CN104072400B - Oxiracetam compound and pharmaceutical composition thereof - Google Patents
Oxiracetam compound and pharmaceutical composition thereof Download PDFInfo
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- CN104072400B CN104072400B CN201410321549.0A CN201410321549A CN104072400B CN 104072400 B CN104072400 B CN 104072400B CN 201410321549 A CN201410321549 A CN 201410321549A CN 104072400 B CN104072400 B CN 104072400B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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 art, be specifically related to oxiracetam compound and the pharmaceutical composition containing 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 activation, protect and promote the functional rehabilitation effect of 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 the brain injury that various chemical factors causes clinically, various cerebral anoxia and chronic cerebral functional defect etc.To dull-witted, shock, old mental deterioration syndrome (as be losing one's memory, adaptability reduces, old weak and psychogenic activity obstacle etc.), the brain development of feeble-minded children and the memory of normal people, the raising of working efficiency all have certain curative effect.Oxiracetam also has positive effect providing in cognitive function of chronic schizophrenics, quality of life.In addition oxiracetam has the effect of extremely low toxicity and good tolerance and 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 by metal ion or other oxides, particularly in the area that some summer temps are higher, this existence due to metal ion or other oxide compounds causes the rising of related substance in oxiracetam preparation particularly evident, and we inevitably introduce the metal ion of trace and touch some oxide compounds in preparation, storage, transport or use oxiracetam preparation process.Oxiracetam is also more responsive to light simultaneously, easily degrades under being exposed to light.
Patent CN102050774A reports 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 individually disclose the synthetic method of (S)-oxiracetam.Patent CN102249975A discloses (S)-Oxiracetam crystal form I and preparation method thereof.Patent CN102351770B discloses a kind of oxiracetam two crystal type.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 directly can affect process and the production of bulk drug and preparation, and can affect the stability of preparation, solubleness and bioavailability.In the solid preparation that the polymorphic of medicine is made, solubleness directly affects bioavailability, and usually, the medicine that solubleness is large, bioavailability can be higher.Therefore, the polymorphic of medicine all has great importance with the quality of pharmaceutical preparation, security and validity.
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%, can the fine particle that uniformly disperses of promptly disintegration after said preparation is oral, easy administration, water-dispersion deutostoma clothes can be added, also can be contained in mouth and suck clothes 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 be made up of it and hard capsule, said composition contains the oxiracetam of effective therapeutic dose, drug stabilizing agent and the auxiliary materials such as Egtazic Acid disodium, xitix.This patent has only carried out the influence factor test of high temperature, illumination to described oxiracetam preparation, also do not investigate the steadiness of its prolonged storage.
Find after analyzing after deliberation, above-mentioned disclosed oxiracetam oral solid formulation product Shortcomings in 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 to improve prior art, the quality stability of further raising oxiracetam listing formulation products, the Key Quality Indicator such as its impurity, dissolution rate, content are controlled in the scope of safety, obtaining the oxiracetam preparation product of the high quality of resistance to long term storage and use, high stability, is the important process guaranteeing oxiracetam clinical drug safety.
Summary of the invention
A kind of oxiracetam crystal had good stability that the present invention obtains on the basis of great many of experiments, even if moisture absorption weightening finish is also not obvious under high humidity conditions.With oxiracetam crystal of the present invention for raw material, be prepared into preparation, comprise tablet and injection liquid, there is better stability.
Specifically, the invention provides:
A kind of oxiracetam compound, its structural formula is:
The X-ray powder diffraction that described oxiracetam compound uses the measurement of Cu-K alpha-ray to obtain is that 14.4 °, 18.1 °, 19.6 °, 20.0 °, 21.8 °, 22.7 °, 24.6 °, 25.1 ° places show characteristic peak at 2 θ.
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.
Described oxiracetam compound wherein crystal KBr compressing tablet-transmission method measures infrared spectra and has 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: be dissolved in by oxiracetam in the mixed solvent of tetrahydrofuran (THF)/ethylene glycol completely, regulate liquid pH value to 5-6.5 with acetic acid, add gac again, whip attachment, filtration decarburization is degerming, obtain settled solution, settled solution is moved in pressurized vessel, and the pressure in pressurized vessel is 1Mpa, in pressurized vessel, the temperature of settled solution is under the condition of 60-70 DEG C, slowly add isopropyl ether, produce white precipitate, filter, use methyl alcohol successively, 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, and be incubated filtered while hot after 3-8 hour, 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, makes crystal constantly grow up, rearing crystal time is 4-8 hour;
5) cool, by the cooling crystallization at-5-5 DEG C of the filtrate containing crystal, cooling time is 1-4 hour;
6) carry out centrifugal, dry, obtain the crystallization of needle-like oxiracetam.
A tablet containing oxiracetam, comprises oxiracetam, weighting agent, disintegrating agent and lubricant, it is characterized in that, have 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.
