CN110393802A - Dextrorotation oxiracetam dispersible tablet and preparation method thereof - Google Patents
Dextrorotation oxiracetam dispersible tablet and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of dextrorotation oxiracetam dispersible tablet, using particular crystalline form dextrorotation oxiracetam as active constituent, using microcrystalline cellulose and sorbierite as filler, sodium carboxymethyl starch is disintegrating agent, and dextrorotation oxiracetam dispersible tablet is prepared through direct powder compression according to specific ratio of adjuvant.Active constituent stable crystal form in dispersible tablet of the present invention accelerates preservation that crystal form variation does not occur within 12 months under conditions of 40oC, 75% relative humidity, while the dispersion sheet hardness prepared is moderate, and disintegration time is short, and dissolution rate is fast.Dispersible tablet preparation process of the present invention is simple, and technique is easily controllable, easy to operate, is suitble to industrialized production.
Description
Technical field
The present invention relates to dextrorotation oxiracetam dispersible tablets, and in particular to a kind of dextrorotation oxiracetam dispersible tablet and its system
Preparation Method.
Background technique
Oxiracetam, No. CAS is 62613-82-5, is synthesized for the first time by Italian SmithKline ratio Qie Mu company in 1974,
The nootropic agents of new generation of listing in 1987 can promote Phosphorylcholine and adjacent acyl ethanol amine synthesis, promote brain metabolism, pass through
Blood-brain barrier improves intelligence and memory to the irritating effect of specific central nervous pathway.Studies have shown that oxiracetam dextrorotation
For body (dextrorotation oxiracetam, CAS 68252-28-8) in calmness, there are special biological activity, and its poison in anti-epileptic field
Property it is low, drug safe range is big, is expected to the substitute as existing high toxicity anti-epileptic class drug.Chinese patent
CN101766596A discloses a kind of using dextrorotation oxiracetam as the solid pharmaceutical preparation of active constituent, and it includes dextrorotation hydroxyl oxygen pyrrole vinegar
Amine and pharmaceutically acceptable auxiliary material, this method replace oxiracetam in the prior art with dextrorotation oxiracetam, thus
Enhance pharmaceutical activity.Dextrorotation oxiracetam hygroscopicity is strong, and traditional wet granulation technology has an impact product quality, content
Decline is obvious, and related content of material dramatically increases, and product stability is poor, while being easy that there are crystal transfers.
Summary of the invention
In order to solve the problems in the prior art, the purpose of the present invention provide a kind of dextrorotation oxiracetam dispersible tablet and
Preparation method.Dextrorotation oxiracetam dispersible tablet of the present invention is active constituent using the dextrorotation oxiracetam of specific crystal formation,
It is aided with specific ratio of adjuvant, dextrorotation oxiracetam dispersible tablet is prepared using direct powder compression, active constituent is brilliant
Type is stablized, while the dispersion sheet hardness prepared is moderate, and disintegration time is short, and dissolution rate is fast.It is of the present invention that " powder is directly pressed
Piece method " refers to the method that the mixture of drug and auxiliary material is directly carried out tabletting without pelletization, and process flow is such as
Under: drug+auxiliary material --- crushes --- sieving --- mixing --- adding mix lubricant --- tabletting.
To achieve the purpose of the present invention, the present invention uses following technical scheme.
In dextrorotation oxiracetam dispersible tablet of the present invention comprising 45~75% crystal form dextrorotation oxiracetam, 5~
15% microcrystalline cellulose, 3~15% sorbierites, 5~20% sodium carboxymethyl starches, 1-5% lubricant, 0.5-2% corrigent, with
Mass percent meter.
The dextrorotation oxiracetam of crystal form of the present invention is radiated using Cu-K α, and obtained X-ray powder spreads out
Penetrate spectrum 2 θ of angle of reflection be 14.14 ± 0.2 °, 17.76 ± 0.2 °, 18.72 ± 0.2 °, 20.16 ± 0.2 °, 21.20 ± 0.2 °,
21.52 ± 0.2 °, 24.17 ± 0.2 °, 25.88 ± 0.2 ° have diffraction maximum.
