CN102101836A - New crystal form of S-oxiracetam and preparation method thereof - Google Patents
New crystal form of S-oxiracetam and preparation method thereof Download PDFInfo
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- CN102101836A CN102101836A CN2009102424708A CN200910242470A CN102101836A CN 102101836 A CN102101836 A CN 102101836A CN 2009102424708 A CN2009102424708 A CN 2009102424708A CN 200910242470 A CN200910242470 A CN 200910242470A CN 102101836 A CN102101836 A CN 102101836A
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Abstract
The invention discloses a new crystal form of S-oxiracetam and a preparation method thereof. The new crystal form is characterized in that: characteristic absorption peaks exist when a reflected angle 2 theta is about 12.1, 17.5, 19.7, 21.4, 24.7, 29.3 and 32.0 in an X-ray powder diffraction pattern.
Description
Technical field
The present invention relates to S-oxiracetam new crystal and preparation method thereof.
Background technology
S-oxiracetam (s-oxiracetam), chemical name: (S)-and 4-hydroxyl-2-carbonyl-1-pyrrolidone acetamide, chemical structural formula is as follows:
Oxiracetam is a brain metabolism improving medicine of new generation, belong to the novel pyrrolidine ketones derivant, in Europe, the U.S., Japan and Korea S's listing and be widely used in clinically, cerebro-vascular diseases, brain injury, brain tumor (postoperative), intracranial infection, dementia, brain degenerative disease etc. are all had good efficacy.Prove that by pharmacological research and clinical trial widely its effect is strong 2～5 times than piracetam. be a kind of nootropics that has wide application prospects.
In the molecular structure of oxiracetam, 4 carbon atoms of pyrrolidone ring are a unsymmetrical carbon.The pharmacological action of having described S configuration oxiracetam among the patent WO9306826A1 is better than its R configuration; Document Tetrahedron:Asymmetry, 1992,3 (11), 1431-1440 discloses the synthetic method of S configuration oxiracetam, but its crystallization method is not carried out open elaboration, more its crystal formation is not studied.
The inventor has found a kind of stable new crystal of S-oxiracetam, called after I type in the process of further investigation crystallization method.
Summary of the invention
Purpose of the present invention provides a kind of stable new crystal of S-oxiracetam, this crystal formation called after I type, and its X-ray powder diffraction pattern is about 12.1,17.5 at reflection angle 2 θ, and 19.7,21.4,24.7,29.3, there is charateristic avsorption band at 32.0 places.
Among the present invention, the mensuration of 2 θ values is used CuK α light source, precision is ± 0.2 °, therefore, " pact " in above-mentioned " X-ray powder diffraction pattern charateristic avsorption band reflection angle 2 θ are about " should be defined as 2 θ ± 0.2 °, represent above-mentioned 2 θ values of getting to allow certain reasonably limit of error, its limit of error is ± 0.2 °.
S-oxiracetam new crystal I provided by the invention has good stability, is fit to scale operation, helps the operation in the preparation process, advantages such as controllable product quality.
Another object of the present invention is the preparation method who discloses S-oxiracetam new crystal I.
S-oxiracetam new crystal I of the present invention can be by conventional method preparation.For example, by ethanol, methyl alcohol, Virahol, acetone or its mixed solvent heating for dissolving, cooling crystallization; By ethanol, methyl alcohol, Virahol, acetone, butanone or its mixed solvent and a certain proportion of water heating for dissolving, cooling crystallization; Aqueous solution lyophilize.
The present invention also provides the pharmaceutical composition made from S-oxiracetam new crystal I of the present invention, includes the S-oxiracetam new crystal I of the present invention and the suitable pharmaceutical excipient of physiology significant quantity.
Pharmaceutical preparation of the present invention can be an oral preparations, also can be injection.Oral preparations can be any pharmaceutically useful oral dosage form, and these formulations comprise tablet, capsule, oral liquid, syrup, granule, pill, powder etc.; Injection can be the powder pin, also can be small-volume injection and bulk capacity injection.
Oral solid pharmaceutical formulation of the present invention can contain pharmaceutical excipient commonly used, such as tackiness agent, weighting agent, thinner, tablet agent, lubricant, disintegrating agent, tinting material, seasonings and wetting agent, can carry out dressing to tablet in case of necessity.The weighting agent that is suitable for comprises Mierocrystalline cellulose, mannitol, lactose and other similar weighting agent.Suitable disintegrating agent comprises starch, polyvinylpyrrolidone and starch derivative, for example sodium starch glycollate.Suitable lubricant, for example Magnesium Stearate.The acceptable wetting agent of appropriate drug comprises sodium lauryl sulphate.Can fill by mixing, the method that compressing tablet etc. are commonly used prepares solid oral composition.Mix repeatedly active substance is distributed in those compositions of a large amount of weighting agents of whole use.
