CN105012240B - A kind of method that solvent method prepares blonanserin micron medicine - Google Patents
A kind of method that solvent method prepares blonanserin micron medicine Download PDFInfo
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- CN105012240B CN105012240B CN201510335815.XA CN201510335815A CN105012240B CN 105012240 B CN105012240 B CN 105012240B CN 201510335815 A CN201510335815 A CN 201510335815A CN 105012240 B CN105012240 B CN 105012240B
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Abstract
The invention discloses a kind of method for preparing blonanserin micron medicine.Under Ultrasonic Conditions, a certain amount of blonanserin is dissolved in organic solvent, then it is slowly added drop-wise in certain density water stabilizer, is more than the affinity to blonanserin to the affinity of water using organic phase, as organic phase is slowly diffused into water, the concentration increase of blonanserin in solution, form nucleus to separate out, so as to obtain the blonanserin micron particles that particle diameter is 1 10 μm, its uniform particle sizes, specific surface area increase, be advantageous to improve the bioavilability of blonanserin medicine.The present invention is simple to operate, does not introduce other medicines auxiliary material, and equipment investment is small, and yield is high.
Description
Technical field
The present invention relates to a kind of method for preparing medicine, particularly a kind of method for preparing blonanserin micron medicine, category
In chemicals preparing technical field.
Background technology
Entitled 2- (4- ethyl -1- the piperazinyls) -4- (4- fluorophenyls) -5,6,7 of blonanserin (Blonanserin) chemistry,
8,9,10- hexahydro cycloocta- [b] pyridines, are atypia antipsychotic drugs of new generation, to dopamine D2And 5-HT2Two kinds of A
Other antipsychotics of the selectivity ratios of acceptor are stronger, and safe tolerance is substantially better than Traditional antipsychotics, side effect
It is small.Its molecular structure such as following formula represents：
Blonanserin is a kind of insoluble drug, and research finds conventional blonanserin drug dissolution compared with day basis triturate
There is bigger difference.Because insoluble medicine particle diameter and dissolution rate have compared with Important Relations, insoluble medicine particle diameter is big, and dissolution is poor, causes biological profit
Expenditure reduces.If blonanserin is made into micron order, its dissolving out capability will be effectively improved, promotes the stabilization of blonanserin medicine
Release and absorption.Micron medicine can promote drug absorption for Nano medication, and and can reduces particle aggregation, and
The crystal formation of medicine is not changed.The medicinal powder granularity fine and even processed by micron technology, dissolution is good, total surface area increase, energy
The release for effectively facilitating medicine absorbs, and improves the bioavilability of medicine.The micronized method of medicine mainly has at present：(1) machine
Tool comminuting method, including air-flow crushing, ball-milling method etc..As CN104606172 uses mechanical crushing method by antiallergic montelukast
Speed lapping is into 1-5 μm of powder；CN103223104 prepares treatment diabetes medicament using mechanical crushing method.Mechanical crushing
Method is one of the most widely used method of micronization, has the advantages of cost is low, and yield is big, but it consumes energy greatly, preparation
Drug particles pattern is irregular, surface irregularity；(2) pack, i.e., colloid is made in active ingredient pharmaceutical carrier parcel
Grain.It is swollen to treat for 23-68 μm of capsulae enterosolubilis that CN104606214 uses spray congealing dry technology that capsaicine is made into particle diameter
Knurl；CN104338138A carries medicament preparation using polymer drug carrier, and hydrophilic anti-tumor medicine is made into 4 μm or so
Compound particle.Pack needs to introduce new auxiliary material, is limited by pharmaceutical formula, increases the difficulty of medicine Quality Control.(3) physics
Chemical method, such as：Solvent evaporation, solvent replacement, sovent diffusion etc., it is mainly used in the preparation of pharmaceutical carrier.(4) supercritical fluid
Technology.This method equipment investment is big, low yield, using being restricted.Retrieval find, at present, except routine mechanical crushing method, not
It was found that other micronized technologies of blonanserin medicine, therefore, research is a kind of simple to operate, investment is small, do not introduce other auxiliary materials and
The preparation method of the homogeneous blonanserin micron medicine of diameter of aspirin particle, turn into the class of pharmacy corporation and R＆D institution's common concern
Topic.
The content of the invention
, can be with using the method it is an object of the invention to provide a kind of method that solvent method prepares blonanserin micron medicine
It is 1-10 μm of blonanserin micron medicine to obtain particle diameter, overcomes that prior art micron particles are uneven, and pattern is irregular, easily
The defects of reunion.