Preferably, filler (the sum of microcrystalline cellulose and sorbierite) and the mass ratio of disintegrating agent (sodium carboxymethyl starch) are
2~3:2.Further, the mass ratio of microcrystalline cellulose and sorbierite is 1~3:1 in filler.
It include 45~75% crystal form dextrorotation hydroxyl oxygen pyrrole vinegar in dextrorotation oxiracetam dispersible tablet of the present invention
Amine, 5~15% microcrystalline celluloses, 3~15% sorbierites, 5~20% sodium carboxymethyl starches, 1-3% lubricant, 1-2% flavoring
Agent, by percentage to the quality；The mass ratio of the sum of the microcrystalline cellulose and sorbierite and sodium carboxymethyl starch is 2~3:2；Institute
The mass ratio for stating microcrystalline cellulose and sorbierite is 1~3:1；The magnesium stearate lubricant, the corrigent are selected from A Siba
Sweet tea.
Lubricant of the present invention is selected from magnesium stearate, calcium stearate, zinc stearate, polyethylene glycol, talcum powder and micro-
At least one of powder silica gel；It is preferred that at least one of magnesium stearate, calcium stearate, talcum powder and superfine silica gel powder.Corrigent
Selected from least one of acesulfame potassium, stevioside, Aspartame, xylitol；It is preferred that at least one in xylitol, Aspartame
Kind.
The dextrorotation oxiracetam of the crystal form is prepared with the following method: dextrorotation oxiracetam is dissolved in two
The in the mixed solvent that methylacetamide and ethyl acetate volume ratio are 1:1~1:6 dissolves by heating, dextrorotation oxiracetam with mix
The mass volume ratio (g/mL) of solvent is 1:1~1:7；Filtering, filtrate is sealed, is stirred with the speed of 100~300r/min
17~23h is mixed, is filtered again, filtrate stands solvent flashing and forms crystallization after filtering, crystallization is collected, by the crystallization of collection in 20-
40 DEG C, relative humidity dry 3-6h under conditions of being 60-80%, both.
The dextrorotation oxiracetam of the crystal form is prepared with the following method: dextrorotation oxiracetam is dissolved in two
The in the mixed solvent that methylacetamide and ethyl acetate volume ratio are 1:1~1:3 heats 30-60 DEG C of dissolution, dextrorotation hydroxyl oxygen pyrrole vinegar
The mass volume ratio (g/mL) of amine and mixed solvent is 1:3~1:5；Filtering, filtrate is sealed, with 150~250r/min
Speed stir 18~20h, filter again, after filtering filtrate stand solvent flashing formed crystallization, collect crystallization, by the knot of collection
At 20-40 DEG C, relative humidity dry 4-6h under conditions of being 60-75% was both obtained crystalline substance.
The preparation method of dextrorotation oxiracetam dispersible tablet of the present invention, comprising the following steps:
(1) dextrorotation oxiracetam the preparation of crystal form dextrorotation oxiracetam: is dissolved in dimethyl acetamide and second
Acetoacetic ester volume ratio is the in the mixed solvent of 1:1~1:3, the mass volume ratio (g/mL) of dextrorotation oxiracetam and mixed solvent
For 1:3~1:5；Filtering, filtrate is sealed, and is stirred 18~20h with the speed of 150~250r/min, is filtered again, filters
Filtrate stands solvent flashing and forms crystallization afterwards, collects crystallization, and by the crystallization of collection at 20-40 DEG C, relative humidity is 60-75%'s
Under the conditions of dry 4-6h crystal form dextrorotation oxiracetam is made；
(2) direct powder compression: crystal form dextrorotation oxiracetam, microcrystalline cellulose, sweet is weighed respectively by charge ratio
Reveal alcohol, sodium carboxymethyl starch, cross 80 meshes, lubricant and corrigent is added, be uniformly mixed, direct tablet compressing, both the right side of the present invention
Revolve oxiracetam dispersible tablet.
