ± 0.2,19.6 ± 0.2,21.4 ± 0.2,21.7 ± 0.2,24.3 ± 0.2,25.2 ± 0.2 and 29.6 ± 0.2 places have diffraction peak at 2 θ angles.
In a kind of preferred version of the present invention, the A N-type waferN has the said X-ray diffracting spectrum of table 1,
The XRD characteristic peak of table 1 Edaravone crystal form A
Further, the X-ray diffracting spectrum of A N-type waferN of the present invention is basically like Fig. 1.
Edaravone A N-type waferN of the present invention, it has the ir spectra of following charateristic avsorption band: 3456,3129,1805,1601,1580,1522,1497; 1457,1389,1367,1344,1314,1303,1236,1197; 1153,1045,1028,1016,917,804,766 and 752cm
-1
The invention also discloses a kind of preparation method of above-mentioned Edaravone A N-type waferN: get HPLC purity at the phenyl of the 1-more than 99%-3-methyl-5-pyrazolone, be lower than 80 ℃ and stir down it is dissolved in the solvent, again cooling stirring and crystallizing also; Filter; Washing, drying promptly gets.
Wherein solvent is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, acetonitrile, acetone, sherwood oil, ether, MTBE, C
4-C
8A kind of solvent in the alkane solvents or several kinds of mixed solvents.This solvent is preferably selected from one or more mixing in methyl alcohol, ethanol, Virahol, sherwood oil, ether, Skellysolve A, the normal hexane.This solvent is preferably a kind of and ethanol mixed solvent formed of 1:4～8 by volume in sherwood oil, ether, Skellysolve A or the normal hexane further; Be most preferably a kind of and ethanol mixed solvent formed of 1:5～7 by volume in sherwood oil, ether, Skellysolve A or the normal hexane.
In above-mentioned preparation process, the 1-phenyl-3-methyl-solvent temperature of 5-pyrazolone in solvent is preferably 50 ℃ ~ 75 ℃; Dissolution time is preferably 10～50min, further is preferably 10～30min.
In above-mentioned preparation process; The dissolution process and the crystallization process of 1-phenyl-3-methyl-5-pyrazolone are all under agitation carried out; Stirring velocity when in solvent, dissolving is preferably 200～400 commentaries on classics/min, and the stirring velocity when the cooling crystallization is preferably 420～600 commentaries on classics/min.
The present invention has found a kind of new Edaravone A crystal formation in the study on the synthesis to Edaravone.This crystal formation and preparation method thereof can effectively reduce related substance, the raising purity of product, increases reaction yield.The product stability of this crystal formation strengthens, and particularly under hot and humid condition, is easy to store.Its better chemical character and stable crystal are arranged and have been given its good solvability in addition; When the preparation medicine, can reach satisfied dosage accuracy, increased security of products; Therefore minimizing is suitable for preparing stabilised pharmaceutical to patient's danger.
Description of drawings
The X-diffractogram of the Edaravone white crystals that accompanying drawing 1 makes for embodiment 1.
The IR infrared spectrogram of the Edaravone white crystals that accompanying drawing 2 makes for embodiment 1.
Embodiment
Following detailed embodiment has described and how to prepare the whole bag of tricks of all cpds and/or embodiment of the present invention and be interpreted as illustrative just, is not the restriction to above-mentioned disclosure.Those skilled in the art's accurately variation of recognition reaction thing and reaction conditions and technical elements rapidly.
Embodiment 1: the preparation of Edaravone A N-type waferN
In reaction flask in ethanol: the ratio of normal hexane 6:1 adds 96ml ethanol, and 16ml normal hexane and HPLC purity are 99.0% Edaravone bullion 32.2g, keeps the stirring velocity of 300 commentariess on classics/min, control solution-stabilizedly to begin backflow to 65 ℃, and solid dissolves.Begin cooling behind the stir about 30min, strengthen stirring velocity to 500 commentaries on classics/min, begin to separate out solid at 45 ℃, 10 ℃ of stirring and crystallizing 1h; Filter, filter cake washs with ethanol and normal hexane, 90 ℃ of drying under reduced pressure 9 hours; Get white crystals product 25.6g, purity 99.9%, productive rate 79.5%.