The technical concept of the present invention is such, under Ultrasonic Conditions, a certain amount of blonanserin is dissolved in organic molten
Agent, then it is slowly added drop-wise in certain density water stabilizer, the affinity of water is more than to cloth south using organic phase
The affinity of color woods, as organic phase is slowly diffused into water, the concentration increase of blonanserin, forms nucleus and separates out in solution,
Obtain blonanserin micron particles.Specifically, the method that the solvent method that the present invention provides prepares blonanserin micron medicine, step
It is as follows：
Under Ultrasonic Conditions, a certain amount of blonanserin is dissolved in organic solvent, is then slowly dropped to certain
In the water stabilizer of concentration, reaction at a certain temperature forms nucleus precipitation, obtains blonanserin micron particles, closes ultrasound,
It is still aging, high speed centrifugation, supernatant is removed, with distillation water washing, high speed centrifugation, removes supernatant, by sample true again
Dried in empty drying box, obtain the blonanserin micron particles that white powder particle diameter is 1-10 μm；
Wherein, organic solvent used is that the hydrophilies such as the alcohols containing hydrophilic radical, aldehyde ketone, ethers and acids are organic molten
One or more in agent, preferably methanol, ethanol, ethylene glycol, diethylene glycol, propane diols, glycerine, acetone, N- methyl
One or more in pyrrolidones, tetrahydrofuran, acetonitrile, DMF, most preferably methanol, ethanol, acetone
In one or more；The concentration of blonanserin is 0.01mol/L-3mol/ in the solution that blonanserin is formed with organic solvent
L, preferably 0.02mol/L-1mol/L, most preferably 0.03mol/L；
Water stabilizer is can be with organic solvent miscible with water, including alcohols, aldoketones and ethers, one of which or several
Kind, preferably methanol, ethanol, isopropanol, polyethylene glycol, acetone, 1-METHYLPYRROLIDONE, tetrahydrofuran, acetonitrile, N, N- bis-
One or more in NMF, most preferably one or more in ethanol, polyethylene glycol, isopropanol, acetone；Water is steady
The mass concentration for determining agent concentration is 0.1%-10%, preferably 0.5%-5%, most preferably 1%；Reaction temperature is 0-60
DEG C, preferably 0-30 DEG C, most preferably 0-20 DEG C；
Ultrasonic frequency is 10KHZ-120KHZ, preferably 20KHZ-80KHZ, most preferably 40KHZ；
Centrifugal speed is 1000r/min-7000r/min, preferably 2000r/min-6000r/min, most preferably
4000r/min。
Digestion time 0.5-6h, preferably 1-4h, most preferably 1h.
What the present invention obtained has the beneficial effect that：
The present invention prepares blonanserin micron particles using solvent method, does not change the crystal formation of medicine, reduces particle diameter,
One, specific surface area increases, and is advantageous to improve the bioavilability of blonanserin medicine.
Brief description of the drawings
Fig. 1：Comminution by gas stream blonanserin particle electron microscope.
Fig. 2：Blonanserin micron particles electron microscope prepared by the solvent method of the present invention.
Embodiment
Following examples are used to illustrate the present invention, but do not limit the present invention with embodiment.
Embodiment 1
1% polyethylene glycol water stabilizer 100ml is added in 250ml conical flask, is placed on 0-4 DEG C of ice-water bath
In.Blonanserin 0.285g (0.78mmol) is weighed, is dissolved in 26ml ethanol, compound concentration is 0.03mol/l blonanserin
Ethanol solution, add it in 50ml constant pressure funnels.The constant pressure funnel is placed in the conical flask equipped with Aqueous Solutions of Polyethylene Glycol
On, ultrasonic cleaner is opened, under the ultrasound condition of 40KHZ frequencies, (1ml/ is slowly added dropwise in blonanserin ethanol solution
Min) into Aqueous Solutions of Polyethylene Glycol, system becomes cloudy, and continues ultrasonic 30min after being added dropwise.Gained mixed solution is stood
After 1h, it be centrifuged at a high speed until being kept completely separate, upper liquid of inclining.By gained sample with distillation water washing after again
Centrifugation, resulting solid sample is placed in 50 DEG C of vacuum drying chambers and is dried, that is, obtains solid sample, m.p.:123-
125℃.Its pattern and size distribution are surveyed by ESEM and particle size analyzer；With infrared spectrometer and1H NMR comparative analysis micro mists
Structure has unchanged after change.
Determine that its particle diameter is 3-5 μm through electron-microscope scanning, as shown in Fig. 2 smashing the micron cloth of method preparation using air-flow with Fig. 1
Nan Selin compares, and micron blonanserin morphology rule prepared by solvent method, size is homogeneous, is not easy to reunite.