Pharmaceutical composition containing 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) by weighting agent, disintegrating agent and mix lubricant evenly after add in step (1) gained material, adopt compressing tablet after dry granulation, oxiracetam tablet must be obtained.
An injection containing oxiracetam, comprises the composition of following weight part: oxiracetam 4 weight part, 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 if moisture absorption weightening finish is no more than 0.5% under high humidity conditions.
3, the tablet stability that the pharmaceutical composition containing oxiracetam crystal of the present invention obtains is good, places after 24 months total assorted lower than 0.2%.
4, the injection good stability that the pharmaceutical composition containing oxiracetam crystal of the present invention is obtained, places after 24 months total assorted lower than 0.2%.
Accompanying drawing explanation
Fig. 1 is that embodiment 1 obtains oxiracetam X-ray powder diffraction figure.
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, 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, makes the solution of about 1.0mg/ml as need testing solution by moving phase (0.01mol/L potassium dihydrogen phosphate (with phosphorus acid for adjusting pH to 3.0)); 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 the above-mentioned chromatographic condition determined, precision measures each 20 μ l of above-mentioned solution respectively, injecting chromatograph, and record color atlas, measures foreign matter content by principal constituent Self-control method.
[assay] measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
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; Determined wavelength is 284nm; Theoretical plate number calculates should be not less than 2000 by oxiracetam peak.
Assay method gets this product 20, accurately weighed, porphyrize, precision takes appropriate 10mg, puts in 50ml measuring bottle, adds 90% methyl alcohol appropriate, within ultrasonic 30 minutes, make dissolving, with 90% methanol dilution to scale, shake up, filter, precision measures subsequent filtrate 10 μ l injection liquid chromatography, record color atlas, by external standard method with calculated by peak area, to obtain final product.
[dissolution rate] gets this product, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex X C second methods), with pH6.8 phosphate buffered saline buffer 900ml for dissolution medium, rotating speed is per minute 50 turns, operates in accordance with the law, through 15 minutes time, get solution to filter, according to the chromatographic condition under assay item, precision measures subsequent filtrate 5ml, injection liquid chromatography, record 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 in 0.1ml to 50ml measuring bottle, adds stripping medium to scale, shakes up, product solution, is measured in the same method in contrast.By external standard method with the stripping quantity of the every sheet 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, be stirred to it all to dissolve, liquid pH value to 5 is regulated with acetic acid, add gac again, whip attachment, filtration decarburization is degerming, obtain settled solution, settled solution is moved in pressurized vessel, and the pressure in pressurized vessel is 1Mpa, in pressurized vessel, the temperature of settled solution is under the condition of 60 DEG C, slowly add isopropyl ether 300ml, produce white precipitate, filter, use methyl alcohol successively, 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, and be incubated filtered while hot after 8 hours, filtrate is again with the millipore filtration essence filter of 0.45 μm;
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, makes crystal constantly grow up, rearing crystal time is 4 hours;
5) cool, by the cooling crystallization at-5 DEG C of the filtrate containing crystal, cooling time is 1 hour;
6) carry out centrifugal, 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 the X-ray powder diffractogram (see Fig. 1) using the measurement of Cu-K alpha-ray to obtain 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, liquid pH value to 6.5 is regulated with acetic acid, add gac again, whip attachment, filtration decarburization is degerming, obtain settled solution, settled solution is moved in pressurized vessel, and the temperature that the pressure in pressurized vessel is settled solution in 1Mpa, pressurized vessel is under the condition of 70 DEG C, slowly adds isopropyl ether 250ml, produce white precipitate, filter, use methyl alcohol, deionized water wash successively, 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 80 DEG C, and be incubated filtered while hot after 3 hours, 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, makes crystal constantly grow up, rearing crystal time is 8 hours;
5) cool, by the cooling crystallization at 5 DEG C of the filtrate containing crystal, cooling time is 4 hours;
6) carry out centrifugal, 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, liquid pH value to 5.5 is regulated with acetic acid, add gac again, whip attachment, filtration decarburization is degerming, obtain settled solution, settled solution is moved in pressurized vessel, and the temperature that the pressure in pressurized vessel is settled solution in 1Mpa, pressurized vessel is under the condition of 65 DEG C, slowly adds isopropyl ether 350ml, produce white precipitate, filter, use methyl alcohol, deionized water wash successively, 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 70 DEG C, and be incubated filtered while hot after 5 hours, 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, makes crystal constantly grow up, rearing crystal time is 6 hours;
5) cool, by the cooling crystallization at 0 DEG C of the filtrate containing crystal, cooling time is 2.5 hours;
6) carry out centrifugal, 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 therefrom 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 oxiracetam of table 1 draws wet comparison
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), water tariff collection is constant, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
Test example 2 prescription screening is tested
With oxiracetam compound (content 99.98% prepared by 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, oxiracetam tablet prepared by auxiliary material in dry starch 4g, micropowder silica gel 1.8g and table 1, investigate related substance and solubleness, 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 |
Prescription 1 preparation method
(1) by oxiracetam and starch, add in step (1) gained material after dry starch, micropowder silica gel mix, 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, add in step (1) gained material after dry starch, micropowder silica gel mix, 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: the related substance obtain oxiracetam and hydroxypropyl methylcellulose acetate succinate and dissolution rate 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 being mixed, compressing tablet after employing dry granulation, obtains 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 being mixed, compressing tablet after employing dry granulation, obtains 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 being mixed, compressing tablet after employing dry granulation, obtains 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 being mixed, compressing tablet after employing dry granulation, obtains 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 being mixed, compressing tablet after employing dry granulation, obtains 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 being mixed, compressing tablet after employing dry granulation, obtains oxiracetam tablet.