Infrared (IR) spectroscopic data is: 3456,3129,1805,1601,1580,1522,1497,1457,1389,1367,1344,1314,1303,1236,1197,1153,1045,1028,1016,917,804,766 and 752cm
-1
Under following experiment condition, measure powder X-ray-diffracting spectrum (accompanying drawing 1):
Inspection apparatus: German Bruker D8Advance X-Ray diffractometer inspection condition: target type: Cu; Wavelength:
manages pressure: 40kv; Pipe stream: 40mA; Initial angle: 3; End angle: 40; Step-length: 0.02; Crack: 1.0/1.0/Ni/0.2
Following table be should present method the powder X-ray-diffraction spectrogram data of Edaravone of preparation
Embodiment 2: the preparation of Edaravone A N-type waferN
In reaction flask in ethanol: the ratio of sherwood oil 6:1 adds 72ml ethanol, and 12ml sherwood oil and HPLC purity are 99.0% Edaravone bullion 25.0g, keeps the stirring velocity of 300 commentariess on classics/min, control solution-stabilizedly to begin backflow to 70 ℃, and solid dissolves.Begin cooling behind the stir about 30min, strengthen stirring velocity to 500 commentaries on classics/min, begin to separate out solid at 40 ℃, 10 ℃ of stirring and crystallizing 1h; Filter, filter cake washs with the mixed solution of ethanol and sherwood oil, 90 ℃ of drying under reduced pressure 9 hours; Get white crystals product 19.0g, purity 99.8%, productive rate 76.2%.Infrared (IR) spectrum is identical with embodiment 1 with the X-powder diffraction spectrum.
Embodiment 3: the preparation of Edaravone A N-type waferN
In reaction flask in ethanol: the ratio of ether 6:1 adds 150ml ethanol, and 25ml ether and HPLC purity are 99.0% Edaravone bullion 50.0g, keeps the stirring velocity of 300 commentariess on classics/min, control solution-stabilizedly to begin backflow to 70 ℃, and solid dissolves.Begin cooling behind the stir about 30min, strengthen stirring velocity to 500 commentaries on classics/min, begin to separate out solid at 40 ℃, 10 ℃ of stirring and crystallizing 1h; Filter, filter cake washs with the mixed solution of ethanol and ether, 90 ℃ of drying under reduced pressure 9 hours; Get white crystals product 38.4g, purity 99.8%, productive rate 76.8%.Infrared (IR) spectrum is identical with embodiment 1 with the X-powder diffraction spectrum.
The character of effect embodiment Edaravone crystal form A
One, solvability
Precision takes by weighing an amount of Edaravone A crystal (press embodiment 1 preparation), slowly adds proper amount of solvent, and powerful jolting is all dissolved to solid.Test its solvability at a certain temperature, find A crystal and existing crystal formation (the Edaravone crystal of preparing by the method for CN102060771A, at this with its called after crystal form B) comparison, solubleness increases, and the result sees the following form 2.
Table 2 Edaravone crystalline solubleness
Can be got by test-results: the Edaravone crystal form A that the present invention relates to is compared with existing crystal formation, and its solubleness in water has improved 50%; Solubleness in 0.1N aqueous hydrochloric acid (simulated gastric fluid) has improved 1 times, so the Edaravone of crystal form A has solvability preferably, is more suitable for preparing stabilised pharmaceutical, comprises transfusion, liquid drugs injection, liquid for oral use or powder pin.
Two, stability analysis
1, differential scanning calorimetry (DSC) test
Instrument: NETZSC H DSC 204 type differential thermal analyzers;
Temperature rise rate: 10 ℃/min;
DSC peak temperature: 128.4 ℃.
Proof Edaravone A crystal peak-peak occurs at 128.4 ℃, and peak value is single, proves that Edaravone A crystal formation has stable heat exchange range, and crystal itself is comparatively stable.
2, high temperature test
The Edaravone sample is positioned in the petridish, places 60 ℃ of thermostatic drying chambers, sampling detects during respectively at 5 days, 10 days, and with result's contrast of primary sample, the result sees table 3.
The high temperature test of table 3 Edaravone crystal form A (60 ℃)
The above results can get, and Edaravone crystal form A involved in the present invention is in high temperature test (60 ℃), and its proterties, content and relative substance all do not have bigger variation, its stability is described better.
60 ℃ of thermostatic drying chambers are placed 10 days Edaravone crystal form A sample, with X-ray powder diffraction (XRD) and infrared (IR) detection, and same Fig. 1 of result, 2 and table 1, consistent with original (0 day) sample, explain that crystal form A is to thermally-stabilised.
3, exposure experiments to light
Sample all had share to uncovered petridish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, surveys inspection respectively at sampling in 5,10 days, and contrasts with 0 day result, the result sees the following form 4:
The exposure experiments to light of table 4 Edaravone crystal form A
The above results can get; Edaravone crystal form A involved in the present invention compares with other crystal formations in long-term exposure experiments to light, shows satisfactory stability property; Its proterties, content and relative substance all do not have bigger variation, therefore are fit to long-term stability with its drug prepared preparation and deposit.