Micron blonanserin spectral detection data prepared by solvent method：
IR absworption peaks (cm1):2828,2819,1580,1550,1507,1468,1444,1125,873。
1H NMR (500MHZ, CDCl3, δ/ppm):1.131(m,3H,-CH3), 1.363-1.435 (m, 6H ,-CH2-),
1.783(m,2H,-CH2-), 2.464-2.478 (d, 2H ,-CH2-), 2.567 (s, 6H ,-CH2-), 2.883 (m, 2H ,-CH2-),
3.537(s,4H,-CH2-), 6.295 (s, 1H ,-CH-C-N), 7.073 (m, 2H, Ar-H), 7.214 (m, 2H, Ar-H)
Embodiment 2
1% polyethylene glycol water stabilizer 100ml is added in 250ml conical flask, is placed on 0-4 DEG C of ice-water bath
In.Blonanserin 0.184g (0.50mmol) is weighed, is dissolved in 25ml ethanol, compound concentration is 0.02mol/l blonanserin
Ethanol solution, add it in 50ml constant pressure funnels.The constant pressure funnel is placed in the conical flask equipped with Aqueous Solutions of Polyethylene Glycol
On, ultrasonic cleaner is opened, under the ultrasound condition of 60KHZ frequencies, (1ml/ is slowly added dropwise in blonanserin ethanol solution
Min) into Aqueous Solutions of Polyethylene Glycol, system becomes cloudy, and continues ultrasonic 30min after being added dropwise.Gained mixed solution is stood
After 2h, 4000r/min centrifugations are carried out to it, until being kept completely separate, upper liquid of inclining.By gained sample with distillation water washing after again
Secondary centrifugation, resulting solid sample is placed in 50 DEG C of vacuum drying chambers and is dried, that is, obtains solid sample, m.p.:
123-125℃.Electronic Speculum and particle size instrument are scanned through, particle diameter is 1-8 μm；With infrared spectrometer and1H NMR comparative analyses are micro-
Structure is unchanged after efflorescence, and crystal formation is unchanged before and after XRD contrast micronizings.
Embodiment 3
1% polyethylene glycol water stabilizer 400ml is added in 500ml conical flask, is placed on 15-20 DEG C of ice-water bath
In.Blonanserin 1.004g (2.73mmol) is weighed, is dissolved in 91ml ethanol, compound concentration is 0.03mol/l blonanserin
Ethanol solution, add it in 100ml constant pressure funnels.The constant pressure funnel is placed in the conical flask equipped with Aqueous Solutions of Polyethylene Glycol
On, ultrasonic cleaner is opened, under the ultrasound condition of 40KHZ frequencies, (1ml/ is slowly added dropwise in blonanserin acetone soln
Min) into Aqueous Solutions of Polyethylene Glycol, system becomes cloudy, and continues ultrasonic 30min after being added dropwise.Gained mixed solution is stood
After 1h, it be centrifuged at a high speed until being kept completely separate, upper liquid of inclining.By gained sample with distillation water washing after again
Centrifugation, resulting solid sample is placed in 50 DEG C of vacuum drying chambers and is dried, that is, obtains blonanserin micron medicine,
m.p.:123-125℃.Its particle diameter is surveyed as 1-10 μm by ESEM and particle size analyzer；With infrared spectrometer and1H NMR are contrasted
Structure is unchanged after analysis micronizing, and crystal formation is unchanged before and after XRD contrast micronizings.
Embodiment 4-14
Blonanserin 0.275g (0.75mmol) is weighed, is dissolved in 25ml solvent (is shown in Table 1) respectively, being configured to concentration is
0.03mol/l solution, under the ultrasound condition of 40KHZ frequencies, it is slowly dropped in different water stabilizers and (is shown in Table
1), system becomes cloudy, and continues ultrasonic 30min after being added dropwise.By gained mixed solution stand 1h after, it is carried out at a high speed from
The heart, upper liquid of inclining.By gained sample with being centrifuged again after distillation water washing, resulting solid sample is placed in 50 DEG C of vacuum
It is dried in drying box, that is, obtains blonanserin micron medicine, m.p.:123-125℃.Surveyed by ESEM and particle size analyzer
Its particle diameter is shown in Table 1；With infrared spectrometer and1Structure is unchanged after H NMR comparative analyses micronizing, before and after XRD contrast micronizings
Crystal formation is unchanged.
