CN104072400A - Oxiracetam compound and pharmaceutical composition thereof - Google Patents
Oxiracetam compound and pharmaceutical composition thereof Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
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Abstract
The invention belongs to the technical field of medicine, and provides an oxiracetam compound and a pharmaceutical composition thereof. The X-ray powder diffraction of the oxiracetam compound by Cu-Kalpha ray measurement has characteristic peaks when 2theta is 12.2 degrees, 14.4 degrees, 18.1 degrees, 19.6 degrees, 20.0 degrees, 21.8 degrees, 22.7 degrees, 24.6 degrees or 25.1 degrees. The oxiracetam compound has high crystal purity, and the related substance content is lower than 0.05%. The oxiracetam has favorable stability, and the moisture absorption weight gain does not exceed 0.5% even under high-humidity conditions. The tablet prepared by the pharmaceutical composition containing the oxiracetam has favorable stability, and the total impurity content is lower than 0.2% after the tablet is stored for 24 months. The injection prepared by the pharmaceutical composition containing the oxiracetam has favorable stability, and the total impurity content is lower than 0.2% after the injection is stored for 24 months.
Description
Technical field
The invention belongs to medical technical field, the pharmaceutical composition that is specifically related to oxiracetam compound and contains oxiracetam.
Background technology
Oxiracetam (oxiracetam, CAS62613-82-5) is developed by Italian ISF S.P.A company, is anti-hypoxia class nootropics of new generation, belongs to GABOB cyclic derivatives.Oxiracetam can optionally act on pallium and hippocampus; there is the functional rehabilitation effect of activation, protection and promotion neurocyte; and itself is without direct vasoactive, also without central excitation effect, be a kind of lasting promoter action to the improvement of learning memory.Oxiracetam can improve brain metabolism, is used for the treatment of clinically the brain injury that various chemical factors cause, various cerebral anoxias and chronic brain functional defect etc.To dull-witted, shock, old mental deterioration syndrome (as be losing one's memory, adaptability reduces, old weakness and spirituality moving obstacle etc.), the raising of the brain development of feeble-minded children and normal people's memory, working efficiency all has certain curative effect.Oxiracetam also has positive effect providing aspect cognitive function of chronic schizophrenics, quality of life.In addition oxiracetam has extremely low toxicity and good tolerance and the effect of the unexistent antithrombin Ⅲ of piracetam.Therefore, oxiracetam has a extensive future.
Oxiracetam, due to the chemical structure (glycine derivative) of itself, can discharge hydrogen ion with many metal ion generation complex reactions simultaneously; In addition due to the existence of hydroxyl in structure, oxiracetam is easily oxidized by metal ion or other oxide compounds, particularly in the higher area of some summer temps, this existence due to metal ion or other oxide compounds causes in oxiracetam preparation the rising of related substance particularly evident, and we in preparation, store, transport or use oxiracetam preparation process in inevitably can introduce micro-metal ion and touch some oxide compounds.Oxiracetam is also more responsive to light simultaneously, is exposed to easily degraded under light.
Patent CN102050774A has reported a kind of process for purification of oxiracetam compound; Patent CN101121688A discloses improving one's methods of a kind of oxiracetam; Patent CN101575309A, CN101367757, CN101575309 disclose respectively the synthetic method of (S)-oxiracetam.Patent CN102249975A discloses (S)-oxiracetam crystal formation I and preparation method thereof.Patent CN102351770B discloses a kind of oxiracetam two crystal types.Patent WO2013/020391A1 discloses S-oxiracetam crystal form II and preparation method.
For the polymorphic of medicine, different polymorphics can have different characteristics, as chemical stability, fusing point, apparent solubility, dissolution rate and density etc.These character can directly affect processing and the production of bulk drug and preparation, and can affect stability, solubleness and the bioavailability of preparation.In the solid preparation of making at the polymorphic of medicine, solubleness directly affects bioavailability, conventionally, the medicine that solubleness is large, bioavailability can be higher.Therefore, the polymorphic of medicine all has great importance with quality, security and the validity of pharmaceutical preparation.
