CN102617437B - Novel crystal formations of levogyration oxiracetam and preparation method thereof - Google Patents
Novel crystal formations of levogyration oxiracetam and preparation method thereof Download PDFInfo
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Abstract
The invention relates to novel crystal formations of levogyration oxiracetam, including a crystal formation A, a crystal formation B and a crystal formation C, which have excellent stability and are very suitable for the preparation of common formulations of levogyration oxiracetam. The invention further discloses a preparation method and characterization of the crystal formations, as well as a pharmaceutical composition containing the crystal formations.
Description
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to new crystal, preparation method and the pharmaceutical composition of levo-oxiracetam.
Background technology
Oxiracetam (oxiracetam, CAS No.:62613-82-5) chemistry Esomeprazole by name, for Italian ISFS.P.A company in 1974 synthetic anti-hypoxia class nootropics (compound is disclosed in US4118396) first, it is ring GABOB derivative, can promote Phosphorylcholine and phosphatidyl ethanolamine synthetic, promote brain metabolism, see through hemato encephalic barrier, specificity nervus centralis road is had to hormesis, can improve intelligence and memory, to cerebro-vascular diseases, cerebral trauma, brain tumor, intracranial infection, brain degenerative diseases etc. also have good curative effect, and this drug toxicity is extremely low, without mutagenesis and carcinogenesis and genotoxicity.
The people such as Giorgio have disclosed chemical structure and the preparation method of oxiracetam in US4118396.The people such as Chiodini disclose in WO9306826A, and clinical effectiveness proves that the drug effect of the oxiracetam of S configuration (left-handed) is better than R configuration (dextrorotation).Yao's bravery has disclosed the new crystal of the S-oxiracetam of called after crystal formation I at CN102101836A, the X-ray powder diffraction figure of this crystal formation is about 12.1 at 2 θ, 17.5,19.7,21.4,24.7,29.3, there is characteristic peak at 32.0 degree places, and this crystal formation is by after dissolving with ethanol equal solvent, and cooling crystallization makes.The people such as Chen Yuying disclose a kind of S-oxiracetam crystal formation in CN102249975A, in the X-ray powder diffraction pattern of this crystal formation, demonstrate the X-ray powder diffraction data with following d value and the expression of relative intensity RI value: 7.075 (M), 5.355 (S), 5.092 (S), 4.590 (M), 4.325 (M), 4.259 (S), 4.041 (VS), 3.808 (M), 3.542 (M), 3.445 (M), 3.393 (M), 2.972 (M), 2.914 (S), its crystallisation process makes with acetone and water.Xia Zhihong discloses the oxiracetam with two crystal water in CN102351770A, and its X-ray powder diffraction pattern is about 17.3,19.1 at 2 θ, 21.6,23.2,27.0,28.4,30.0,31.0,31.7,33.2, the position display of 36.9,39.3,40.2,45.7,51.2 degree has characteristic peak, DMF and the crystallization of ethylene glycol mixing solutions for this compound.
Oxiracetam huge market demand, but being disclosed in compound all there is certain stability problem, and the crystal formation of therefore developing more stable new oxiracetam is very necessary.
Summary of the invention
The invention provides the new crystal of three kinds of levo-oxiracetams, called after crystal form A, crystal form B and crystal C respectively, and the preparation method of these crystal formations.
A kind of levo-oxiracetam crystal form A, the X-ray powder diffraction pattern that this crystal formation uses Cu-K alpha-ray to record is 10.48 ± 0.02 ° at 2 θ, 12.50 ± 0.02 °, 13.94 ± 0.02 °, 15.01 ± 0.02 °, 16.51 ± 0.02 °, 17.38 ± 0.02 °, 18.69 ± 0.02 °, 19.29 ± 0.02 °, 20.18 ± 0.02 °, 20.58 ± 0.02 °, 20.85 ± 0.02 °, 21.25 ± 0.02 °, 21.97 ± 0.02 °, 23.36 ± 0.02 °, 24.20 ± 0.02 °, 25.09 ± 0.02 °, 25.93 ± 0.02 °, 26.26 ± 0.02 °, 30.02 ± 0.02 °, 30.71 ± 0.02 °, locate charateristic avsorption band for 31.09 ± 0.02 °.
The method following steps of above-mentioned levo-oxiracetam crystal form A: get s-oxiracetam, with methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, DMF, DMSO or 1, one or more mixed solvents in 4-dioxane dissolve completely under heating condition, at normal pressure or be evaporated to dryly, obtain levo-oxiracetam crystal form A.
Wherein DMF is DMF, and DMSO is the english abbreviation of dimethyl sulfoxide (DMSO), and this is well known to those skilled in the art.