The different solvents of table 1 and water stabilizer prepare blonanserin micron particles
Embodiment 15
1% polyethylene glycol water stabilizer 100ml is added in 250ml conical flask, is placed on 0-4 DEG C of ice-water bath
In.Blonanserin 0.184g (0.5mmol) is weighed, compound concentration is 0.02mol/l blonanserin ethanol solution, is added into
Into constant pressure funnel.The constant pressure funnel is placed on the conical flask equipped with Aqueous Solutions of Polyethylene Glycol, opens ultrasonic cleaner,
Under the ultrasound condition of 60KHZ frequencies, (1ml/min) is slowly added dropwise into Aqueous Solutions of Polyethylene Glycol in blonanserin ethanol solution,
System becomes cloudy, and continues ultrasonic 30min after being added dropwise.After gained mixed solution is stood into 1.5h, high speed centrifugation is carried out to it
Separation is until be kept completely separate, upper liquid of inclining.By gained sample with being centrifuged again after distillation water washing, by resulting solid-like
Product are placed in 50 DEG C of vacuum drying chambers and are dried, that is, obtain solid sample, m.p.:123-125℃.It is scanned through Electronic Speculum and grain
Instrument measurement is spent, particle diameter is 3-7 μm；With infrared spectrometer and1Structure is unchanged after H NMR comparative analyses micronizing, and XRD contrasts are micro-
Crystal formation is unchanged before and after efflorescence.
Embodiment 16
2% polyethylene glycol water stabilizer 100ml is added in 250ml conical flask, is placed on 0-4 DEG C of ice-water bath
In.Blonanserin 0.326g (0.89mmol) is weighed, is dissolved in 30ml ethanol, compound concentration is 0.03mol/l blonanserin second
Alcoholic solution, add it in 50ml constant pressure funnels.The constant pressure funnel is placed on the conical flask equipped with Aqueous Solutions of Polyethylene Glycol,
Ultrasonic cleaner is opened, under the ultrasound condition of 40KHZ frequencies, blonanserin ethanol solution is slowly added dropwise (1ml/min)
Into Aqueous Solutions of Polyethylene Glycol, system becomes cloudy, and continues ultrasonic 30min after being added dropwise.After gained mixed solution is stood into 2h,
It is centrifuged at a high speed until being kept completely separate, upper liquid of inclining.By gained sample with distillation water washing after centrifuge again,
Resulting solid sample is placed in 50 DEG C of vacuum drying chambers and is dried, that is, obtains solid sample, m.p.:123-125℃.
Electronic Speculum and particle size instrument are scanned through, particle diameter is 1-10 μm；With infrared spectrometer and1Tied after H NMR comparative analyses micronizing
Structure is unchanged, and crystal formation is unchanged before and after XRD contrast micronizings.
Claims (5)
1. a kind of method for preparing blonanserin micron medicine, it is characterized in that：Under Ultrasonic Conditions, by a certain amount of Bu Nanse
Woods is dissolved in organic solvent, is then slowly dropped in certain density water stabilizer, and reaction at a certain temperature is formed
Nucleus separates out, and system becomes cloudy, needs to continue to keep ultrasonic 30min after being added dropwise, and obtains blonanserin micron particles, closes super
Sound, still aging, high speed centrifugation, supernatant is removed, with distillation water washing, high speed centrifugation, removes supernatant, sample is existed again
Dried in vacuum drying chamber, obtain blonanserin micron particles；
Wherein, organic solvent used is in hydrophilic organic solvent methanol, ethanol, acetone, 1-METHYLPYRROLIDONE, acetonitrile
One or more, it is characterized in that the concentration of blonanserin is 0.03mol/L in the solution that blonanserin is formed with organic solvent；
Water stabilizer used is can be with the one or more in polyethylene glycol miscible with water, acetone, it is characterized in that water is stable
The mass concentration of agent is 1%.
2. preparation method according to claim 1, it is characterized in that reaction temperature is 0-20 DEG C.
3. preparation method according to claim 1, it is characterized in that ultrasonic frequency 40KHZ.
4. preparation method according to claim 1, it is characterized in that digestion time 1h.
5. preparation method according to claim 1, it is characterized in that centrifugal speed 4000r/min.
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| CN107080735A (en) * | 2017-04-25 | 2017-08-22 | 华益药业科技(安徽)有限公司 | A kind of Indomethacin powder |
| CN110575438A (en) * | 2018-06-07 | 2019-12-17 | 湖南省湘中制药有限公司 | preparation and application of blonanserin solid dispersion |
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| CN1634113A (en) * | 2004-10-29 | 2005-07-06 | 中国地质大学（武汉） | Method for preparing azithromycin superfine powder by ultrasound homogenization dissolvent diffusion method |
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| CN1634113A (en) * | 2004-10-29 | 2005-07-06 | 中国地质大学（武汉） | Method for preparing azithromycin superfine powder by ultrasound homogenization dissolvent diffusion method |
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| Stabilizing dispersions of hydrophobic drug molecules using cellulose ethers during anti-solvent synthesis of micro-particulates;Xiangxin Meng等;《Colloids and Surfaces B: Biointerfaces》;20081209;第70卷;第7-14页 * |
| 布南色林微米化药物的制备;梁冉等;《中国化学会 全国第十一届有机合成化学学术研讨会》;20141016;第152页 * |
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