The form of oral liquid for example can be water-based or oily suspensions, solution, emulsion, syrup or elixir, perhaps can be a kind of used water before use or other suitable composite drying products of carrier.This liquid preparation can contain conventional additive, such as suspension agent, for example sorbyl alcohol, syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible-fat, emulsifying agent, for example Yelkin TTS, anhydro sorbitol monooleate or gum arabic; Non-aqueous carrier (they can comprise edible oil), for example Prunus amygdalus oil, fractionated coconut oil, such as oily ester, propylene glycol or the ethanol of the ester of glycerine; Sanitas, for example para hydroxybenzene methyl esters or propylparaben or Sorbic Acid, and if desired, can contain conventional flavouring agent or tinting material.
Used pharmaceutical excipient is selected from the above preparation: N.F,USP MANNITOL, sorbyl alcohol, Sodium Pyrosulfite, sodium bisulfite, Sulfothiorine, cysteine hydrochloride, Thiovanic acid, methionine(Met), vitamins C, the EDTA disodium, EDTA calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphoric acid salt or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium-chlor, Repone K, Sodium.alpha.-hydroxypropionate, Xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, Mierocrystalline cellulose and derivative thereof, alginate, gelatin, polyvinylpyrrolidone, glycerine, soil temperature 80, agar, lime carbonate, Calcium hydrogen carbonate, tensio-active agent, polyoxyethylene glycol, cyclodextrin, beta-cyclodextrin, the phospholipid material, kaolin, talcum powder, calcium stearate, Magnesium Stearate etc.
Injection preparation, wherein the powder injection specification is 0.5g-8.0g, is preferably 1.0-4.0g; Bulk capacity injection (more than the 50ml) specification is 0.5%-20%, is preferably 2%-10%; Small-volume injection (20ml is following) specification is 5%-30%, is preferably 10%-20%.
Described powder injection, bulk capacity injection (more than the 50ml), small-volume injection (20ml is following) is characterized in that described pharmaceutically acceptable pharmaceutical excipient comprises one or more in pharmaceutical carrier, isotonic regulator, pH regulator agent, oxidation inhibitor, the intercalating agent.
Above-mentioned is the powder injection of activeconstituents with S-oxiracetam new crystal I, it is characterized in that described pharmaceutical carrier can be one or more in N.F,USP MANNITOL, glucose, sorbyl alcohol, sodium-chlor, dextran, sucrose, lactose, gelatin hydrolysate, trehalose, niacinamide, Citric Acid, citrate, pantothenic acid and salt thereof, l-asparagine, amino acid and amino acid salts, cholate, cyclodextrin and the derivative thereof.
Above-mentioned is the injection preparation of activeconstituents with S-oxiracetam new crystal I, it is characterized in that, described pH regulator agent is water-soluble conditioning agent, can be in hydrochloric acid, phosphoric acid, Hydrogen bromide, formic acid, acetic acid, Potassium ethanoate, sodium-acetate, boric acid, borax, Citric Acid, disodium citrate, Citric Acid trisodium, Sodium Citrate, Citric acid monohydrate Food grade, Potassium dihydrogen citrate, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, phosphoric acid salt, dihydrogen phosphate, hydrophosphate, tartrate, bitartrate, amino acid and the salt thereof one or more.
Above-mentioned is the injection preparation of activeconstituents with S-oxiracetam new crystal I, it is characterized in that, described isotonic regulator can be a sodium-chlor, one or more in glucose, glycerine, propylene glycol, N.F,USP MANNITOL, glucose, sorbyl alcohol, dextran, niacinamide, Citric Acid, citrate, pantothenic acid and salt thereof, l-asparagine, amino acid and the amino acid salts.
Above-mentioned is the injection preparation of activeconstituents with S-oxiracetam new crystal I, it is characterized in that described oxidation inhibitor can be one or more in sulfurous acid, sulphite, hydrosulphite, pyrosulfite, thiosulphate, thioglycerol, gallic acid and salt halfcystine, xitix and the salt thereof.
Pharmaceutical preparation of the present invention can be by the preparation of pharmaceutics routine techniques.
Embodiment
Can further describe the present invention by the following examples, yet invention of the present invention is not limited to the following examples, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done within the scope of the claims and adjust also should be thought and belongs to scope of the present invention.