A kind of levo-oxiracetam crystal form B, the X-ray powder diffraction pattern that this crystal formation uses Cu-K alpha-ray to record is 12.45 ± 0.02 ° at 2 θ, 13.90 ± 0.02 °, 14.97 ± 0.02 °, 16.50 ± 0.02 °, 17.36 ± 0.02 °, 19.28 ± 0.02 °, 20.52 ± 0.02 °, 20.80 ± 0.02 °, 21.95 ± 0.02 °, 23.31 ± 0.02 °, 25.10 ± 0.02 °, 25.85 ± 0.02 °, 26.22 ± 0.02 °, 28.06 ± 0.02 °, 30.01 ± 0.02 °, locate charateristic avsorption band for 30.65 ± 0.02 °.
The method of above-mentioned levo-oxiracetam crystal form B comprises the steps: to get s-oxiracetam, with methyl alcohol, and ethanol, Virahol, propyl carbinol, acetone, DMF, DMSO, one or more in Isosorbide-5-Nitrae-dioxane mix obtained mixed solvent with water, under heating condition, dissolve completely, cooling and stirring crystallization, obtains S-oxiracetam crystal form B after vacuum-drying.
It will be clear that herein and be made up of above-mentioned organic solvent and water in order to the mixed solvent that dissolves S-oxiracetam, wherein organic solvent can be single, can be also the mixing of above-mentioned two kinds or above organic solvent.
Preferably, in the method for above-mentioned levo-oxiracetam crystal form B, described organic solvent and the volume ratio of water are 3～15: 1.
Preferably, in the method for above-mentioned levo-oxiracetam crystal form B, described recrystallization temperature is-10～35 DEG C.
A kind of S-oxiracetam crystal C, the X-ray powder diffraction pattern that this crystal formation uses Cu-K alpha-ray to record is 13.79 ± 0.02 ° at 2 θ, 16.56 ± 0.02 °, 17.84 ± 0.02 °, 18.66 ± 0.02 °, 20.14 ± 0.02 °, 21.23 ± 0.02 °, 22.04 ± 0.02 °, 24.17 ± 0.02 °, locate charateristic avsorption band for 25.95 ± 0.02 °.
The method of above-mentioned levo-oxiracetam crystal C comprises the steps: to get S-oxiracetam, with methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, DMF, DMSO, 1, one or more in 4-dioxane mix obtained mixed solvent reflux and dissolve with water, cooling standing crystallization, obtains s-oxiracetam crystal C after vacuum-drying.Mixed solvent implication is the same herein.
Preferably, in the method for above-mentioned levo-oxiracetam type C, described organic solvent and the volume ratio of water are 3～15: 1.
Preferably, in the method for above-mentioned levo-oxiracetam type C, described recrystallization temperature is-10～35 DEG C.
The present invention also provides a kind of pharmaceutical composition, comprises one or more and pharmaceutical excipient in S-oxiracetam crystal form A, crystal form B, crystal C.
Pharmaceutical excipient refers in the time that preparation prescription designs, and adds the general designation of the medicinal material of all except main ingredient in prescription for solving formability, validity, stability, the security of preparation.Such as, make required weighting agent, tackiness agent, disintegrating agent, lubricant, glidant, pressor, effervescent, surfactant, membrane-forming agent, toning agent, correctives, sanitas, dispersion agent, perfume compound etc. in solid preparation; Such as, make the needed vehicle of injection type, stablizer, injection liquid solvent, solubility promoter, acid-base modifier, lyophilized vaccine, antioxidant, complexing of metal ion agent etc.
Brief description of the drawings
The X-ray powder diffraction figure of the levo-oxiracetam crystal form A that Fig. 1 embodiment 2 makes
The DSC figure of the levo-oxiracetam crystal form A that Fig. 2 embodiment 2 makes
The TG figure of the levo-oxiracetam crystal form A that Fig. 3 embodiment 2 makes
The X-ray powder diffraction figure of the levo-oxiracetam crystal form B that Fig. 4 embodiment 6 makes
The DSC figure of the levo-oxiracetam crystal form B that Fig. 5 embodiment 6 makes
The TG figure of the levo-oxiracetam crystal form B that Fig. 6 embodiment 6 makes
The X-ray powder diffraction figure of the levo-oxiracetam crystal C that Fig. 7 embodiment 11 makes
The DSC figure of the levo-oxiracetam crystal C that Fig. 8 embodiment 11 makes
The TG figure of the levo-oxiracetam crystal C that Fig. 9 embodiment 11 makes
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is described further.
the preparation of embodiment 1 levo-oxiracetam
According to TETRAHEDRON:ASYMMETRY 1992,3 (11), the method that 1431-40 discloses is prepared levo-oxiracetam 503.0g, and HPLC purity is 99.1%.