Chinese patent CN200410023403.4 discloses a kind of Orazitan dispersion tablet and preparation method thereof, prescription consists of oxiracetam 10～90%, disintegrating agent 2～90%, lubricant and glidant 0～20%, tackiness agent 0～20%, after said preparation is oral, promptly disintegration becomes homodisperse fine particle, easy administration, can add water-dispersion deutostoma clothes, also can be contained in mouth and suck and take or swallow, but the stability problem of the not mentioned preparation of this patent.Chinese patent CN201210071676.0 discloses a kind of method of stable oxiracetam composition and the film coated tablet of being made up of it and hard capsule, the oxiracetam that said composition contains effective therapeutic dose, medicine stablizer and the auxiliary materials such as Egtazic Acid disodium, xitix.This patent has only been carried out the influence factor test of high temperature, illumination to described oxiracetam preparation, also do not investigate the steadiness of its prolonged storage.
After analyzing after deliberation, find, above-mentioned disclosed oxiracetam oral solid formulation product Shortcomings aspect quality stability: the quality stability of product is poor, in long-term storage process, active component content significantly reduces, foreign matter content significantly raises, dissolution rate significantly declines, and quality is stable not, is unfavorable for ensureing clinical drug safety.
Therefore, still need prior art to improve, further improve the quality stability of oxiracetam listing formulation products, the Key Quality Indicator such as its impurity, dissolution rate, content are controlled in safe scope, obtaining the high quality of resistance to long-term storage and use, the oxiracetam preparation product of high stability, is an important process guaranteeing oxiracetam clinical drug safety.
Summary of the invention
A kind of oxiracetam crystal having good stability that the present invention obtains on the basis of great many of experiments, even moisture absorption weightening finish is also not obvious under high humidity.Taking oxiracetam crystal of the present invention as raw material, be prepared into preparation, comprise tablet and injection liquid, there is better stability.
Particularly, the invention provides:
A kind of oxiracetam compound, its structural formula is:
The X-ray powder diffraction that described oxiracetam compound uses Cu-K alpha-ray to measure is 14.4 °, 18.1 °, 19.6 °, 20.0 °, 21.8 °, 22.7 °, 24.6 °, 25.1 ° at 2 θ and locates to show characteristic peak.
Characteristic diffraction peak is intensity 2.4%, 6.9%, 23.4%, 25.9%, 15.6%, 100%, 26.9%, 6.2% successively.
Described oxiracetam compound is in differential scanning amount method thermogram, and peak temperature is 168-171 DEG C.
Wherein crystal KBr compressing tablet of described oxiracetam compound-transmission method is measured infrared spectra and is had following absorption: 3076cm
-1, 2918cm
-1, 1730cm
-1, 1693cm
-1, 1424cm
-1, 1417cm
-1, 1666cm
-1, 1164cm
-1, 1905cm
-1, 1321cm
-1, 1310cm
-1.
The preparation method of described oxiracetam compound is: oxiracetam is dissolved in completely in the mixed solvent of tetrahydrofuran (THF)/ethylene glycol, regulate liquid pH value to 5-6.5 with acetic acid, add again gac, whip attachment, filter decarburization degerming, obtain settled solution, settled solution is moved in pressurized vessel, and pressure in pressurized vessel is 1Mpa, the temperature of settled solution is under the condition of 60-70 DEG C in pressurized vessel, slowly add isopropyl ether, produce white precipitate, filter, use successively methyl alcohol, deionized water wash, drying under reduced pressure, obtain the Powdered oxiracetam compound of white micro-crystals.
2) by step 1) the oxiracetam crystallization that obtains joins in toluene and is warming up to 65～80 DEG C, is incubated filtered while hot after 3-8 hour, and filtrate is again with the millipore filtration essence filter of 0.45um;
3) collect filtrate, first filtrate is slowly warmed up to 45-60 DEG C, then is slow cooling to 10-15 DEG C;
4) growing the grain in filtrate: growing the grain at the temperature of 10-15 DEG C, crystal is constantly grown up, rearing crystal time is 4-8 hour;
5) cooling, by the filtrate of containing crystal cooling crystallization at-5-5 DEG C, be 1-4 hour cooling time;
6) carry out centrifugally, dry, obtain the crystallization of needle-like oxiracetam.
A tablet that contains oxiracetam, comprises oxiracetam, weighting agent, disintegrating agent and lubricant, it is characterized in that there is hydroxypropyl methylcellulose acetate succinate.
The tablet of oxiracetam, the weight ratio of each component is:
Described weighting agent is selected from one or more in starch, lactose, Icing Sugar, N.F,USP MANNITOL, Microcrystalline Cellulose, pregelatinized Starch.