Embodiment 1
S-oxiracetam 2g 60ml methyl alcohol heating for dissolving, cooling crystallization, suction filtration, 50 ℃ of vacuum-dryings obtain S-oxiracetam crystal formation I.
S-oxiracetam 1.6g 20ml ethanol and 2ml water heating for dissolving, cooling crystallization, suction filtration, 50 ℃ of vacuum-dryings obtain S-oxiracetam crystal formation I.
S-oxiracetam 2.7g 20ml methyl alcohol and 2ml water heating for dissolving, cooling crystallization, suction filtration, 50 ℃ of vacuum-dryings obtain S-oxiracetam crystal formation I.
Embodiment 4
S-oxiracetam 1g 10ml water dissolution, lyophilize obtains S-oxiracetam crystal formation I.
The mensuration of embodiment 5 S-oxiracetam crystal formation I physical propertys
Place on the powder diffractometer by the powder of X-ray diffraction method S-oxiracetam crystal formation I, with 8 degree/minute scanning speed scan between the 2 θ angles at 2.6～40 degree, use Cu-Ka 40Kv～100mAX x radiation x.
The X-ray powder diffraction of accompanying drawing 1 S-oxiracetam crystal formation I
Embodiment 6 stability studies
Get same batch S-oxiracetam crystal formation I, get and be loaded in right amount in three culture dish, place following condition (4500lx ± 500lx illumination, 45 ℃ of high temperature, 92.5% high humidity) to investigate its stable crystal form down respectively, measurement result is as shown in the table.
Embodiment 7
Make 1000 S-oxiracetam sheets with following materials of weight proportions.
Preparation technology:
1.S-oxiracetam crystal formation I and auxiliary material are crossed 80 mesh sieves respectively, and be standby.
2. get S-oxiracetam crystal formation I and pregelatinized Starch, the Microcrystalline Cellulose thorough mixing is even, with purified water system softwood, 18 mesh sieves are granulated, drying, whole grain.
3. it is even to add sodium starch glycolate and Magnesium Stearate thorough mixing, compressing tablet, promptly.
Embodiment 8 S-oxiracetam liquid drugs injections
Prescription:
The preparation method:
Get water for injection 3000ml, add sodium ethylene diamine tetracetate calcium stirring and dissolving, add the S-oxiracetam crystal formation I of recipe quantity, stirring and dissolving, add the sodium bisulfite of recipe quantity, make dissolving, regulating the pH value with hydrochloric acid soln and sodium hydroxide solution is 3-6, add 0.1% needle-use activated carbon by amount of preparation, soup is heated to about 60 ℃, stirs 20min, behind the filtering decarbonization, add the injection water to total amount, intermediate detects.Intermediate detect qualified after, adopt the smart filter of 0.22 μ m millipore filtration again, can is in ampoule, every bottle of 5ml or 10ml seal, moist heat sterilization gets final product.
The X-ray powder diffraction of accompanying drawing 1 S-oxiracetam crystal formation I.
Claims (4)
1. the new crystal of a S-oxiracetam is characterized in that this crystalline X-ray powder diffraction pattern is about 12.1,17.5 at reflection angle 2 θ, 19.7,21.4,24.7,29.3, and there is charateristic avsorption band at 32.0 places.
2. the preparation method of a S-oxiracetam new crystal: by ethanol, methyl alcohol, Virahol, acetone or its mixed solvent heating for dissolving, cooling crystallization.
3. the preparation method of a S-oxiracetam new crystal: by ethanol, methyl alcohol, Virahol, acetone, butanone or its mixed solvent and a certain proportion of water heating for dissolving, cooling crystallization.