The utility model has the advantages that
The present invention provides a kind of dextrorotation oxiracetam dispersible tablet, with particular crystalline form dextrorotation oxiracetam (anti-
2 θ of firing angle be 14.14 ± 0.2 °, 17.76 ± 0.2 °, 18.72 ± 0.2 °, 20.16 ± 0.2 °, 21.20 ± 0.2 °, 21.52 ±
0.2 °, 24.17 ± 0.2 °, 25.88 ± 0.2 ° has diffraction maximum) it is active constituent, using microcrystalline cellulose and sorbierite as filler,
Sodium carboxymethyl starch is disintegrating agent, and dextrorotation oxiracetam is prepared through direct powder compression according to specific ratio of adjuvant
Dispersible tablet, active constituent stable crystal form in dispersible tablet accelerate to save 12 months and not send out under conditions of 40 DEG C, 75% relative humidity
Raw crystal form variation, while the dispersion sheet hardness prepared is moderate, disintegration time is short, and 10min is molten in phosphate buffer (pH6.8)
Out more than 90%.The method of the present invention avoids pelletization, thus outstanding advantages of energy time-saving energy-saving, simple process, few process,
Shorten the production cycle simultaneously, improve industrial automatization, greatly improve labor productivity, reduce production cost, reduces drug
The factor of unstable quality in process guarantees product quality.Dispersible tablet preparation process of the present invention is simple, and technique is easy to control
System, it is easy to operate, it is suitble to industrialized production.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiment is only used
In invention is further explained, it should not be understood as limiting the scope of the invention, person skilled in art can
To make some nonessential modifications and adaptations to the present invention according to aforementioned present invention content.The preparation process of crystal form of the present invention
In, it is filtered into conventional solid-liquid separate mode known in the art.
Embodiment 1
1g dextrorotation oxiracetam is dissolved in the in the mixed solvent (dimethyl acetamide 2mL, ethyl acetate 3mL) of 5mL
In solution, 45 DEG C of heating for dissolving, filtering seals filtrate, with the speed stirring 19h or so of 200r/min, filters again,
Filtrate stands solvent flashing and forms crystallization after filtering, collects crystallization, by the crystallization of collection at 30 DEG C, item that relative humidity is 75%
Dry 4h, obtains dextrorotation oxiracetam crystal under part.Obtained dextrorotation oxiracetam crystal is subjected to powder diffraction experiment:
Powder diffraction measures (XRPD): test equipment condition: carrying out room temperature test using Bruker D2 PHASER powder diffractometer, surveys
Strip part are as follows: with Cu KaFor light source, voltage 30kV, electric current 10mA test 0.014 ° of step-length, scanning speed
0.1s/step, 5-40 ° of scanning range (2 θ).Through detecting, the dextrorotation oxiracetam crystal of preparation is in 2 θ of angle of diffraction
14.14±0.2°、17.76±0.2°、18.72±0.2°、20.16±0.2°、21.20±0.2°、21.52±0.2°、24.17
± 0.2 °, 25.88 ± 0.2 ° has diffraction maximum.
Embodiment 2
2g dextrorotation oxiracetam is dissolved in the in the mixed solvent (dimethyl acetamide 2mL, ethyl acetate 3mL) of 6mL
In solution, 30 DEG C of heating for dissolving, filtering seals filtrate, with the speed stirring 18h or so of 150r/min, filters again,
Filtrate stands solvent flashing and forms crystallization after filtering, collects crystallization, by the crystallization of collection at 40 DEG C, item that relative humidity is 75%
Dry 4h, obtains dextrorotation oxiracetam crystal under part.It is measured through powder diffraction, dextrorotation oxiracetam prepared by embodiment 2
Crystal form is identical as dextrorotation oxiracetam crystal form prepared by embodiment 1.