Described disintegrating agent is selected from one or more in dry starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, PVP K30, croscarmellose sodium.
Described lubricant is selected from one or more in micropowder silica gel, talcum powder, Magnesium Stearate.
The pharmaceutical composition that contains described oxiracetam is prepared into tablet, and its preparation method comprises the following steps:
(1) by oxiracetam and hydroxypropyl methylcellulose acetate succinate mixing and stirring;
(2) weighting agent, disintegrating agent and mix lubricant are added in step (1) gained material after evenly, adopt compressing tablet after dry granulation, must obtain oxiracetam tablet.
An injection that contains oxiracetam, the composition that comprises following weight part: oxiracetam 4 weight parts, Liquid Macrogol 4-6 weight part, Pidolidone 0.3-0.7 weight part.
The present invention compared with prior art has the following advantages and positively effect:
1, oxiracetam crystal of the present invention, purity is high, and its related substances is lower than 0.05%;
2, oxiracetam crystal of the present invention, good stability, even moisture absorption weightening finish is no more than 0.5% under high humidity.
3, the tablet stability that the pharmaceutical composition that contains oxiracetam crystal of the present invention makes is good, places after 24 months total assorted lower than 0.2%.
4, the injection good stability that the pharmaceutical composition that contains oxiracetam crystal of the present invention makes, places after 24 months total assorted lower than 0.2%.
Brief description of the drawings
Fig. 1 is that embodiment 1 obtains oxiracetam X-ray powder diffraction figure.
Embodiment
Below the invention will be further described for the description by embodiment, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, can make various amendments or improvement, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
Medicine and reagent: glycyl amide hydrochloride (Wuhan milky way Chemical Co., Ltd., lot number: 14-150, chemical pure); Oxiracetam reference substance (National Institute for Food and Drugs Control, purity: 99.7%).
It is appropriate that [related substance] takes oxiracetam fine work, and the solution of making about 1.0mg/ml by moving phase (0.01mol/L potassium dihydrogen phosphate (with phosphorus acid for adjusting pH to 3.0)) is as need testing solution; It is appropriate that precision measures trial-product, is progressively diluted to the solution of 0.01mg/ml, in contrast solution by moving phase.Under above-mentioned definite chromatographic condition, precision measures the each 20 μ l of above-mentioned solution respectively, and injecting chromatograph, records color atlas, with principal constituent Self-control method mensuration foreign matter content.
[assay] measured according to high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia version in 2010).
Chromatographic condition and system suitability octadecyl silane are weighting agent; With 0.01mol/L potassium dihydrogen phosphate, the acid for adjusting pH value to 3.0 that phosphorates is moving phase; Detection wavelength is 284nm; Theoretical plate number is calculated and should be not less than 2000 by oxiracetam peak.
Assay method is got 20 of this product, accurately weighed, porphyrize, precision takes appropriate 10mg, puts in 50ml measuring bottle, adds 90% methyl alcohol appropriate, within ultrasonic 30 minutes, make to dissolve, be diluted to scale with 90% methyl alcohol, shake up, filter, precision measures subsequent filtrate 10 μ l injection liquid chromatographies, record color atlas,, to obtain final product with calculated by peak area by external standard method.
[dissolution rate] gets this product, according to dissolution method (two annex X C the second methods of Chinese Pharmacopoeia version in 2010), taking pH6.8 phosphate buffered saline buffer 900ml as dissolution medium, rotating speed is that per minute 50 turns, in accordance with the law operation, in the time of 15 minutes, get solution and filter, according to the chromatographic condition under assay item, precision measures subsequent filtrate 5ml, injection liquid chromatography, records color atlas.Precision takes oxiracetam reference substance 25mg, puts in 25ml measuring bottle, to add acetonitrile-water (3:2) and dissolve and be diluted to scale, shakes up, precision measures 0.1ml in 50ml measuring bottle, adds stripping medium to scale, shakes up, product solution, is measured in the same method in contrast.Stripping quantity by external standard method with every of calculated by peak area.