Test example 3 tablet test of long duration
Under marketed products terms of packing, 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 investigates result
Conclusion: place oxiracetam sheet 24 months every quality index under long-term room-temperature condition without considerable change, total assorted lower than 0.2%, show that oxiracetam tablet stability prepared by present method is good.
Embodiment 9
Under the condition of cleaning, 4g Liquid Macrogol is dropped in dosing utensil, adds 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, filter carbon removal; After above-mentioned preparation liquid is down to room temperature, 40g adds oxiracetam, adds water for injection to 10000ml, through 0.22 μm of filtering with microporous membrane, filling; Lamp is examined; Warehouse-in; Obtain oxiracetam injection.
Embodiment 10
Under the condition of cleaning, 5g Liquid Macrogol is dropped in dosing utensil, adds 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, filter carbon removal; After above-mentioned preparation liquid is down to room temperature, 40g adds oxiracetam, adds water for injection to full dose, through 0.22 μm of filtering with microporous membrane, filling; Lamp is examined; Warehouse-in; Obtain oxiracetam injection.
Embodiment 11
Under the condition of cleaning, 5.5g Liquid Macrogol is dropped in dosing utensil, adds 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, filter carbon removal; After above-mentioned preparation liquid is down to room temperature, 40g adds oxiracetam, adds water for injection to full dose, through 0.22 μm of filtering with microporous membrane, filling; Lamp is examined; Warehouse-in; Obtain oxiracetam injection.
Test example 4 injection test of long duration
Under marketed products terms of packing, 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 investigates result
Conclusion: place oxiracetam injection 24 months every quality index under long-term room-temperature condition without considerable change, related substance total amount, lower than 0.1%, shows that oxiracetam injection prepared by present method has good stability.
Claims (5)
1. an oxiracetam compound, its structural formula is:
It is characterized in that, the X-ray powder diffraction that described oxiracetam compound uses the measurement of Cu-K alpha-ray to obtain is that 14.4 °, 18.1 °, 19.6 °, 20.0 °, 21.8 °, 22.7 °, 24.6 °, 25.1 ° places show characteristic peak at 2 θ;
Wherein characteristic diffraction peak 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;
Described oxiracetam compound wherein crystal KBr compressing tablet-transmission method measures infrared spectra and has 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:
1) oxiracetam crude product 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 gac again, whip attachment, filtration decarburization is degerming, obtain settled solution, settled solution is moved in pressurized vessel, and the temperature that the pressure in pressurized vessel is settled solution in 1Mpa, pressurized vessel is under the condition of 60-70 DEG C, slowly adds isopropyl ether, produce white precipitate, filter, use methyl alcohol, deionized water wash successively, drying under reduced pressure, obtain 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, and be incubated filtered while hot after 3-8 hour, filtrate is again with the millipore filtration essence filter of 0.45 μm;
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, makes crystal constantly grow up, rearing crystal time is 4-8 hour;
5) cool, by the cooling crystallization at-5-5 DEG C of the filtrate containing crystal, cooling time is 1-4 hour;
6) carry out centrifugal, dry, obtain the crystallization of needle-like oxiracetam.
2. comprise a composition for oxiracetam compound as claimed in claim 1, it is characterized in that compound is prepared into tablet or injection.
3. composition according to claim 2, wherein tablet comprises oxiracetam, weighting agent, disintegrating agent and lubricant, it is characterized in that, containing HPMCAS.
4. composition according to claim 2, is characterized in that, the tablet of described oxiracetam, and the weight ratio of each component is:
5. composition according to claim 2, is characterized in that, injection comprises the composition of following weight part: oxiracetam 4 weight part, Macrogol 3000 .4-0.6 weight part, Pidolidone 0.3-0.7 weight part.
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| 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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| CN102558014B (en) * | 2011-11-09 | 2013-11-06 | 天津市汉康医药生物技术有限公司 | Oxiracetam compound with steady crystal form |
| CN103342673B (en) * | 2013-07-31 | 2015-11-18 | 石药集团欧意药业有限公司 | A kind of Oxiracetam crystal form and preparation method thereof |
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