the preparation of implementation column 2 levo-oxiracetam crystal form As
Get embodiment 1 and make S-oxiracetam 10.0g, complete by methyl alcohol heating for dissolving, be under reduced pressure concentrated into dryly, obtain levo-oxiracetam crystal form A.
the preparation of implementation column 3 levo-oxiracetam crystal form As
Get
embodiment 1make levo-oxiracetam 10.0g, complete by Virahol heating for dissolving, be under reduced pressure concentrated into dryly, obtain levo-oxiracetam crystal form A.
the preparation of implementation column 4 levo-oxiracetam crystal form As
Get
embodiment 1make levo-oxiracetam 15.0g, complete by DMF heating for dissolving, be under reduced pressure concentrated into dryly, obtain levo-oxiracetam crystal form A.
the preparation of implementation column 5 levo-oxiracetam crystal form Bs
Get
embodiment 1make levo-oxiracetam 50.0g, by ethanol and water (volume ratio is 3: 1) mixed solvent heating for dissolving, be then cooled to 0 DEG C, stirring and crystallizing, suction filtration, finally vacuum-drying at 45～55 DEG C, obtain 31.2g levo-oxiracetam crystal form B, yield 62.4%.
the preparation of implementation column 6 levo-oxiracetam crystal form Bs
Get
embodiment 1make levo-oxiracetam 50.0g, by ethanol and water (volume ratio is 10: 1) mixed solvent heating for dissolving, be then cooled to 15 DEG C, stirring and crystallizing, suction filtration, finally vacuum-drying at 45～55 DEG C, obtain 39.8g levo-oxiracetam crystal form B, yield 79.6%.
the preparation of embodiment 7 levo-oxiracetam crystal form Bs
Get
embodiment 1make levo-oxiracetam 50.0g, by propyl carbinol and water (volume ratio is 15: 1) mixed solvent heating for dissolving, be then cooled to 20 DEG C, stirring and crystallizing, suction filtration, finally vacuum-drying at 45～55 DEG C, obtain 40.5g levo-oxiracetam crystal form B, yield 81.0%.
the preparation of embodiment 8 levo-oxiracetam crystal form Bs
Get
embodiment 1make levo-oxiracetam 50.0g, by DMF and water (volume ratio is 10: 1) mixed solvent heating for dissolving, be then cooled to 35 DEG C, stirring and crystallizing, suction filtration, finally vacuum-drying at 45～55 DEG C, obtain 36.2g levo-oxiracetam crystal form B, yield 72.4%.
the preparation of embodiment 9 levo-oxiracetam crystal Cs
Get
embodiment 1the levo-oxiracetam 30.0g making, dissolves by Virahol and water (volume ratio 3: 1) mixed solvent reflux, is cooled to 0 DEG C, leave standstill crystallization, then vacuum-drying at 45～55 DEG C, obtains 17.6g levo-oxiracetam crystal C, yield 58.7%.
the preparation of embodiment 10 levo-oxiracetam crystal Cs
Get
embodiment 1the levo-oxiracetam 30.0g making, with Isosorbide-5-Nitrae-dioxane and the dissolving of water (volume ratio 5: 1) mixed solvent reflux, be cooled to 5 DEG C, leave standstill crystallization, then vacuum-drying at 45～55 DEG C, obtain 21.5g levo-oxiracetam crystal C, yield 71.6%.
the preparation of embodiment 11 levo-oxiracetam crystal Cs
Get
embodiment 1the levo-oxiracetam 30.0g making, with Isosorbide-5-Nitrae-dioxane and the dissolving of water (volume ratio 10: 1) mixed solvent reflux, be cooled to 25 DEG C, leave standstill crystallization, then vacuum-drying at 45～55 DEG C, obtain 20.2g levo-oxiracetam crystal C, yield 67.3%.
the preparation of embodiment 12 levo-oxiracetam crystal Cs
Get
embodiment 1the levo-oxiracetam 30.0g making, dissolves by propyl carbinol and water (volume ratio 10: 1) mixed solvent reflux, is cooled to 15 DEG C, leave standstill crystallization, then vacuum-drying at 45～55 DEG C, obtains 23.7g levo-oxiracetam crystal C, yield 79.0%.
the preparation of embodiment 13 levo-oxiracetam crystal Cs
Get
embodiment 1the levo-oxiracetam 30.0g making, dissolves by different DMSO and water (volume ratio 15: 1) mixed solvent reflux, is cooled to 35 DEG C, leave standstill crystallization, then vacuum-drying at 45～55 DEG C, obtains 24.4g levo-oxiracetam crystal C, yield 81.3%.