4. the preparation method of a S-oxiracetam new crystal: aqueous solution lyophilize.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351770A (en) * | 2011-08-12 | 2012-02-15 | 江西新先锋医药有限公司 | Oxiracetam compound and pharmaceutical composition thereof |
| CN102531988A (en) * | 2011-08-11 | 2012-07-04 | 重庆润泽医疗器械有限公司 | Purification method for sinistrogyration oxiracetam |
| CN102871959A (en) * | 2012-05-31 | 2013-01-16 | 北京阜康仁生物制药科技有限公司 | Stable (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide pharmaceutical composition |
| WO2013020388A1 (en) * | 2011-08-11 | 2013-02-14 | 重庆润泽医疗器械有限公司 | Method for purifying (s)-oxiracetam |
| WO2013020391A1 (en) * | 2011-08-11 | 2013-02-14 | 重庆润泽医疗器械有限公司 | (s)-4-hydroxy-2-oxo-1-pyrrolidineacetamide racemate crystal form ii and preparation method therefor |
| US20140221670A1 (en) * | 2011-08-11 | 2014-08-07 | Chongqing Runze Medical Instruments Co., Ltd. | 4-hydroxy-2-oxo-1-pyrrolidineacetamide racemate crystal form i and preparation method therefor |
| WO2015067130A1 (en) * | 2013-11-06 | 2015-05-14 | 重庆润泽医药有限公司 | (s)-oxiracetam crystal form iii, preparation method therefor, and application thereof |
| US9238622B2 (en) | 2010-05-21 | 2016-01-19 | Chongqing Runze Pharmaceutical Co., Ltd. | Crystal form I of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide, preparing method and use thereof |
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| US4686296A (en) * | 1985-07-26 | 1987-08-11 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| WO2005115978A1 (en) * | 2004-05-25 | 2005-12-08 | Ahn-Gook Pharmaceutical Co., Ltd. | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| 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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2009
- 2009-12-16 CN CN2009102424708A patent/CN102101836A/en active Pending
Patent Citations (4)
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| US4686296A (en) * | 1985-07-26 | 1987-08-11 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| WO2005115978A1 (en) * | 2004-05-25 | 2005-12-08 | Ahn-Gook Pharmaceutical Co., Ltd. | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| 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 |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9238622B2 (en) | 2010-05-21 | 2016-01-19 | Chongqing Runze Pharmaceutical Co., Ltd. | Crystal form I of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide, preparing method and use thereof |
| CN102531988A (en) * | 2011-08-11 | 2012-07-04 | 重庆润泽医疗器械有限公司 | Purification method for sinistrogyration oxiracetam |
| WO2013020389A1 (en) * | 2011-08-11 | 2013-02-14 | 重庆润泽医疗器械有限公司 | Method for purifying levo-oxiracetam |
| WO2013020388A1 (en) * | 2011-08-11 | 2013-02-14 | 重庆润泽医疗器械有限公司 | Method for purifying (s)-oxiracetam |
| WO2013020391A1 (en) * | 2011-08-11 | 2013-02-14 | 重庆润泽医疗器械有限公司 | (s)-4-hydroxy-2-oxo-1-pyrrolidineacetamide racemate crystal form ii and preparation method therefor |
| US20140221670A1 (en) * | 2011-08-11 | 2014-08-07 | Chongqing Runze Medical Instruments Co., Ltd. | 4-hydroxy-2-oxo-1-pyrrolidineacetamide racemate crystal form i and preparation method therefor |
| US20140235871A1 (en) * | 2011-08-11 | 2014-08-21 | Chongqing Runze Medical Instruments Co., Ltd | (s)-4-hydroxy-2-oxo-1-pyrrolidineacetamide racemate crystal form ii and preparation method therefor |
| US9440918B2 (en) | 2011-08-11 | 2016-09-13 | Chongqing Runze Pharmaceutical Co., Ltd. | Method for purifying (S)-Oxiracetam |
| US9126928B2 (en) * | 2011-08-11 | 2015-09-08 | Chongqing Runze Pharmaceutical Co., Ltd. | 4-hydroxy-2-oxo-1-pyrrolidineacetamide racemate crystal form I and preparation method therefor |
| US9126929B2 (en) * | 2011-08-11 | 2015-09-08 | Chongqing Runze Pharmaceutical Co., Ltd. | (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide racemate crystal form II and preparation method therefor |
| CN102351770B (en) * | 2011-08-12 | 2012-07-04 | 江西新先锋医药有限公司 | Oxiracetam compound and pharmaceutical composition thereof |
| CN102351770A (en) * | 2011-08-12 | 2012-02-15 | 江西新先锋医药有限公司 | Oxiracetam compound and pharmaceutical composition thereof |
| CN102871959A (en) * | 2012-05-31 | 2013-01-16 | 北京阜康仁生物制药科技有限公司 | Stable (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide pharmaceutical composition |
| WO2015067130A1 (en) * | 2013-11-06 | 2015-05-14 | 重庆润泽医药有限公司 | (s)-oxiracetam crystal form iii, preparation method therefor, and application thereof |
| US9670156B2 (en) | 2013-11-06 | 2017-06-06 | Chongqing Ruzer Pharmaceutical Company Limited | Crystal form III of (S)-oxiracetam, preparation method and use thereof |
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Application publication date: 20110622 |