4, high wet test
Sample all had share to uncovered petridish, thickness≤5mm places room temperature (25 ℃), and relative humidity is in 75 ± 5% the fixed temperature and humidity incubator, to survey inspection respectively at sampling in 5,10 days, and contrasts with 0 day result, and the result sees the following form 5:
The high wet test of table 5 Edaravone crystal form A
The above results can know that Edaravone crystal form A involved in the present invention compares with existing crystal formation in high wet test; Show satisfactory stability property; No obvious moisture absorption phenomenon under humidity environment proves that this crystal formation can place for a long time under the certain humidity environment, crystalline nature is stable.
Claims (8)
1. an Edaravone A N-type waferN is characterized in that this crystal has following X-ray diffracting spectrum
2. Edaravone A N-type waferN according to claim 1 is characterized in that this crystalline X-ray diffracting spectrum is basically like Fig. 1.
3. Edaravone A N-type waferN according to claim 1 is characterized in that this crystal has the ir spectra of following charateristic avsorption band: 3456,3129,1805,1601,1580; 1522,1497,1457,1389,1367,1344; 1314,1303,1236,1197,1153,1045; 1028,1016,917,804,766 and 752cm
-1
4. the preparation method of the described Edaravone A of claim 1 N-type waferN is characterized in that getting HPLC purity at the phenyl of the 1-more than 99%-3-methyl-5-pyrazolone, be lower than 80 ℃ and stir under it is dissolved in the solvent; Cooling and stirring and crystallizing are filtered again, washing; Drying promptly gets.
5. method according to claim 4 is characterized in that said solvent is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, acetonitrile, acetone, sherwood oil, ether, MTBE, C
4-C
8A kind of solvent in the alkane solvents or several kinds of mixed solvents.
6. method according to claim 5 is characterized in that said solvent is selected from one or more mixing in methyl alcohol, ethanol, Virahol, sherwood oil, ether, Skellysolve A, the normal hexane; Said solvent is the mixed solvent formed of 1:4～8 by volume of a kind of and ethanol in sherwood oil, ether, Skellysolve A or the normal hexane further.
7. method according to claim 4 is characterized in that the 1-phenyl-3-methyl-solvent temperature of 5-pyrazolone in solvent is 50 ℃ ~ 75 ℃, and dissolution time is 10～50min.
8. method according to claim 4 is characterized in that the stirring velocity of 1-phenyl-when 3-methyl-5-pyrazolone dissolves is 200～400 commentaries on classics/min in solvent, the stirring velocity when the cooling crystallization is 420～600 commentaries on classics/min.
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Cited By (6)
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| CN103319409A (en) * | 2013-07-12 | 2013-09-25 | 四川省惠达药业有限公司 | Edaravone compound, medicinal composition thereof, and preparation methods of compound and composition |
| CN103833640A (en) * | 2012-11-16 | 2014-06-04 | 上海医药工业研究院 | Edaravone crystal, preparation method and application thereof |
| CN104163801A (en) * | 2014-01-27 | 2014-11-26 | 洪军 | Edaravone compound |
| CN105753785A (en) * | 2016-03-23 | 2016-07-13 | 海南合瑞制药股份有限公司 | Edaravone compound and preparation method thereof |
| CN111138365A (en) * | 2019-12-30 | 2020-05-12 | 海南全星制药有限公司 | Edaravone compound and pharmaceutical composition thereof |
| CN113365983A (en) * | 2019-04-17 | 2021-09-07 | 新航益泰科股份有限公司 | Phenylmethylpyrazolinone compounds having novel crystal forms |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833640A (en) * | 2012-11-16 | 2014-06-04 | 上海医药工业研究院 | Edaravone crystal, preparation method and application thereof |
| CN103833640B (en) * | 2012-11-16 | 2016-06-22 | 国药集团国瑞药业有限公司 | A kind of Edaravone crystal, its preparation method and application thereof |
| CN103319409A (en) * | 2013-07-12 | 2013-09-25 | 四川省惠达药业有限公司 | Edaravone compound, medicinal composition thereof, and preparation methods of compound and composition |
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| CN105753785A (en) * | 2016-03-23 | 2016-07-13 | 海南合瑞制药股份有限公司 | Edaravone compound and preparation method thereof |
| CN105753785B (en) * | 2016-03-23 | 2018-03-02 | 海南合瑞制药股份有限公司 | A kind of crystal formation of Edaravone and preparation method thereof |
| CN113365983A (en) * | 2019-04-17 | 2021-09-07 | 新航益泰科股份有限公司 | Phenylmethylpyrazolinone compounds having novel crystal forms |
| CN111138365A (en) * | 2019-12-30 | 2020-05-12 | 海南全星制药有限公司 | Edaravone compound and pharmaceutical composition thereof |
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