Embodiment 1
1) 50g oxiracetam is dissolved in completely in the mixed solvent of tetrahydrofuran (THF) 600ml and ethylene glycol 300ml, being stirred to it all dissolves, by acetic acid adjusting liquid pH value to 5, add again gac, whip attachment, filter decarburization degerming, obtain settled solution, settled solution is moved in pressurized vessel, and pressure in pressurized vessel is 1Mpa, the temperature of settled solution is under the condition of 60 DEG C in pressurized vessel, slowly add isopropyl ether 300ml, produce white precipitate, filter, use successively methyl alcohol, deionized water wash, drying under reduced pressure, obtain the Powdered oxiracetam compound of white micro-crystals,
2) by step 1) the oxiracetam crystallization that obtains joins in toluene and is warming up to 65 DEG C, is incubated filtered while hot after 8 hours, and filtrate is again with the millipore filtration essence filter of 0.45 μ m;
3) collect filtrate, first filtrate is slowly warmed up to 60 DEG C, then is slow cooling to 15 DEG C;
4) growing the grain in filtrate: growing the grain at the temperature of 15 DEG C, crystal is constantly grown up, rearing crystal time is 4 hours;
5) cooling, by the filtrate of containing crystal cooling crystallization at-5 DEG C, be 1 hour cooling time;
6) carry out centrifugally, dry, obtain the crystallization of needle-like oxiracetam.
Adopt efficient liquid phase chromatographic analysis, purity is 99.95%, related substance 0.04%, and yield is 94.3%.The fusing point of this oxiracetam compound is 168-171 DEG C.
The middle characteristic peak of X-ray powder diffraction spectrogram (seeing Fig. 1) that uses Cu-K alpha-ray to measure is 12.2 °, 14.4 °, 18.1 °, 19.6 °, 20.0 °, 21.8 °, 22.7 °, 24.6 °, 25.1 ° at 2 θ and shows characteristic peak.
Characteristic diffraction peak is intensity 2.4%, 6.9%, 23.4%, 25.9%, 15.6%, 100%, 26.9%, 6.2% successively.
Infrared spectrogram is as follows: 3076cm
-1, 2918cm
-1, 1730cm
-1, 1693cm
-1, 1424cm
-1, 1417cm
-1, 1666cm
-1, 1164cm
-1, 1905cm
-1, 1321cm
-1, 1310cm
-1.
Embodiment 2
1) 50g oxiracetam is dissolved in completely in the mixed solvent of tetrahydrofuran (THF) 675ml and ethylene glycol 225ml, by acetic acid adjusting liquid pH value to 6.5, add again gac, whip attachment, filter decarburization degerming, obtain settled solution, settled solution is moved in pressurized vessel, and pressure in pressurized vessel is that the temperature of settled solution in 1Mpa, pressurized vessel is, under the condition of 70 DEG C, slowly to add isopropyl ether 250ml, produce white precipitate, filter, use successively methyl alcohol, deionized water wash, drying under reduced pressure, obtains the Powdered oxiracetam compound of white micro-crystals;
2) by step 1) the oxiracetam crystallization that obtains joins in toluene and is warming up to 80 DEG C, is incubated filtered while hot after 3 hours, and filtrate is again with the millipore filtration essence filter of 0.45um;
3) collect filtrate, first filtrate is slowly warmed up to 45 DEG C, then is slow cooling to 10 DEG C;
4) growing the grain in filtrate: growing the grain at the temperature of 10 DEG C, crystal is constantly grown up, rearing crystal time is 8 hours;
5) cooling, by the filtrate of containing crystal cooling crystallization at 5 DEG C, be 4 hours cooling time;
6) carry out centrifugally, dry, obtain the crystallization of needle-like oxiracetam.
Adopt efficient liquid phase chromatographic analysis, purity is 99.98%, related substance 0.02%, and yield is 95.1%.The fusing point of this oxiracetam compound is 168-171 DEG C.