Embodiment 3
2g dextrorotation oxiracetam is dissolved in the in the mixed solvent (dimethyl acetamide 4mL, ethyl acetate 4mL) of 8mL
In solution, 60 DEG C of heating for dissolving, filtering seals filtrate, with the speed stirring 20h or so of 250r/min, filters again,
Filtrate stands solvent flashing and forms crystallization after filtering, collects crystallization, by the crystallization of collection at 20 DEG C, item that relative humidity is 60%
Dry 6h, obtains dextrorotation oxiracetam crystal under part.It is measured through powder diffraction, dextrorotation oxiracetam prepared by embodiment 3
Crystal form is identical as dextrorotation oxiracetam crystal form prepared by embodiment 1.
Embodiment 4
Prescription: dextrorotation oxiracetam 60g, 10g microcrystalline cellulose of the crystal form of reference 1 method of embodiment preparation,
10g sorbierite, 16g sodium carboxymethyl starch, 3g magnesium stearate, 1g Aspartame.Preparation method: crystallization is weighed respectively by charge ratio
Form dextrorotation oxiracetam, microcrystalline cellulose, mannitol, sodium carboxymethyl starch cross 80 meshes, and lubricant and flavoring is added
Agent is uniformly mixed, is put into rotary tablet machine, turntable revolving speed 20r/min, stuffing pressure 35N, depth of fill 15mm,
Direct tablet compressing, both dextrorotation oxiracetam dispersible tablet of the present invention.
Embodiment 5
Prescription: dextrorotation oxiracetam 45g, 20g microcrystalline cellulose of the crystal form of reference 2 method of embodiment preparation,
10g sorbierite, 20g sodium carboxymethyl starch, 4g superfine silica gel powder, 1g xylitol.Preparation method: crystalline is weighed respectively by charge ratio
Formula dextrorotation oxiracetam, microcrystalline cellulose, sorbierite, sodium carboxymethyl starch cross 80 meshes, and lubricant and corrigent is added,
It is uniformly mixed, is put into rotary tablet machine, turntable revolving speed 20r/min, stuffing pressure 35N, depth of fill 15mm, directly
Tabletting, both dextrorotation oxiracetam dispersible tablet of the present invention.
Embodiment 6
Prescription: referring to dextrorotation oxiracetam 73g, 9g microcrystalline cellulose, the 3g of the crystal form of 3 method of embodiment preparation
Sorbierite, 12g sodium carboxymethyl starch, 1g talcum powder, 1g Aspartame.
Preparation method: crystal form dextrorotation oxiracetam, microcrystalline cellulose, mannitol, carboxylic are weighed respectively by charge ratio
Methyl starch sodium crosses 80 meshes, and lubricant and corrigent is added, and is uniformly mixed, is put into rotary tablet machine, turntable revolving speed
20r/min, stuffing pressure 35N, depth of fill 15mm, direct tablet compressing, both dextrorotation oxiracetam dispersible tablet of the present invention.
Embodiment 7
Prescription: referring to dextrorotation oxiracetam 75g, 6g microcrystalline cellulose, the 6g of the crystal form of 3 method of embodiment preparation
Sorbierite, 12g sodium carboxymethyl starch, 2g magnesium stearate, 1g Aspartame.
Preparation method: crystal form dextrorotation oxiracetam, microcrystalline cellulose, mannitol, carboxylic are weighed respectively by charge ratio
Methyl starch sodium crosses 80 meshes, and lubricant and corrigent is added, and is uniformly mixed, is put into rotary tablet machine, turntable revolving speed
20r/min, stuffing pressure 35N, depth of fill 15mm, direct tablet compressing, both dextrorotation oxiracetam dispersible tablet of the present invention.
Embodiment 8
According to Chinese Pharmacopoeia version annex the second method of XC in 2015, dextrorotation oxiracetam made from embodiment 4-7 point is measured
The dissolution rate of discrete piece.Method particularly includes: using phosphate buffer (pH6.8) 900mL as dissolution medium, revolving speed is per minute 50
Turn, operate according to methods, when through 5min and 10min, take solution appropriate respectively, filter, filtrate is calculated molten through liquid chromatogram with external standard method
Extracting rate.Test result see the table below 1.