embodiment 14 levo-oxiracetam crystal form As, B, the determination of physical appearance of C
By X-ray method, S oxiracetam crystal form A, B, C powder are placed in respectively on powder diffractometer (Bruker D8 Advance), with Cu-Ka 40kV～100mAX x radiation x, with 8 degree/point sweep velocity 2.6～40 degree 2 θ scan.By differential thermal analysis (DSC) and thermogravimetric analysis (TG) method, on NETZSCH DSC 204 type differential thermal analyzers and NETZSCH TG209 type thermogravimetric analyzer, with 10 DEG C/min temperature rise rate, 30-300 DEG C of temperature range interscan.
embodiment 15 stable crystal form tests
Levo-oxiracetam crystal form A, crystal form B, crystal C are carried out to influence factor test, accelerated stability test, and test method is referring to " Chinese Pharmacopoeia (2010) " second annex XIXC " bulk drug and pharmaceutical preparation stability test governing principle ".
(1), influence factor test:
1. high temperature test: get the above-mentioned levo-oxiracetam crystal formation making, place 10 days at 60 DEG C of temperature, in the 5th day and sampling in the 10th day, measure indices and 0 o'clock sample and compare, test-results is in Table.
2. high wet test: get the above-mentioned levo-oxiracetam crystal formation making, place 10 days under RH75%, in the 5th day and sampling in the 10th day, measure indices and 0 o'clock sample and compare, test-results is in Table.
3. strong illumination test: get the above-mentioned levo-oxiracetam crystal formation making, place 10 days under the condition in illumination for (4500 ± 500) lx, in the 5th day and sampling in the 10th day, measure indices and 0 o'clock sample and compare, test-results is in Table.
(2) accelerated stability test:
Levo-oxiracetam crystal form A, crystal form B, crystal C are carried out in climatic chamber (MMM Medcenter Climacell) to the stability test of 6 months.Test conditions is respectively: 40 DEG C/75% relative humidity (RH), and respectively at sampling in 1,2,3,6 month, carry out purity and foreign impurity matters test (high performance liquid chromatography) and XRPD and characterize, the results are shown in following table:
Can find out from upper table result, levo-oxiracetam crystal form A, crystal form B and crystal C all have satisfactory stability, and wherein the good stability of crystal form B and crystal C is in crystal form A.
prescription and the preparation of the pharmaceutical composition of embodiment 16 levo-oxiracetam crystal formations
(1) prescription
(2) preparation technology: the supplementary material of recipe quantity is sieved, wet granulation after fully mixing, the dry rear intermediate that detects, qualified rear compressing tablet, to obtain final product.
It should be noted that and the foregoing is only preferred embodiment of the present invention, be not limited to scope of the present invention.
Claims (1)
1. the preparation method of a levo-oxiracetam crystal C, wherein said " levo-oxiracetam crystal C " refers to that the X-ray powder diffraction pattern that uses Cu-K alpha-ray to record is 13.79 ± 0.02 ° at 2 θ, 16.56 ± 0.02 °, 17.84 ± 0.02 °, 18.66 ± 0.02 °, 20.14 ± 0.02 °, 21.23 ± 0.02 °, 22.04 ± 0.02 °, 24.17 ± 0.02 °, locate the levo-oxiracetam compound of charateristic avsorption band for 25.95 ± 0.02 °, it is characterized in that, the method comprises the steps:
(1) get levo-oxiracetam, mix obtained mixed solvent reflux with Isosorbide-5-Nitrae-dioxane with water and dissolve;
(2) cooling standing crystallization;
(3) after vacuum-drying, obtain levo-oxiracetam crystal C,
Wherein, the volume ratio of described Isosorbide-5-Nitrae-dioxane and water is 3～15:1, and described recrystallization temperature is-10～35 DEG C.
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| CN103554000B (en) * | 2013-11-06 | 2015-03-11 | 重庆润泽医药有限公司 | (S)-oxiracetam crystal form III, and preparation method and application thereof |
| CN105837490B (en) * | 2016-04-22 | 2018-03-02 | 海南合瑞制药股份有限公司 | A kind of crystal formation of Oxiracetam and preparation method thereof |
| CN107638415A (en) * | 2016-07-22 | 2018-01-30 | 重庆润泽医药有限公司 | Good levo-oxiracetam spansule of a kind of content uniformity and preparation method thereof |
| CN108066294A (en) * | 2016-11-11 | 2018-05-25 | 重庆润泽医药有限公司 | A kind of method that pressed powder prepares levo-oxiracetam oral disnitegration tablet |
| CN108066292A (en) * | 2016-11-11 | 2018-05-25 | 重庆润泽医药有限公司 | A kind of levo-oxiracetam oral disnitegration tablet and preparation method thereof |
| CN108567752A (en) * | 2017-03-14 | 2018-09-25 | 重庆润泽医药有限公司 | Left-handed oxiracetam oral disnitegration tablet and preparation method thereof |
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| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
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