Embodiment 3
50g oxiracetam is dissolved in completely in the mixed solvent of tetrahydrofuran (THF) 500ml and ethylene glycol 400ml, by acetic acid adjusting liquid pH value to 5.5, add again gac, whip attachment, filter decarburization degerming, obtain settled solution, settled solution is moved in pressurized vessel, and pressure in pressurized vessel is that the temperature of settled solution in 1Mpa, pressurized vessel is, under the condition of 65 DEG C, slowly to add isopropyl ether 350ml, produce white precipitate, filter, use successively methyl alcohol, deionized water wash, drying under reduced pressure, obtains the Powdered oxiracetam compound of white micro-crystals;
2) by step 1) the oxiracetam crystallization that obtains joins in toluene and is warming up to 70 DEG C, is incubated filtered while hot after 5 hours, and filtrate is again with the millipore filtration essence filter of 0.45um;
3) collect filtrate, first filtrate is slowly warmed up to 50 DEG C, then is slow cooling to 12 DEG C;
4) growing the grain in filtrate: growing the grain at the temperature of 12 DEG C, crystal is constantly grown up, rearing crystal time is 6 hours;
5) cooling, by the filtrate of containing crystal cooling crystallization at 0 DEG C, be 2.5 hours cooling time;
6) carry out centrifugally, dry, obtain the crystallization of needle-like oxiracetam.
Adopt efficient liquid phase chromatographic analysis, purity is 99.92%, related substance 0.05%, and yield is 96.0%.The fusing point of this oxiracetam compound is 168-171 DEG C.
Test example 1 stability test
Investigate embodiment 1,2,3 products therefroms and commercially available product oxiracetam (Guangdong Shixin Pharmaceutical Co., Ltd., 20110122, lower same) at 40 DEG C, different relative humidity (RH) condition (75%, 92.5%) under, the mensuration of moisture in hydrate crystal of the present invention:
The different oxiracetams of table 1 draw relatively wet
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), it is constant that moisture keeps, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
Test example 2 prescription screening tests
Oxiracetam compound (the content 99.98% of preparing with the embodiment of the present invention 1, always mix 0.02%) and commercially available oxiracetam compound (content 99.7%, total assorted 0.13%) each 4g is raw material, add starch 35g, auxiliary material in dry starch 4g, micropowder silica gel 1.8g and table 1 is prepared oxiracetam tablet, related substance and solubleness are investigated, and measurement result is in table 3:
Table 2 prescription screening
| Prescription | Oxiracetam | Hydroxypropyl methylcellulose acetate succinate |
| 1 | Embodiment 1 | — |
| 2 | Embodiment 1 | 1.5g |
| 3 | Embodiment 1 | 3g |
| 4 | Embodiment 1 | 5g |
| 5 | Embodiment 1 | 8g |
| 6 | Embodiment 1 | 10g |
1 preparation method writes out a prescription
(1) by oxiracetam and starch, after mixing, dry starch, micropowder silica gel add in step (1) gained material, and compressing tablet after employing dry granulation, obtains oxiracetam tablet.
Prescription 2-6 preparation method
(1) by oxiracetam and hydroxypropyl methylcellulose acetate succinate mixing and stirring;
(2) by starch, after mixing, dry starch, micropowder silica gel add in step (1) gained material, and compressing tablet after employing dry granulation, obtains oxiracetam tablet.
Table 3 related substance test-results
| Prescription | 1 | 2 | 3 | 4 | 5 | 6 |
| Dissolution rate (%) | 69.2 | 76.1 | 98.1 | 98.8 | 99.1 | 85.5 |
| Total impurities (%) | 0.38 | 0.27 | 0.08 | 0.07 | 0.09 | 0.41 |
Test-results shows: related substance and dissolution rate that oxiracetam and hydroxypropyl methylcellulose acetate succinate are made are better than additive method.
Embodiment 4
Prescription
Preparation method
(1) oxiracetam, hydroxypropyl methylcellulose acetate succinate are mixed;
(2) add in step (1) gained material after lactose, sodium starch glycolate and talcum powder are mixed, adopt compressing tablet after dry granulation, obtain oxiracetam tablet.
Embodiment 4
Prescription
Preparation method
(1) oxiracetam, hydroxypropyl methylcellulose acetate succinate are mixed;
(2) add in step (1) gained material after N.F,USP MANNITOL, cross-linked polyvinylpyrrolidone and Magnesium Stearate are mixed, adopt compressing tablet after dry granulation, obtain oxiracetam tablet.
Embodiment 5
Prescription
Preparation method
(1) oxiracetam, hydroxypropyl methylcellulose acetate succinate are mixed;
(2) add in step (1) gained material after Microcrystalline Cellulose, croscarmellose sodium and Magnesium Stearate are mixed, adopt compressing tablet after dry granulation, obtain oxiracetam tablet.