The dissolution rate of the dextrorotation oxiracetam dispersible tablet of the present invention of table 1 is investigated
| Embodiment | 5min dissolution rate (%) | 10min dissolution rate (%) |
| Embodiment 4 | 81.4% | 95.3% |
| Embodiment 5 | 80.9% | 94.7 |
| Embodiment 6 | 79.8% | 92.6% |
| Embodiment 7 | 80.1% | 93.0% |
As can be seen from Table 1, dispersible tablet prepared by the present invention dissolution rate in phosphate buffer (pH6.8) is fast,
5min dissolution rate is dissolved out close to 80%, 10min more than 90%.
Embodiment 9
Stability test
Dextrorotation oxiracetam dispersible tablet made from embodiment 4-7 is accelerated under conditions of 40 DEG C, 75% relative humidity
3 months, 6 months and 12 months are saved, drug is then further taken out and tests its crystal phenomenon, investigate stability.Test result is seen below
Table 2.
The stability of crystal form of the dextrorotation oxiracetam dispersible tablet of the present invention of table 2 is investigated
Active constituent stable crystal form in dextrorotation oxiracetam dispersible tablet prepared by the present invention, at 40 DEG C, 75% is relatively wet
Accelerate to save under conditions of degree and crystal form variation does not occur within 12 months, while the dispersion sheet hardness prepared is moderate, disintegration time is short, fits
Close clinical use.
Claims (9)
1. a kind of dextrorotation oxiracetam dispersible tablet, it is characterised in that: include 45 in the dextrorotation oxiracetam dispersible tablet
~75% crystal form dextrorotation oxiracetam, 5~15% microcrystalline celluloses, 3~15% sorbierites, 5~20% carboxymethyl starch
Sodium, 1-5% lubricant, 0.5-2% corrigent, by percentage to the quality；The dextrorotation oxiracetam of the crystal form uses
Cu-K α radiation, obtained X- ray powder diffraction are composed in 2 θ of angle of reflectionFor14.14±0.2°、17.76±0.2°、18.72±
0.2 °, 20.16 ± 0.2 °, 21.20 ± 0.2 °, 21.52 ± 0.2 °, 24.17 ± 0.2 °, 25.88 ± 0.2 ° has diffraction maximum.
2. dextrorotation oxiracetam dispersible tablet as described in claim 1, it is characterised in that: the microcrystalline cellulose and sorb
The mass ratio of the sum of alcohol and sodium carboxymethyl starch is 2~3:2.
3. dextrorotation oxiracetam dispersible tablet as described in claim 1, it is characterised in that: the microcrystalline cellulose and sorb
The mass ratio of alcohol is 1~3:1.
4. dextrorotation oxiracetam dispersible tablet as described in claim 1, it is characterised in that: the dextrorotation oxiracetam point
In discrete piece comprising 45~75% crystal form dextrorotation oxiracetam, 5~15% microcrystalline celluloses, 3~15% sorbierites, 5~
20% sodium carboxymethyl starch, 1-3% lubricant, 1-2% corrigent, by percentage to the quality；The microcrystalline cellulose and sorbierite it
With with the mass ratio of sodium carboxymethyl starch be 2~3:2；The mass ratio of the microcrystalline cellulose and sorbierite is 1~3:1；It is described
Magnesium stearate lubricant, the corrigent are selected from Aspartame.
5. dextrorotation oxiracetam dispersible tablet according to any one of claims 1-4, it is characterised in that: the lubricant choosing
From at least one of magnesium stearate, calcium stearate, zinc stearate, polyethylene glycol, talcum powder and superfine silica gel powder；The flavoring
Agent is selected from least one of acesulfame potassium, stevioside, Aspartame, xylitol.