Embodiment 6
Prescription
Preparation method
(1) oxiracetam, hydroxypropyl methylcellulose acetate succinate are mixed;
(2) add in step (1) gained material after Microcrystalline Cellulose, dry starch, sodium starch glycolate, talcum powder, Magnesium Stearate are mixed, adopt compressing tablet after dry granulation, obtain oxiracetam tablet.
Embodiment 7
Prescription
Preparation method
(1) oxiracetam, hydroxypropyl methylcellulose acetate succinate are mixed;
(2) add in step (1) gained material after pregelatinized Starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, micropowder silica gel are mixed, adopt compressing tablet after dry granulation, obtain oxiracetam tablet.
Embodiment 8
Prescription
Preparation method
(1) oxiracetam, hydroxypropyl methylcellulose acetate succinate are mixed;
(2) add in step (1) gained material after Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, micropowder silica gel are mixed, adopt compressing tablet after dry granulation, obtain oxiracetam tablet.
Test example 3 tablet test of long duration
Under listing drug packaging condition, embodiment 4-8 sample is deposited under temperature (25 ± 2) DEG C, relative humidity 60% ± 10% condition, respectively at 0,3,6,12,18,24 sampling at the end of month, measure indices, the results are shown in Table 4.
Table 4 tablet test of long duration is investigated result
Conclusion: under long-term room temperature condition, place 24 months every quality index of oxiracetam sheet without considerable change, total assorted lower than 0.2%, show that oxiracetam tablet stability prepared by present method is good.
Embodiment 9
Under clean condition, 4g Liquid Macrogol is dropped in dosing utensil, add stirring and dissolving in water for injection 7000ml, be cooled to room temperature, add 3gL-L-glutamic acid, stir evenly, add the needle-use activated carbon of 0.1% (g/ml), whip attachment, filters carbon removal; Be down to after room temperature until above-mentioned preparation liquid, 40g adds oxiracetam, adds water for injection to 10000ml, through 0.22 μ m filtering with microporous membrane, filling; Lamp inspection; Warehouse-in; Obtain oxiracetam injection.
Embodiment 10
Under clean condition, 5g Liquid Macrogol is dropped in dosing utensil, add stirring and dissolving in water for injection 7000ml, be cooled to room temperature, add 3.5gL-L-glutamic acid, stir evenly, add the needle-use activated carbon of 0.1% (g/ml), whip attachment, filters carbon removal; Be down to after room temperature until above-mentioned preparation liquid, 40g adds oxiracetam, adds water for injection to full dose, through 0.22 μ m filtering with microporous membrane, filling; Lamp inspection; Warehouse-in; Obtain oxiracetam injection.
Embodiment 11
Under clean condition, 5.5g Liquid Macrogol is dropped in dosing utensil, add stirring and dissolving in water for injection 7000ml, be cooled to room temperature, add 6gL-L-glutamic acid, stir evenly, add the needle-use activated carbon of 0.1% (g/ml), whip attachment, filters carbon removal; Be down to after room temperature until above-mentioned preparation liquid, 40g adds oxiracetam, adds water for injection to full dose, through 0.22 μ m filtering with microporous membrane, filling; Lamp inspection; Warehouse-in; Obtain oxiracetam injection.
Test example 4 injection test of long duration
Under listing drug packaging condition, embodiment 9-11 sample is deposited under temperature (25 ± 2) DEG C, relative humidity 60% ± 10% condition, respectively at 0,3,6,12,18,24 sampling at the end of month, measure indices, the results are shown in Table 5.
Table 5 injection test of long duration is investigated result
Conclusion: place 24 months every quality index of oxiracetam injection without considerable change under long-term room temperature condition, related substance total amount, lower than 0.1%, shows that oxiracetam injection prepared by present method has good stability.
Claims (9)
1. an oxiracetam compound, its structural formula is:
It is characterized in that, the X-ray powder diffraction that described oxiracetam compound uses Cu-K alpha-ray to measure is 14.4 °, 18.1 °, 19.6 °, 20.0 °, 21.8 °, 22.7 °, 24.6 °, 25.1 ° at 2 θ and locates to show characteristic peak.
2. a kind of oxiracetam compound according to claim 1, wherein characteristic diffraction peak intensity 2.4%, 6.9%, 23.4%, 25.9%, 15.6%, 100%, 26.9%, 6.2% successively.
3. according to the oxiracetam compound described in claim 1-2 any one, it is characterized in that, described oxiracetam compound is in differential scanning amount method thermogram, and peak temperature is 168-171 DEG C.
4. according to the oxiracetam compound described in claim 1-2 any one, it is characterized in that, wherein crystal KBr compressing tablet of described oxiracetam compound-transmission method is measured infrared spectra and is had following absorption: 3076cm
-1, 2918cm
-1, 1730cm
-1, 1693cm
-1, 1424cm
-1, 1417cm
-1, 1666cm
-1, 1164cm
-1, 1905cm
-1, 1321cm
-1, 1310cm
-1.
5. according to the oxiracetam compound described in claim 1-2 any one, it is characterized in that, the preparation method of described oxiracetam compound is:
1) oxiracetam crude product is dissolved in the mixed solvent of tetrahydrofuran (THF)/ethylene glycol completely, regulate liquid pH value to 5-6.5 with acetic acid, add again gac, whip attachment, filter decarburization degerming, obtain settled solution, settled solution is moved in pressurized vessel, and pressure in pressurized vessel is that the temperature of settled solution in 1Mpa, pressurized vessel is, under the condition of 60-70 DEG C, slowly to add isopropyl ether, produce white precipitate, filter, use successively methyl alcohol, deionized water wash, drying under reduced pressure, obtains the Powdered oxiracetam compound of white micro-crystals;
2) by step 1) oxiracetam that obtains joins in toluene and is warming up to 65-80 DEG C, is incubated filtered while hot after 3-8 hour, and filtrate is again with the millipore filtration essence filter of 0.45 μ m;
3) collect filtrate, first filtrate is warmed up to 45-60 DEG C, then cools to 10-15 DEG C;
4) growing the grain in filtrate: growing the grain at the temperature of 10-15 DEG C, crystal is constantly grown up, rearing crystal time is 4-8 hour;
5) cooling, by the filtrate of containing crystal cooling crystallization at-5-5 DEG C, be 1-4 hour cooling time;
6) carry out centrifugally, dry, obtain the crystallization of needle-like oxiracetam.
6. according to a kind of oxiracetam compound described in claim 1-2 any one, it is characterized in that compound is prepared into tablet or injection.
7. a kind of tablet that contains oxiracetam according to claim 6, comprises oxiracetam, weighting agent, disintegrating agent and lubricant, it is characterized in that there is HPMCAS.
8. a kind of tablet that contains oxiracetam according to claim 6, is characterized in that, the tablet of described oxiracetam, and the weight ratio of each component is:
9. a kind of injection that contains oxiracetam according to claim 6, is characterized in that the composition that comprises following weight part: oxiracetam 4 weight parts, Liquid Macrogol 0.4-0.6 weight part, Pidolidone 0.3-0.7 weight part.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105837490A (en) * | 2016-04-22 | 2016-08-10 | 海南合瑞制药股份有限公司 | Oxiracetam compound and preparation method thereof |
| CN106692073A (en) * | 2015-07-30 | 2017-05-24 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam sterile powder and preparation method thereof |
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| CN102249977A (en) * | 2011-08-11 | 2011-11-23 | 重庆润泽医疗器械有限公司 | 4-hydroxy-2-oxo-1-pyrrolidine acetamide racemate crystal I and preparation method thereof |
| CN102558014A (en) * | 2011-11-09 | 2012-07-11 | 天津市汉康医药生物技术有限公司 | Oxiracetam compound with steady crystal form |
| CN103342673A (en) * | 2013-07-31 | 2013-10-09 | 石药集团欧意药业有限公司 | Oxiracetam crystal form and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102249977A (en) * | 2011-08-11 | 2011-11-23 | 重庆润泽医疗器械有限公司 | 4-hydroxy-2-oxo-1-pyrrolidine acetamide racemate crystal I and preparation method thereof |
| CN102558014A (en) * | 2011-11-09 | 2012-07-11 | 天津市汉康医药生物技术有限公司 | Oxiracetam compound with steady crystal form |
| CN103342673A (en) * | 2013-07-31 | 2013-10-09 | 石药集团欧意药业有限公司 | Oxiracetam crystal form and preparation method thereof |
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| CN106692073A (en) * | 2015-07-30 | 2017-05-24 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam sterile powder and preparation method thereof |
| CN105837490A (en) * | 2016-04-22 | 2016-08-10 | 海南合瑞制药股份有限公司 | Oxiracetam compound and preparation method 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 |
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