6. dextrorotation oxiracetam dispersible tablet according to any one of claims 1-4, it is characterised in that: the lubricant choosing
From at least one of magnesium stearate, calcium stearate, talcum powder and superfine silica gel powder；The corrigent is selected from xylitol, A Si
At least one of Ba Tian.
7. dextrorotation oxiracetam dispersible tablet as claimed in any one of claims 1 to 6, it is characterised in that: the crystal form
Dextrorotation oxiracetam prepare with the following method: dextrorotation oxiracetam is dissolved in dimethyl acetamide and ethyl acetate body
Product is dissolved by heating than the in the mixed solvent for being 1:1~1:6, the mass volume ratio (g/mL) of dextrorotation oxiracetam and mixed solvent
For 1:1~1:7；Filtering, filtrate is sealed, and is stirred 17~23h with the speed of 100~300r/min, is filtered again, filters
Filtrate stands solvent flashing and forms crystallization afterwards, collects crystallization, and by the crystallization of collection at 20-40 DEG C, relative humidity is 60-80%'s
Under the conditions of dry 3-6h, both.
8. dextrorotation oxiracetam dispersible tablet as claimed in claim 7, it is characterised in that: the dextrorotation hydroxyl of the crystal form
Oxygen pyrrole vinegar amine is prepared with the following method: it is 1 that dextrorotation oxiracetam, which is dissolved in dimethyl acetamide and ethyl acetate volume ratio:
The in the mixed solvent of 1~1:3 heats 30-60 DEG C of dissolution, the mass volume ratio (g/mL) of dextrorotation oxiracetam and mixed solvent
For 1:3~1:5；Filtering, filtrate is sealed, and is stirred 18~20h with the speed of 150~250r/min, is filtered again, filters
Filtrate stands solvent flashing and forms crystallization afterwards, collects crystallization, and by the crystallization of collection at 20-40 DEG C, relative humidity is 60-75%'s
Under the conditions of dry 4-6h, both.
9. the preparation method of dextrorotation oxiracetam dispersible tablet as described in claim any one of 1-8, comprising the following steps: (1)
The preparation of crystal form dextrorotation oxiracetam: dextrorotation oxiracetam is dissolved in dimethyl acetamide and ethyl acetate volume ratio
For the in the mixed solvent of 1:1~1:3, the mass volume ratio (g/mL) of dextrorotation oxiracetam and mixed solvent is 1:3~1:5；
Filtering, filtrate is sealed, and is stirred 18~20h with the speed of 150~250r/min, is filtered again, filtrate stands after filtering
Solvent flashing forms crystallization, collects crystallization, and by the crystallization of collection at 20-40 DEG C, relative humidity is dry under conditions of being 60-75%
Crystal form dextrorotation oxiracetam is made in 4-6h；(2) direct powder compression: crystal form dextrorotation hydroxyl is weighed respectively by charge ratio
Oxygen pyrrole vinegar amine, microcrystalline cellulose, mannitol, sodium carboxymethyl starch cross 80 meshes, and lubricant and corrigent is added, and are uniformly mixed,
Direct tablet compressing, both dextrorotation oxiracetam dispersible tablet of the present invention.
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| CN112057428A (en) * | 2020-10-22 | 2020-12-11 | 上海翰森生物医药科技有限公司 | Pharmaceutical composition of varenicline tartrate and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766596A (en) * | 2009-01-04 | 2010-07-07 | 北京润德康医药技术有限公司 | Solid preparation with dextro-oxiracetam as active component |
| CN102603607A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (R)-oxiracetam |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101766596A (en) * | 2009-01-04 | 2010-07-07 | 北京润德康医药技术有限公司 | Solid preparation with dextro-oxiracetam as active component |
| CN102603607A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (R)-oxiracetam |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112057428A (en) * | 2020-10-22 | 2020-12-11 | 上海翰森生物医药科技有限公司 | Pharmaceutical composition of varenicline tartrate and preparation method thereof |
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